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Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.
Supplement to: Garassino MC, Martelli O, Broggini M, et al, on behalf of the TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol 2013; published online July 22. http://dx.doi.org/10.1016/S1470-2045(13)70310-3.
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A randomised trial of erlotinib versus docetaxel as second-line treatment of patients with
advanced non-small cell lung cancer and wild-type epidermal growth factor receptor
(TAILOR)
SUPPLEMENTARY APPENDIX
Page 3
2
CONTRIBUTORS AS is the Principal Investigator. MCG, MB and VT conceptualised the study. All the TAILOR steering committee members designed the study. IF, ER collected data. ER, IF AND VT did the statistical analysis. GF, AB, FL, LM, MT, RL were the main clinical investigators. MB, SV, FB, MM, MG, CL did the molecular and pathological examinations. GG was the chair of the IDMSC. MCG, VT, MB AND SM developed an early draft, and all investigators reviewed and approved the submitted report. TAILOR STEERING COMMITTEE: AS (Principal Investigator), MCG, GF, Joanna Landi, Angela Spena, FB, MG, Giorgio Gherardi, Fatebenefratelli e Oftalmico Hospital Milano, Italy. MB, Elena Copreni, IF, MM, Davide Poli, ER, VT, IRCCS-Istituto Ricerche Farmacologiche "Mario Negri", Milano, Italy. Marcello Gambacorta, CL, SV, Niguarda Cà Granda Hospital, Milano, Italy. SM, Institute for Cancer Research and Treatment, Candiolo, Italy. RL, Papa Giovanni XXIII Hospital, Bergamo, Italy. OM, S. Giovanni Addolorata Hospital, Roma, Italy. Lorenzo Rosso, Luigi Santambrogio, IRCCS “Ca' Granda” General Hospital, University of Milan, Italy. TAILOR IDMSC GG, (Chair) Lombardi Comprehensive Cancer Center, Washington DC. Roberto D’Amico, Università degli Studi di Modena e Reggio Emilia, Italy. Thomas Fleming, University of Washington, Seattle, WA. Edmondo Terzoli, Istituto Regina Elena, Roma, Italy. INVESTIGATORS: MCG, GF, Sheila Piva, Nicla Maria La Verde, Fatebenefratelli e Oftalmico Hospital Milano, Italy. FL, Bruno Gori, Luciano Stumbo, Vittoria Lapadula, Umberto I Policlinico, Roma, Italy. RL, AB, Lucia Bonomi, Carlo Tondini, Papa Giovanni XXIII Hospital, Bergamo, Italy. LM, Fabrizio Nelli, Maria Agnese Fabbri, Belcolle Hospital, Viterbo, Italy. MT, Claudia Bareggi, Elisa Locatelli, IRCCS Ca’ Granda Ospedale Maggiore Policlinic, Milano, Italy. Ida Pavese, San Pietro Hospital, Roma, Italy. Maria Giuseppina Sarobba, Antonia Arru, Azienda Ospedaliera Universitaria, Sassari, Italy. Roberta Buosi, Oscar Alabiso, Ospedale Maggiore della Carità, Novara, Italy. Alessandro Bertolini, Elisabetta Menatti, Valtellina e Valchiavenna Hospital, Sondrio, Italy. Antonio Russo, Giuseppe Cicero, Sergio Palmeri, Paolo Giaccone Policlinic, Palermo, Italy. Maria Mauri , Olga Martelli , S. Giovanni Addolorata Hospital, Roma, Italy. Andrea Mancuso, San Camillo Forlanini Hospital, Roma, Italy. Antonio Ardizzoia, Isabella Vittimberga, A. Manzoni Hospital, Lecco, Italy. Claudio Graiff, Emanuela Vattemi, Bolzano Central Hospital, Bolzano, Italy. Vittorio Ferrari, Spedali Civili, Brescia, Italy. Enrico Cortesi, Sapienza University,Umberto I Policlinico, Roma, Italy. Luigi Cavanna, G. Saliceto Hospital, Piacenza, Italy. Antonio Pazzolla, S.S. Annunziata Hospital, Sassari, Italy. Daniele Fagnani, Desio e Vimercate Hospital, Vimercate, Italy. Anna Calcagno, Legnano Hospital, Legnano, Italy. Alessandro Del Conte, S. Maria degli Angeli Hospital, Pordenone, Italy. Bruno Massidda, Presidio Monserrato Cagliari Hospital, Cagliari, Italy. Camilla Casi, ASL 7 AltavaldelsaCampostaggia Hospital, Siena, Italy. Franco Spremberg, S. Giovanni Evangelista Hospital, Tivoli, Italy. Cristina Locatelli, San Carlo Borromeo Hospital, Milano, Italy. Emodio Barletta, G. Rummo Hospital, Benevento, Italy. Mario Comandè, Melegnano e Gorgonzola Hospital, Melegnano, Italy. Paolo Foa, San Paolo Polo Hospital, Milano, Italy. Sonia Fatigoni, S. Maria Hospital, Terni, Italy. Andrea De Censi, Galliera Hospitals, Genova, Italy. Massimiliano Cergnul, Santa Maria Hospital, Castellanza, Italy. Giuseppe Valmadre, Morelli Sondalo, Valtellina e Valchiavenna Hospital, Sondalo, Italy. Libero Ciuffreda, San Giovanni Battista Hospital, Torino, Italy. Efisio De Fraia, Armando Businco Hospital, Cagliari, Italy. Giovanna Antonelli, San Vincenzo Hospital, Taormina, Italy. Giuseppe Nastasi, PesentiFenaroli Hospital, Alzano Lombardo, Italy. Giuseppe Grimaldi, Umberto I Hospital, Nocera Inferiore, Italy. Giammaria Fiorentini, S. Giuseppe Antica Sede Hospital, Empoli, Italy. Ida Colantonio, S. Croce e S. Carlo Hospital, Cuneo, Italy. COORDINATION SUPPORT: Joanna Landi, Angela Spena, Aurora Rizzo, Anna Bianchi, Serena Girelli, Fatebenefratelli e Oftalmico Hospital Milano, Italy. Luca Clivio, IRCCS-Istituto Ricerche Farmacologiche "Mario Negri", Milano, Italy. INDEPENDENT STATISTICIANS Stefania Galimberti, Maria Grazia Valsecchi Università degli Studi Milano Bicocca, Milano, Italy. Pinuccia Valagussa, Michelangelo Foundation, Milano, Italy. INDEPENDENT RADIOLOGICAL REVIEW BOARD: Alfonso Marchianò, Michelle Magli, Fondazione IRCSS Istituto Nazionale dei Tumori, Milano, Italy. Role of the funding source The study was sponsored by Agenzia Italiana del Farmaco (AIFA), the Italian Drug Regulatory Agency, which provided financial support without imposing restrictions on the investigators with respect to study design, data collection, analysis and interpretation, and report writing. AIFA approved all the protocol amendments and followed the study conduction. Conflicts of interest MCG and OM and VT declare a consultancy with Eli-Lilly. MCG declares a consultancy with Boehringer Ingelheim. VT and RL declare consultancy with Roche. OM and VT declare consultancy with Amgen. All other authors declare that they have no conflicts of interest.
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3
SUPPLEMENTARY FIGURE S1: STUDY DESIGN
PD 1:1
NO CROSS
OVER
DOCETAXEL
75 mg/m2 iv
day 1,21
or
35 mg/m2 iv
day 1,8,15
ERLOTINIB
150 mg po , daily
R
NSCLC
Stage IIIB/IV
Second line treatment
Previous platinum based
doublet
EGFR wild - type
KRAS determined
ECOG PS 0 - 2
PD 1:1
NO CROSS
OVER
DOCETAXEL
75 mg/m2 iv
day 1,21
or
35 mg/m2 iv
day 1,8,15
ERLOTINIB
150 mg po , daily
R
NSCLC
Stage IIIB/IV
Second line treatment
Previous platinum based
doublet
EGFR wild - type
KRAS determined
ECOG PS 0 - 2
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SUPPLEMENTARY FIGURE S2. CHECK FOR ASSUMPTION OF PROPORTIONAL HAZARD
Interaction between variables and log time
Model Overall Survival
(test for interaction)
Progression Free Survival
(test for interaction)
Univariate Chi=0·04 df=1 p=0·85 Chi= 0·43 df=1 p=0·51
Multivariable Chi=14·12 df=10 p=0·17 Chi=11·19 df=10 p=0·34
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SUPPLEMENTARY TABLE S1- DOCETAXEL DRUG-RELATED ADVERSE EVENTS
AllGrades
N. (%)
Grade 3 N. (%)
Grade 4 N. (%)
χ2Erlotinib
vs Docetaxel χ
2 weekly weeklyDocetaxel vs 3w-Docetaxel
Febrile neutropenia
Erlotinib 0 0 0
WeeklyDocetaxel 0 0 0
3w-Docetaxel 5 (7·9) 1(1·6) 3(4·8)
0·032
0·085
Neutropenia
Erlotinib 3 (2·8) 0 1 (0·9)
WeeklyDocetaxel 6 (14·6) 2 (4·9) 0
3w-Docetaxel 25 (39·7) 7 (11·1) 12(19·1)
<0·0001 0·001
Diarrhea
Erlotinib 32 (29·9) 3 (2·8) 0
WeeklyDocetaxel 13 (31·7) 2 (4·9) 0
3w-Docetaxel 9 (14·3) 0 0
0·323 0·027
Alopecia
Erlotinib 2 (1·9) 0 0
WeeklyDocetaxel 8 (19·5) 2 (4·9) 0
3w-Docetaxel 26 (41·3) 10 (15·9) 3(4·8)
<0·0001 0·016
Asthenia
Erlotinib 40 (37·4) 4 (3·7) 2 (1·9)
WeeklyDocetaxel 13 (31·7) 5 (12·2) 0
3w-Docetaxel 38 (60·3) 5 (7·9) 0
0·199 0·163
Neurological
Erlotinib 5 (4·7) 1 (0·9)* 1 (0·9)
WeeklyDocetaxel 6 (14·6) 5 (12·2)* 0
3w-Docetaxel 11 (17·5) 5 (7·9)* 1 (1·6)
0·013 0·953
Nausea/vomiting
Erlotinib 11 (10·3) 1 (0·9) 0
WeeklyDocetaxel 10 (24·4) 3 (7·3) 0
3w-Docetaxel 14 (22·2) 0 0
0·053 0·139
Dermatological
Erlotinib 62 (57·9) 10 (9·4) 5 (4·7)
WeeklyDocetaxel 1 (2·4) 0 0
3w-Docetaxel 3 (4·8) 0 0
<0·0001 0·447
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SUPPLEMENTARY TABLE S2 - TIMES TO EVALUATION
Arm Evaluation
no. N pts
Median months
Lower quartile
Upper quartile
First 96 1·9 1·6 2·3 Second 32 4·3 3·8 5·5 Third 10 7·2 6·3 7·9 Fourth 4 9·5 8·7 10·5
Docetaxel
Fifth 2 11·2 11·1 11·3
First 100 1·9 1·6 2·3 Second 26 4·4 3·8 5·5 Third 11 7·3 5·8 7·7 Fourth 11 8·6 7·4 9·8
Erlotinib
Fifth 7 11·8 9·8 12·1
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SUPPLEMENTARY TABLE S3- MULTIVARIABLE ANALYSIS
Multivariate Analysis - OS Multivariate Analysis - PFS
HR 95% CI p-value HR 95% CI p-value
KRAS
(mutated vs wild-type)
1·24
0·87
1·77
0·233
1·01
0·71
1·41
0·977
Histology
(squa/NASvsadenocarcinoma)
0·96
0·67
1·39
0·846
1·11
0·79
1·55
0·559
(others vs adenocarcinoma) 0·57 0·30 1·10 0·094 1·11 0·62 1·98 0·736
Smoking habits
(ex/current vs never-smokers)
0·89
0·59
1·35
0·579
1·06
0·73
1·56
0·756
Sex
(F vs M)
0·75
0·52
1·10
0·144
0·94
0·67
1·31
0·701
ECOG-PS
(2 vs 0,1)
3·32
1·92
5·73
<·0001
3·04
1·78
5·21
<·0001
Best Response
(CR/PR vs adjuvant)
0·84
0·47
1·51
0·567
0·93
0·54
1·61
0·800
(SD vs adjuvant)
0·94
0·51
1·73
0·844
1·18
0·67
2·09
0·559
(PD vs adjuvant)
1·40
0·77
2·56
0·270
1·49
0·85
2·61
0·167
TreatmentArm
(DocetaxelvsErlotinib)
0·73
0·54
1·00
0·049
0·71
0·53
0·95
0·023
Page 9
Università degli Studi di Milano-Bicocca DIPARTIMENTO DI MEDICINA CLINICA E PREVENZIONE
Edificio U8 – Monza 20052, Via Cadore 48 tel. 02/64488351 – fax 02/64488363 – http://www.dimep.medicina.unimib.it
Monza, 30 May 2011
Statistical revision of the TAILOR study Power analysis After review of the study rationale and design in the light of new external evidence and after consideration of the slow recruitment, power calculations were performed under different plausible scenarios. Study recruitment will continue until the end of 2011 and it is expected to reach a final number of patients between 210 and 230. Power calculations were done for these two sizes, considering different figures for survival probabilities (S – primary endpoint) and for progression free survival probabilities (PFS – secondary endpoint) in the two treatment groups (DOC and ERL) and accounting for no losses to follow-up (for survival, this is a realistic option given that census data will be searched for in order to avoid losses) or for up to 5% losses to follow-up. Calculations were based on the following assumptions: - log-rank test on the following system of hypothesis: H0: SDOC (PFSDOC) = SERL (PFSERL) H1: SDOC (PFSDOC) ≠ SERL (PFSERL)
- two-sided test at = 5% level of significance - recruitment period = 4 years – from end of 2007 to 2011 - (uniform) - minimum period of follow-up = 1 year - randomization ratio = 1:1
Power calculations were based on the method proposed by Lachin e Foulkes (1986). Assumptions on endpoints were based on the results of recent studies that motivated a reformulation of the study rationale. These results are summarized in the table below (in bold relevant figures):
Study Random % patients S PFS
in 2 line Median % 6 m % 12 m Median % 4 m % 6m BR.20 DOC 75 7.0 54 30 2.4 - - (Shepherd, JCO) BSC 4.6 38 20 1.5 - - BR.21 ERL 50 6.7 51 30 2.2 - 23 (Shepherd, NEJM) BSC 4.6 43 22 1.8 - 10 Interest DOC 85 8.0 60 34 2.7 38 18 (Kim, Lancet) GEF 7.6 60 32 2.2 32 19
Legenda: DOC=docetaxel; BSC= Best Supportive Care; ERL=Erlotinib; GEF=Gefitinib
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Università degli Studi di Milano-Bicocca DIPARTIMENTO DI MEDICINA CLINICA E PREVENZIONE
Edificio U8 – Monza 20052, Via Cadore 48 tel. 02/64488351 – fax 02/64488363 – http://www.dimep.medicina.unimib.it
Primary Endpoint: survival (S) – figures at 1 year (Table 1) Highlighted (gray) the result of power calculation for the study hypothesis on the 1-year survival in the two randomized treatment groups: DOC = 34%, ERL = 20% . With 210 subjects (worst scenario) the study will have a power of approximately 80% to detect as statistically significant a difference of 14% in the 1-year survival in the two treatment groups, Number of events required for final analysis after 1 year from stop recruitment will be 199. The 14% difference in 1 year survival corresponds to a hazard ratio of 1.49. Power will be more than 80% if sample size will reach 230 patients (best scenario). As shown in table 1, the study will have comparable levels of power for detecting a 14% difference also for similar scenarios in terms of 1-year survival figures in the two treatment groups (for instance, DOC = 32% and ERL = 18%). Table 1: Power calculation on the primary endpoint. Different scenarios of 1-year survival figures and of levels of losses to follow-up are evaluated.
n=210 ERL (%)
DOC (%) losses fup
(%) 15 18 20 22 25 25 0 60.2 32.7 18.6 9.6 - 5 59.0 31.9 18.1 9.5 -
30 0 88.4 69.8 53.3 36.6 16.9 5 87.5 68.4 52.0 35.6 16.5
32 0 93.8 81.1 67.5 51.4 28.1 5 93.2 79.9 66.1 50.1 27.3
34 0 97.0 89.2 79.3 65.6 41.9 5 96.6 88.2 78.0 64.2 40.7
n=230 ERL (%)
DOC (%) losses fup
(%) 15 18 20 22 25 25 0 64.1 35.2 19.9 10.1 - 5 62.8 34.4 19.4 9.9 -
30 0 91.0 73.6 57.0 39.4 18.0 5 90.2 72.3 56.7 38.3 17.6
32 0 95.6 84.4 71.4 55.0 30.3 5 95.1 83.3 70.0 53.7 29.4
34 0 98.0 91.6 82.7 69.6 45.1 5 97.7 90.8 81.5 68.1 43.8
Page 11
Università degli Studi di Milano-Bicocca DIPARTIMENTO DI MEDICINA CLINICA E PREVENZIONE
Edificio U8 – Monza 20052, Via Cadore 48 tel. 02/64488351 – fax 02/64488363 – http://www.dimep.medicina.unimib.it
Secondary Endpoint : progression free survival (PFS) – figures at 6 months (Table 2) Highlighted (gray) the result of power calculation for the study hypothesis on the 6-month progression free survival in the two randomized treatment groups: DOC = 20%, ERL = 10% . With 210 subjects the study will have a 73% power to detect as statistically significant a 10% difference in the progression free survival at 6 months and the power will reach 76% with 230 patients. Table 2: Power calculation on the secondary endpoint. Different scenarios of 6-month progression free survival and of levels of losses to follow-up are evaluated.
n=210 ERL (%)
DOC (%) losses fup
(%) 5 10 15 15 0 89.6 28.8 -
5 89.0 28.3 - 20 0 98.9 72.5 22.1
5 98.8 71.4 21.7 25 0 99.9 94.4 61.3 5 99.9 93.8 60.0
n=230 ERL (%)
DOC (%) persi fup
(%) 5 10 15 15 0 92.1 31.1 -
5 91.6 30.5 - 20 0 99.4 76.2 23.8
5 99.3 75.2 23.3 25 0 99.9 96.0 65.2 5 99.9 95.6 63.9
Page 12
Università degli Studi di Milano-Bicocca DIPARTIMENTO DI MEDICINA CLINICA E PREVENZIONE
Edificio U8 – Monza 20052, Via Cadore 48 tel. 02/64488351 – fax 02/64488363 – http://www.dimep.medicina.unimib.it
References Lachin, J. M., and M. A. Foulkes. Evaluation of sample size and power for analysis of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics 42: 507–519, 1986. Shepherd F.A., Dancey J. et al. Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non–Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy. Journal of Clinical Oncology, 18, 10, 2095-2103, 2000. Shepherd F.A., Pereira J.R. et al. Erlotinib in Previously Treated Non–Small-Cell Lung Cancer. New England Journal of Medicine. 353, 123-132, 2005. Kim, E.S., Hirsh V. et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. The Lancet, 372, 9652, 1809-1818, 2008.
Maria Grazia Valsecchi Galimberti Stefania Professor of Medical Statistics Center of Biostatistics for Clinical Epidemiology Department of Clinical Medicine and Prevention University of Milano-Bicocca
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TAILORAIFA TArceva Italian Lung Optimization tRial
Optimization of erlotinib for the treatment
of patients with advanced non small cell
lung cancer: an Italian randomized trial
CLINICAL STUDY PROTOCOL
id2277000 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com
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CLINICAL STUDY PROTOCOL
Eudract number 2007-004786-17
Sponsor
A. O. Fatebenefratelli e Oftalmico - Milano
With the Support of AIFA (Agenzia Italiana del Farmaco) - Codice AIFA
FARM6F5JER
Coordinating Ethics Committee
Comitato Etico Indipendente (IEC)
dell�A.O. Fatebenefratelli e Oftalmico � Milano
Principal Investigator Alberto Scanni, MD
A.O. Fatebenefratelli e Oftalmico - Milano
Steering Committee Filippo Bianchi, MD
Massimo Broggini, PhD
Gabriella Farina, MD
Irene Floriani, PhD
Marcello Gambacorta, MD
Marina Chiara Garassino, MD
Giorgio Gherardi, MD
Roberto Labianca, MD
Mirko Marabese, PhD
Silvia Marsoni, MD
Olga Martelli, MD
Lorenzo Rosso, MD
Luigi Santambrogio, MD
Silvio Veronese, PhD
DSMC Roberto D�Amico, PhD
Thomas Fleming, PhD
Giuseppe Giaccone, MD
Edmondo Terzoli, MD
Final version, 20.09.2007
Amendment 1, 02.04.2009
Amendment 2, 30.05.2011
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TArceva Italian Lung Optimization tRial
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TAILORAIFA
Clinical Study Protocol
2nd
amendment, 30.05.2011 Page 3 of 66
STUDY CONTACTS
Sponsor A. O. Fatebenefratelli e Oftalmico - Milano
Corso di Porta Nuova, 23
20121 Milano
Principal
Investigator
Alberto Scanni, MD
[email protected]
Coordinating
center
Laboratory of Clinical Trials
Istituto di Ricerche
Farmacologiche �Mario Negri�
Via La Masa, 19-20156 Milano
Tel: +39 02 390141
Fax: +39 02 33200231
Statistician Irene Floriani (final analysis)
Eliana Rulli (interim analysis)
Phone: +39 02 39014695
e-mail: [email protected]
Phone : +39 0239014645
e-mail : [email protected]
Data Manager Elena Copreni Phone: +39 02 39014641
e-mail: [email protected]
Informatics Davide Poli Phone: +39 02 39014643
e-mail: [email protected]
Local Monitor Elena Biagioli
Phone: +39 02 39014655
e-mail: [email protected]
Safety desk Marlen Llerena Phone : + 39 02 39014638
e-mail: [email protected]
Randomization and e-CRF
http://crc.marionegri.it/trials/tailor
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TAILORAIFA
Clinical Study Protocol
2nd
amendment, 30.05.2011 Page 4 of 66
SYNOPSIS
Title TAILORAIFA [TArceva Italian Lung Optimization tRial]
Optimization of erlotinib for the treatment of patients with advanced non-small cell
lung cancer: an Italian randomized trial
Sponsor A. O. Fatebenefratelli e Oftalmico � Milano
Clinical Phase III
Background Erlotinib is registered in all patients affected with NSCLC in second and subsequent
lines with a small benefit. Recent evidence suggest that it should be possible to
select patients according with clinical and biological features. Most of these proofs
are drawn from case series or post hoc analyses and not from properly planned
randomized clinical trials rendering their interpretation controversial. Recent data
suggest that EGFR determined with immunohistochemistry (IHC) or FISH are at the
present time not recommended because they do not reproducibly predict outcome.
Moreover, indirect evidence on subgroup analyses on randomized trial suggest that
chemotherapy might be superior to erlotinib in wild-type EGFR patients.
Study objectives
Primary
To compare the efficacy in terms of OS of erlotinib and docetaxel as second-line
treatment in NSCLC pts without exons 19 or 21 EGFR mutations
Secondary To compare:
Progression free survival
Response rate
Quality of life
To evaluate toxicity, graded according to the NCI-CTAE version 3.0, and the safety
profile, in terms of frequency and nature of serious adverse reactions, of each
treatment arm.
To prospectively assess the prognostic value of K-RAS mutations in patients treated
with a first line platinum containing regimen.
Sub-protocols Other secondary endpoints will be addressed with specific sub-protocols that will
require additional procedures and data. Such sub-protocols will regard the collection
of blood samples, in order to identify different prognosis-related polymorphisms and
to assess their sensitivity and specificity in the detection of EGFR and k-ras
mutations with respect to histological samples.
Study design This is an Italian, multicentre, randomized, open label, phase 3 superiority trial.
In order to define the appropriate population to be entered in the trial, the design is
planned according to three different phases, which follow the journey of patient
disease.
Phase 1: Registration and tissue banking
In this phase pts with NSCLC before or during first line platinum-based
chemotherapy as well as pts recurred after a first line adjuvant platinum-based
chemotherapy will be registered, providing the availability of material for molecular
analysis. Tumour specimens and blood samples will be collected to perform genomic
and immunohistochemical analyses in order to identify the molecular characteristics
of tumour
Phase 2: Randomization of second line therapies
At progression after first line treatment, pts with exons 19 or 21 EGFR mutations will
be electively treated with ERL and followed up, while pts without EGFR mutations will
be randomized to treatment consisting of:
erlotinib 150mg/day until disease progression or unacceptable toxicity developed
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TAILORAIFA
Clinical Study Protocol
2nd
amendment, 30.05.2011 Page 5 of 66
docetaxel 75 mg/m2 on day 1 every 21 days, (3-weekly schedule) or 35 mg/m
2
on day 1, 8 and 15 every 28 days (weekly schedule), until disease progression or
unacceptable toxicity developed
Phase 3: Clinical assessment and further treatments
During treatment and follow-up phases, clinical assessment of pts will be made on
regular basis, in order to collect the relevant data to compare safety and efficacy.
In case of further progression, all pts may receive a standardized third line therapy
with either pemetrexed, 500 mg/m2 on day 1 every 21 days supplemented by folic
acid and vitamin B12, or gemcitabine (1000 mg/m2 days 1, 8, 15 every 28 days)
or
vinorelbine (30 mg/m2
days 1, 8, 15 every 28 days) depending on the first line
treatment received until disease progression or unacceptable toxicity developed.
Number of patients 750-850 pts are needed to be registered in order to randomise the required number
of 220 pts.
Target population Pts with histologically or cytologically documented, locally advanced or metastatic
NSCLC in second line treatment or relapsed after adjuvant treatment.
Inclusion criteria
Exclusion criteria
Age 18 years or older
Histological or cytological confirmation of NSCLC (may be from initial diagnosis of
NSCLC or subsequent biopsy). Only patients with available tissue samples may be
included in the study
Absence of EGFR mutations of exons 19 or 21 (randomization)
Locally advanced or metastatic NSCLC, not amenable to curative surgery or
radiotherapy
One prior platinum-based at adequate doses and taxane-free regimen and anti
EGFR axis drug free. Platinum-based regimen containing other agents (i.e.
bevacizumab, ixapebilone, etc) not targeting the EGFR axis (i.e.
cetuximab) are allowed. Pts who initially presented with early stage disease but
subsequently progressed or recurred are eligible if they received full dose
platinum-based taxane-free adjuvant or neoadjuvant chemotherapy at full
cytotoxic doses or platinum therapy as part of a
chemotherapy/radiotherapy regimen. They will not be eligible if they have only
received platinum at a radio sensitizing dosage (prior surgery and/or localized
irradiation are allowed)
Measurable (uni-dimensional) disease by RECIST in a lesion not previously
irradiated or non-measurable disease
ECOG-PS 0-2
ANC greater than 1.5 x 109/L and platelets greater than 100 x 10
9/L
Bilirubin level either normal or <1.5xULN
AST (SGOT) and ALT (SGPT) <2.5xULN (≤5 x ULN if liver metastases are
present)
Serum creatinine <1.5xULN
Effective contraception for both, male and female pts, if the risk of conception
exists
Recovery from all acute toxicities of prior therapies
Provision of written informed consent to the analysis of biological markers
(registration)
Provision of written informed consent to enter the randomized part of the study
(randomization)
Prior therapy with an experimental agent whose primary mechanism of action is
inhibition of EGFR or its associated tyrosine kinase
Prior chemotherapy with taxanes
Newly diagnosed CNS metastases that have not yet been treated with surgery
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and/or radiation. Pts with previously diagnosed and treated CNS metastases or
spinal cord compression may be considered if they have evidence of clinically SD
(no steroid therapy or steroid dose being tapered) for at least 28 days
Less than 14 days since completion of prior radiotherapy or persistence of any
radiotherapy related toxicity
Any unresolved chronic toxicity from previous anticancer therapy that, in the
opinion of the investigator, makes it inappropriate for the patient to be enrolled in
the study
Known severe hypersensitivity to erlotinib or any of the excipients of this product
Known hypersensitivity to docetaxel, polysorbate 80 or other drugs formulated
with polysorbate 80, or any of the excipients of docetaxel
Other co-existing malignancies or malignancies diagnosed within the last 5 years
with the exception of basal cell carcinoma or cervical cancer in situ
Unable to swallow tablets
Any evidence of clinically active interstitial lung disease (patients with chronic,
stable, radiographic changes who are asymptomatic or patients with
uncomplicated progressive lymphangitic carcinomatosis need not be excluded)
As judged by the investigator, any evidence of severe or uncontrolled systemic
disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic or renal
disease)
As judged by the investigator, any inflammatory changes of the surface of
the eye
Evidence of any other significant clinical disorder or laboratory finding
that makes it undesirable for the patient to participate in the study
Pregnancy
Breast feeding
Length of study This is an event driven study. The study will continue until 199 deaths have
occurred.
The patient accrual period is planned for approximately 48 months. To assess OS,
all pts will be followed for up to 12 months after the last patient is randomized.
Therefore the maximum estimated study duration will be approximately 60 months.
Treatment regimens
Second line therapy Pts with EGFR 19-21 mutations will receive:
erlotinib 150 mg/day until disease progression.
Pts without EGFR 19-21 mutations will be randomized to receive:
erlotinib 150 mg/day or
docetaxel 75 mg/m2 on day 1 every 21 days (3-weekly schedule) or 35 mg/m
2
on day 1, 8 and 15 every 28 days (weekly schedule)
until disease progression or unacceptable toxicity developed.
Third line therapy At further progression of disease, at discretion of the investigators pts will receive a
standardized third line therapy either with pemetrexed 500 mg/m2 on day 1 every
21 days, supplemented by folic acid and vitamin B12, or gemcitabine (1000 mg/m2
days 1, 8, 15 every 28 days) or vinorelbine (30 mg/m
2 days 1, 8, 15 every 28 days)
depending on the previous first line treatment administered. Treatment will continue
until disease progression or unacceptable toxicity developed.
Patient assignment After registration only pts without 19-21 EGFR mutations and fulfilling all the
inclusion/exclusion criteria can be entered into the randomized part of the study.
Allocation to treatment will be centrally performed with 1:1 ratio using a biased-coin
minimization procedure having centre, stage (progressed vs. recurred), prior first
line chemotherapy (containing vinorelbine vs. containing gemcitabine vs.
containing pemetrexed vs. containing other drugs not targeting the EGFR axis),
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ECOG-PS (0-1 vs. 2) and adequacy of histological sample (optimal vs. suboptimal)
as stratification variables.
Pts with 19-21 EGFR mutations will be entered in the non randomized part of the
trial.
Endpoints
Efficacy
OS is defined as the time from the date of randomization to the date of death
from any cause. Subjects who were not reported as having died at the time of the
analysis will be censored at the date they were last known to be alive
PFS is defined as the time from the date of randomization up to the date of first
progression, second primary malignancy or death from any cause, whichever
comes first. Subjects who have not progressed or died while on study will be
censored at the last disease assessment date
Response will be assessed by RECIST
Quality of life will be assessed by QLQ-C30 and QLQ-LC13 questionnaires
Safety Toxicity, graded according to the NCI-CTAE version 3.0
Frequency and nature of serious adverse reactions
Premature withdrawals
Statistical method
Sample size
considerations
According to recently published data, it is reasonable to hypothesize that DOC may
reduce mortality by 33% (HR 0.67) with respect to ERL. This effect translates in an
increased probability of surviving at 1 year from 20% with ERL to 34% with DOC.
In order to detect with a 80% power such an effect at the significance level of 5%,
two-sided, 199 events must be observed overall.
Based on these assumptions, with a uniform accrual of 48 months, a minimum
follow-up for each patient of 12 months, a 5% lost to f-up pts, the total number of
required pts is approximately 220.
Statistical analysis Efficacy will be analysed on an intention-to-treat strategy, therefore all randomized
patients without major protocol violations will be included in the analysis according
to the randomization arm.
All patients who have received at least one dose of the trial medication and had at
least one safety follow-up, whether withdrawn prematurely or not, will be included in
the safety analysis. The safety parameters will be analyzed and presented according
to the therapy the patient received.
Major violations in the eligibility criteria and study conduction will be evaluated on a
case by case basis in a pre-analysis meeting in order to define the population to be
analysed.
CONSORT rules will be applied to describe study flow and protocol deviations.
All time to event curves will be drawn by the Kaplan-Meier method. All comparisons
between arms will be performed by long-rank test. Statistical significance of
difference will also be tested by a multivariable Cox�s model including stratification
variables and clinical-biological features as covariates. Results will be presented as
hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
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ABBREVIATIONS
ADR Adverse drug reaction
AE Adverse event
ALT Alanine transferase
ANC Absolute neutrophil count
AST Aspartate aminotransferase
BAC Bronchioloalveolar carcinoma
BL Baseline
BSA Body surface area
CI Confidence interval
CNS Central nervous system
CR Complete response
CrCl Creatinine clearance
CRF Case report form
CSF Colony stimulating factor
CT Computed tomography
DCF Data clarification form
DOC Docetaxel
EC Ethics Committee
ECG Electrocardiogram
ECOG-PS Eastern Cooperative Oncology Group - performance status
EGFR Epidermal growth factor receptor
EGFR+ EGFR protein expression
EGFR- No EGFR protein expression
ERL Erlotinib
FISH Fluorescent in situ hybridisation
FISH+ High EGFR copy number
FISH- Low EGFR copy number
G-CSF Granulocite colony stimulating factor
GEF Gefitinib
GEM Gemcitabine
HR Hazard ratio
ICH International Conference on Harmonisation
IEC/IRB Ethics committee/institutional review board
IHC Immunohistochemical
ILD Interstitial lung disease
INR International normalised ratio
Im Intramuscular
Iv Intravenous
K-ras+ Presence of K-ras gene mutation
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K-ras- Absence of K-ras gene mutation
L Liter
LD Longest diameter
LDH Lactate dehydrogenase
NCIC-CTG National Cancer Institute of Canada Clinical Trials Group
NCI-CTCAE National Cancer Institute Common Toxicity Criteria for Adverse Events
NSAID Nonsteroidal anti-inflammatory drugs
NSCLC Non small cell lung cancer
OS Overall survival
PCR Polymerase chain reaction
PD Progressive disease
PEM Pemetrexed
PFS Progression free survival
Po Per os
PR Partial response
Pts Patients
QoL Quality of life
RECIST Response evaluation criteria in solid tumors
RR Response rate
SAE Serious adverse event
SD Stable disease
SNP Single nucleotide polymorphism
SUSAR
TNM
Suspected Unexpected Serious Adverse Reaction
Classification of malignant tumor
TKI Tyrosine kinase inhibitor
ULN Upper limit of normal
VNB Vinorelbine
WBC White blood cell
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CONTENTS
STUDY CONTACTS ...................................................................................................................... 3
SYNOPSIS .................................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................ 8
1. BACKGROUND AND RATIONALE ........................................................................................... 14
1.1. Introduction .................................................................................................................... 14
1.1.1. Chemotherapy treatment .............................................................................................. 14 1.1.2. Erlotinib ...................................................................................................................... 14 1.2. Rationale of the study ...................................................................................................... 15
2. STUDY OBJECTIVES.............................................................................................................. 17
2.1. Primary .......................................................................................................................... 17
2.2. Secondary ...................................................................................................................... 17
3. STUDY DESIGN ..................................................................................................................... 17
3.1. Overview of study design .................................................................................................. 17
3.2. Number of centers ........................................................................................................... 18
3.3. Number of patients .......................................................................................................... 18
3.4. Study duration ................................................................................................................ 18
4. PATIENT SELECTION CRITERIA ............................................................................................ 19
4.1. Target population ............................................................................................................ 19
4.2. Inclusion criteria .............................................................................................................. 19
4.3. Exclusion criteria ............................................................................................................. 20
5. PATIENT ENROLLMENT ........................................................................................................ 21
5.1. Registration .................................................................................................................... 21
5.2. Randomization ................................................................................................................ 21
6. TREATMENT PLAN ................................................................................................................ 22
6.1. Body surface area calculation ............................................................................................ 22
6.2. Erlotinib administration .................................................................................................... 22
6.3. Erlotinib dose adjustments ................................................................................................ 23
6.3.1. Erlotinib dose adjustments due to diarrhoea .................................................................... 23 6.3.2. Erlotinib dose adjustments due to rash ........................................................................... 24 6.4. Erlotinib administration warnings and precautions ............................................................... 25
6.5. Ophthalmologic disorders caused by erlotinib ...................................................................... 25
6.6. Interstitial lung disease-like events caused by erlotinib ........................................................ 26
6.7. Docetaxel administration .................................................................................................. 26
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6.8. Docetaxel dose adjustments ............................................................................................. 26
6.8.1. Docetaxel dose adjustments due to haematological toxicity ............................................... 26 6.8.2. Docetaxel dose adjustments due to non haematological toxicity ........................................ 27 6.9. Pemetrexed administration ............................................................................................... 28
6.10. Pemetrexed dose adjustments .......................................................................................... 29
6.10.1. Pemetrexed dose adjustments due to haematological toxicity ........................................... 29 6.10.2. Pemetrexed dose adjustments due to non haematological toxicity ..................................... 29 6.11. Pemetrexed treatment delays due to insufficient folic acid or vitamin B12 supplementation ...... 30
6.12. Vinorelbine administration ................................................................................................ 30
6.13. Vinorelbine dose adjustments............................................................................................ 31
6.13.1. Vinorelbine dose adjustments due to haematological toxicity ............................................. 31 6.13.2. Vinorelbine dose adjustments due to non haematological toxicity ....................................... 31 6.14. Gemcitabine administration .............................................................................................. 32
6.15. Gemcitabine dose adjustments .......................................................................................... 32
6.15.1. Gemcitabine dose adjustments due to haematological toxicity .......................................... 32 6.16. Concomitant therapies ..................................................................................................... 33
7. CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP .......................................... 34
7.1. Registration .................................................................................................................... 34
7.1.1. Patients with a new diagnosis of NSCLC .......................................................................... 34 7.1.2. Patients relapsed or progressed after first line treatment .................................................. 35 7.2. Before randomization ....................................................................................................... 35
7.3. During second line treatment ........................................................................................... 37
7.3.1. Pts with 19-21 EGFR mutations ..................................................................................... 37 7.3.2. Erlotinib arm ............................................................................................................... 37 7.3.3. 3-weekly docetaxel ...................................................................................................... 39 7.3.4. Weekly docetaxel ......................................................................................................... 40 7.4. During third line treatment ............................................................................................... 42
7.5. During follow-up .............................................................................................................. 44
8. BIOLOGICAL EVALUATION ................................................................................................... 45
8.1. Specimen handling .......................................................................................................... 45
8.1.1. Patients entering the study at diagnosis .......................................................................... 45 8.1.2. Patients entering the study at relapse ............................................................................. 46 8.2. Minimal criteria for inclusion in the study ............................................................................ 47
8.2.1. Histological specimens .................................................................................................. 47 8.2.2. Cytological specimens .................................................................................................. 47 8.3. Analysis performed on tissues ........................................................................................... 48
8.3.1. Determination of mutational status of EGFR and K-ras genes ............................................ 48 8.3.2. Immunohistochemistry for p-AKT, DDR1, FGFR ............................................................... 49 8.3.3. Copy number determination of c-MET and FGFR1 genes ................................................... 49 8.3.4. EML4-ALK translocation ................................................................................................ 49 8.3.5. Analysis performed on blood ......................................................................................... 50
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9. ASSESSMENT OF RESPONSE ................................................................................................. 51
9.1. Definition of measurable and non-measurable ..................................................................... 51
9.2. Baseline documentation of �target� and �non-target� lesions ................................................. 52
9.3. Evaluation of best overall response .................................................................................... 52
9.4. Confirmation and review of response ................................................................................. 53
9.5. Reporting of results ......................................................................................................... 53
10. QOL ASSESSMENT .............................................................................................................. 53
10.1. Operative Procedures ....................................................................................................... 54
10.2. QoL timing ...................................................................................................................... 54
11. REMOVAL AND REPLACEMENT OF PATIENTS ...................................................................... 54
11.1. Replacement of patients ................................................................................................... 55
12. REGISTRATION/RANDOMIZATION PROCEDURE ................................................................ 55
12.1. Registration .................................................................................................................... 55
12.2. Randomization ................................................................................................................ 55
13. SAFETY DATA COLLECTION, RECORDING AND REPORTING ................................................ 56
13.1. Definitions ...................................................................................................................... 56
13.1.1. Adverse event ............................................................................................................. 56 13.1.2. Serious adverse event .................................................................................................. 56 13.2. Reporting of procedures for all adverse events .................................................................... 58
13.3. Serious adverse event reporting procedures ........................................................................ 59
14. STATISTICAL CONSIDERATIONS ........................................................................................ 59
14.1. Definition of endpoints ..................................................................................................... 59
14.1.1. Efficacy/activity ........................................................................................................... 59 14.1.2. Safety ........................................................................................................................ 60 14.2. Sample size .................................................................................................................... 60
14.3. Efficacy analyses ............................................................................................................. 60
14.4. Response rate ................................................................................................................. 61
14.5. Safety analyses ............................................................................................................... 61
14.6. Quality of life .................................................................................................................. 61
14.7. Interim analyses .............................................................................................................. 62
15. INDEPENDENT DATA & SAFETY MONITORING COMMITTEE ................................................ 63
16. DATA COLLECTING AND MONITORING ............................................................................... 63
17. ETHICS AND GOOD CLINICAL PRACTICE ............................................................................ 63
17.1. Patient protection ............................................................................................................ 64
17.2. Informed consent ............................................................................................................ 64
18. TRIAL SPONSORSHIP AND FINANCING .............................................................................. 64
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19. PUBLICATION POLICY ........................................................................................................ 65
20. REFERENCES ...................................................................................................................... 65
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1. BACKGROUND AND RATIONALE
1.1. Introduction
Non small cell lung cancer (NSCLC) is the most common cause of cancer deaths worldwide and the
development of more effective therapies remains challenging. Approximately 70% of NSCLC patients
(pts) presents with advanced (stage IIIb-IV) disease [1]. Despite the recent therapeutic progress the
median survival of advanced disease rarely exceeds 8 months and less than 30% of pts is still alive at
one year. Also the prognosis of those pts previously treated with curative intent remains poor and more
than 60% of them recurres. Approximately 60% of pts can receive a second line treatment, but disease
control is limited and median time to progression is less than 3 months.
1.1.1. Chemotherapy treatment
The chemotherapy most common regimens for naïve pts consist of platinum agents (cisplatin or
carboplatin) combined with gemcitabine (GEM), paclitaxel, docetaxel (DOC) or vinorelbine (VNB) and with
similar, although modest, efficacy [2]. Second line chemotherapy has demonstrated only modest
improvement in overall survival (OS) over best supportive care. At present, drugs approved as second
line include DOC, pemetrexed (PEM) and erlotinib (ERL). DOC [3] is the most extensively investigated
drug and demonstrated objective tumour response rate (RR) ranging from 14% to 22% and a median
survival ranging from 7 months to 11 months. Moreover, "3-weekly" (75 mg/m2) and "weekly" (35 mg/
m2) schedules seem to be equivalent [4] with different toxicity and quality of life (QoL) in some items.
Single agent PEM showed a RR of 8.9% to 23% and a median OS ranging between 5.7 months and 10
months. DOC and PEM resulted in clinically equivalent efficacy, but different toxicity profile. The
progression free survival (PFS) was 2.9 months for both treatments, whereas OS was 7.9 and 8.3,
respectively [5].
1.1.2. Erlotinib
The development of agents that target the epidermal growth factor receptor (EGFR) signal transduction
pathways has provided a novel class of therapeutic agents. ERL, an orally active, selective EGFR tyrosine
kinase inhibitor (TKI) recently approved in NSCLC pre-treated pts and gefitinib (GEF) are the most
studied agents of this class of compounds. The use of single agent ERL after failure with chemotherapy is
supported by the results of a recently completed phase 3 study (BR.21), an international trial conducted
by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). The RR was 8.9% in the ERL
group and less than 1% in the placebo group (p<0.001); respectively. Median PFS were 2.2 months and
1.8 months [Hazard Ratio (HR): 0.61, p<0.001] while median OS were 6.7 months and 4.7 months,
respectively (HR: 0.70; p<0.001), in favour of ERL. Five percent of pts interrupted for unexpected
toxicity. Subgroups analysis showed that the magnitude of the benefit was higher in females, in
adenocarcinomas, in never smokers and Asiatic ethnicity [6].
If the use of single agent ERL after failure of at least one prior chemotherapy regimen has been
demonstrated, TALENT [7] and TRIBUTE [8] trials failed to demonstrate any benefit in adding ERL to
chemotherapy in NSCLC pts.
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Results of a large trial comparing GEF and DOC have been recently presented [9]. The study was
designed as a non-inferiority trial in terms of OS between the two arms and was emended following the
emergence of biomarkers data, in order to find a superiority in pts with high EGFR copy number (FISH+).
Final results showed a non inferiority of GEF against DOC in terms of OS (7.6 vs. 8.0 months, HR: 1.02,
95% confidence interval (95% CI) 0.90-1.15) and PFS (HR: 1.4, 95% CI 0.93-1.18). Superiority of GEF
was not detected in FISH+ pts (HR 1.09, 95% CI 0.78-1.51).
1.2. Rationale of the study
In the period between 2008 and 2011, several evidence appeared in published paper or presented
abstract changing the previous scenario that was the basis of the first design of the TAILOR trial.
One large phase III trial, the Iressa Pan-Asia Study [IPASS] trial [10,11], three smaller phase III
randomized controlled trials [12-14] using PFS as the primary endpoint, and one small phase III trial with
OS as the primary end point, all involving first-line EGFR TKIs and chemotherapy doublets, form the basis
of the recent ASCO Provisional Clinical Option (PCO) [15]. This PCO is authoritatively offering clinical
direction and potentially practice-changing data from major studies. First statement is that on the basis
of five phase III RCTs, patients with advanced NSCLC of the lung who are being considered for first-line
therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI)
should have their tumour tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy
is the appropriate first-line therapy. Despite this PCO is limited to mutation testing, it is commenting that
at present FISH and IHC testing for EGFR at the present time are not recommended because the do not
reproducibly predict outcome.
While the situation of EGFR mutated patients appears clear, also if OS results are negative as result of
the cross-over treatment, it is of crucial importance to understand whether patients with wild type tumors
should be treated at relapse or progression with an anti EGFR drug or with chemotherapy.
Surprising is the information on the TKIs performance in wt EGFR patients reported in the four most
recently published trials [10, 16-18]. The molecularly profiled fraction is ranging only from 10 to 38% of
the randomized population, as shown in the table below, and only post-hoc analyses are done. Although
driving inferences from such a low percentage of the enrolled population can carry a high risk of a
selection bias, several considerations can be made by scrutinizing those data.
Data on PFS were reported by two studies, both suggesting a superiority of chemotherapy, although with
a statistically significant result only in the IPASS trial [10]. OS was reported in three trials with
inconsistent, not statistically significant results. However, the presence of unplanned cross-over
treatments at progression makes these results misleading.
In conclusion, while several papers describe in depth the right approach in the 10% represented by the
mutated population, it continues to remain unclear how to manage the remaining majority of patients at
relapse or progression. However, considering the above mentioned methodological limits, the available
evidence seems to suggest a superiority of chemotherapy on TKIs.
Moreover, in this period a consistent literature appeared also on possible mechanisms of primary or
acquired resistance to TKIs. In particular K-ras seems more a prognostic factor than a negative factor,
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instead the presence of c-met amplification, T790 mutation, Her 2 mutation, BRAF mutation, PIK3CA,
AKT1, MAP2K1 mutation, IGFR1 overexpression and EML4/ALK translocation seem to confer resistance to
ERL and gefitinib [19, 20]. These gene alteration are generally mutually exclusive on the principle of
oncogene addiction. Moreover, it seems that squamocellular histology is more resistant to TKIs than
others and our original hypothesis is that in this process two driver mutations, FGFR1 and DDR1 might be
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implicated. It is important also to underline also that all these mutations are �druggable�, this means that
understanding the résistance mechanisms to TKIs is not only important to exclude patients from a
treatment, but it may open a new scenario of therapies for these patients.
2. STUDY OBJECTIVES
2.1. Primary
The primary aim of the study is to to compare the efficacy in terms of OS of ERL and DOC as second-line
treatment in NSCLC pts without exon 19 or 21 EGFR mutations.
2.2. Secondary
To compare:
- Progression free survival (PFS)
- Response rate (RR, see section 14.1.1 for definition)
- Quality of life (QoL).
To provide insights on the prevalence of biological markers, their inter-correlation and their association
with basic clinical variables (histotype, gender, age, smoking habit).
To evaluate toxicity, graded according to the NCI-CTAE version 3.0, and the safety profile, in terms of
frequency and nature of serious adverse reactions, of each treatment arm.
To improve the knowledge on the resistance mechanisms to TKIs.
To prospectively assess the prognostic value of K-RAS mutations in patients treated with a first line
platinum containing regimen.
Other secondary analyses, such as collection of blood samples, in order to identify different prognosis-
related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and k-ras
mutations with respect to histological samples, will be addressed with specific sub protocols that will
require additional procedures and data.
3. STUDY DESIGN
3.1. Overview of study design
This is an Italian, multicentre, randomized, open label, phase 3 superiority trial. In order to define the
appropriate population to be entered in the trial, the design is planned according to three different
phases, which follow the journey of patient disease.
Phase 1: Registration and tissue banking
In this phase pts with NSCLC before or during first line platinum-based taxane free chemotherapy as well
as pts recurred after a first line adjuvant platinum-based taxane free chemotherapy will be registered,
providing the availability of material for molecular analysis. Tumour specimens and blood sample will be
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collected to perform genomic, ICH and proteomic analyses in order to identify the molecular
characteristics of tumour.
Phase 2: Randomization of second line therapies
At progression after first line treatment, pts with EGFR mutations of exons 19 or 21 will be electively
treated with ERL and followed up, while pts without EGFR mutations will be randomized to treatment
consisting of:
erlotinib 150 mg/day
docetaxel 75 mg/m2 on day 1 every 21 days, (3-weekly schedule) or 35 mg/m
2 on day 1, 8 and 15
every 28 days (weekly schedule)
until disease progression or unacceptable toxicity developed.
Allocation to treatment will be centrally performed with 1:1 ratio using a biased-coin minimization
procedure having centre, stage (progressed vs. recurred), prior first line chemotherapy (containing VNB
vs. containing GEM vs. containing PEM vs. containing other drugs not targeting the EGFR axis), adequacy
of histological sample (optimal vs. sub-optimal), ECOG PS (0-1 vs. 2), as stratification variables.
Access to random system will be allowed by phone or via web.
Phase 3: Clinical assessment and further treatments
During treatment and follow-up phase clinical assessment of pts will be made on regular basis, in order to
collect the relevant data to compare safety and efficacy. The study endpoints are defined in section 14.1.
In case of further progression, pts treated with a platinum-based first line chemotherapy with VNB or
GEM will receive a standardized third line therapy with PEM, 500 mg/m2 on day 1 every 21 days
supplemented by folic acid and vitamin B12, while pts treated with a platinum-based first line
chemotherapy with PEM will receive either GEM (1000 mg/m2 days 1, 8, 15 every 28 days)
or VNB (30
mg/m2
days 1, 8, 15 every 28 days) until disease progression or unacceptable toxicity developed.
3.2. Number of centers
Approximately 100 Italian centres will participate in this study.
3.3. Number of patients
750-850 pts needed to be registered in order to randomise the required number of 220 pts. Please refer
to section 14.2 for justification of sample size.
3.4. Study duration
This is an event driven study. The study will continue until 199 deaths have occurred.
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The patient accrual period is planned for approximately 48 months. To assess OS, all pts will be followed
for up to 12 months after the last patient is randomized. The maximum estimated study duration is
approximately 60 months.
STUDY FLOW-CHART
4. PATIENT SELECTION CRITERIA
4.1. Target population
Pts with histologically documented, locally advanced or metastatic NSCLC in second line treatment or
recurred or relapsed after adjuvant treatment.
4.2. Inclusion criteria
For inclusion in the study, pts must fulfil all of the following criteria:
Age 18 years or older
REGISTRATION AND TISSUE SECOND LINE TREATMENT THIRD LINE THERAPY
POSITIVITY
for EGFR 19-21 mutations
NEGATIVITY
for EGFR 19-21 mutations
erlotinib 150 mg po, daily dose
R
docetaxel 75mg/m2 iv on day 1
every 21 days or docetaxel
35mg/m2 iv on days 1,8,15 every
28 days until disease
progression or unacceptable
toxicity developed.
erlotinib 150 mg po,
daily dose
P
R
O
G
R
E
S
S
I
O
N
PEM 500mg/m2 on day 1 every
21 days, supplemented by folinic
acid and vitamin B12 or
VNB 30 mg/m2 days 1, 8, 15,
every 28 days or
GEM 1000 mg/m2 days 1, 8, 15,
every 28 days
if judged by the investigator,
until disease progression or
unacceptable toxicity developed
P
R
O
G
R
E
S
S
I
O
N
TARGET POPULATION
Pts with histologically or
cytologically documented,
locally advanced or metastatic
or recurred/relapsed after
adjuvant treatment NSCLC
previously treated with
platinum based taxan free
regimens
RANDOMIZATION
With a 1 : 1 ratio using a biased-
coin minimization procedure
having
- centre
- stage (relapsed vs. progressed)
- prior chemotherapy (GEM vs.
VNB vs. PEM vs. others)
- ECOG-PS (0-1 vs. 2)
- Adequacy of histological sample
(yes vs. no)
as stratification factors
PRIMARY ENDPOINT
overall survival
SECONDARY ENDPOINTS
Progression free survival
Toxicity and safety
Response rate
Quality of life
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Histological or cytological confirmation of NSCLC (may be from initial diagnosis of NSCLC or
subsequent biopsy). Only patients with available tissue samples may be included in the study (see
major details in section 8 for the minimum sample characteristics)
Absence of EGFR mutations of exons 19 or 21 (randomization)
Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy
One prior platinum-based at adequate doses and taxane-free regimen and anti EGFR axis drug free.
Platinum-based regimen containing other agents (i.e. bevacizumab, ixapebilone etc) not targeting the
EGFR axis (i.e. cetuximab) are allowed. Pts who initially presented with early stage disease but
subsequently progressed or recurred are eligible if they received full dose platinum-based taxane free
adjuvant or neoadjuvant chemotherapy at full cytotoxic doses or platinum therapy as part of a
chemotherapy/radiotherapy regimen. They will not be eligible if they have only received platinum at a
radio sensitizing dosage (prior surgery and/or localized irradiation are allowed)
Measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST) in a lesion not
previously irradiated or non-measurable disease
Eastern Cooperative Oncology Group - performance status (ECOG-PS) 0-2
Absolute neutrophil count (ANC) > 1.5 x 109/liter (L) and platelets > 100 x 10
9/L
Bilirubin level either normal or <1.5 x ULN
AST (SGOT) and ALT (SGPT) <2.5 x ULN (≤ 5 x ULN if liver metastases are present)
Serum creatinine <1.5 x ULN
Effective contraception for both, male and female pts, if the risk of conception exists
Recovery from all acute toxicities of prior therapies
Provision of written informed consent to the analysis of biological markers (registration)
Provision of written informed consent to enter the randomized part of the study (randomization)
4.3. Exclusion criteria
Any of the following is regarded as a criterion for exclusion from the study:
Prior therapy with an experimental agent whose primary mechanism of action is inhibition of EGFR or
its associated tyrosine kinase
Prior therapy with taxanes
Newly diagnosed central nervous system (CNS) metastases that have not yet been treated with
surgery and/or radiation. Pts with previously diagnosed and treated CNS metastases or spinal cord
compression may be considered if they have evidence of clinically stable disease (SD) (no steroid
therapy or steroid dose being tapered) for at least 28 days
Less than 14 days since completion of prior radiotherapy or persistence of any radiotherapy related
toxicity
Any unresolved chronic toxicity from previous anticancer therapy that, in the opinion of the
investigator, makes it inappropriate for the patient to be enrolled in the study
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Known severe hypersensitivity to erlotinib or any of the excipients of this product
Known hypersensitivity to DOC, polysorbate 80 or other drugs formulated with polysorbate 80, or any
of the excipients of DOC
Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception
of basal cell carcinoma or cervical cancer in situ
Unable to swallow tablets
Any evidence of clinically active interstitial lung disease (ILD) (patients with chronic, stable,
radiographic changes who are asymptomatic or patients with uncomplicated progressive lymphangitic
carcinomatosis need not be excluded)
As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g.,
unstable or uncompensated respiratory, cardiac, hepatic or renal disease)
As judged by the investigator, any inflammatory changes of the surface of the eye
Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for
the patient to participate in the study
Pregnancy
Breast feeding
5. PATIENT ENROLLMENT
Patient enrollment can be done in two steps: registration and randomization.
5.1. Registration
Pts with a recent diagnosis of NSCLC, as well as those relapsed after surgery or from the end of adjuvant
treatment can be registered, in order to provide tissue specimens and to allow EGFR and K-ras mutation
detection. All pts with a new diagnosis of locally advanced or metastatic NSCLC should preferentially be
registered at this time in order to allow all the biological evaluations.
Before registration eligible pts must provide his/her informed consent to the analysis of biological
markers.
An eligibility screening form documenting the patient fulfilment of the eligibility criteria is to be completed
by the investigator before registration.
5.2. Randomization
After registration only pts without 19-21 EGFR mutations and fulfilling all the inclusion/exclusion criteria
can be entered into the randomized part of the study. Pts with 19-21 EGFR mutations will be entered in
the non randomized part of the trial.
Before randomization eligible patients must provide his/her informed consent to participate.
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6. TREATMENT PLAN
As second line therapy, pts with EGFR 19-21 mutations will receive erlotinib 150 mg/day until disease
progression or unacceptable toxicity developed, while pts without EGFR 19-21 mutations will be
randomized to receive:
erlotinib 150 mg/day
or
docetaxel 75 mg/m2 on day 1 every 21 days, (3-weekly schedule) or 35 mg/m
2 on day 1, 8 and 15
every 28 days (weekly schedule),
until disease progression or unacceptable toxicity developed.
At further progression of disease, at discretion of the investigators pts will receive a standardized third
line therapy with PEM, 500 mg/m2 on day 1 every 21 days, supplemented by folic acid and vitamin B12,
until disease progression or unacceptable toxicity developed, while pts treated as first line with platinum-
based chemotherapy with PEM will receive either GEM (1000 mg/m2 days 1, 8, 15 every 28 days)
or VNB
(30 mg/m2
days 1, 8, 15 every 28 days), until disease progression or unacceptable toxicity developed.
6.1. Body surface area calculation
The actual dose of DOC and PEM to be administered, will be determined by calculating the body surface
area (BSA) at the beginning of each cycle, this principle applies to individuals whose calculated surface
area is 2.2 m2 or less. In those rare cases where a patient surface area is greater than 2.2, the actual
surface area or 2.2 may be used.
6.2. Erlotinib administration
ERL will be administered at the starting dose of 150 mg/day. ERL is to be taken, preferably in the
morning, with up to 200 ml of water. On visit days, study drug will be taken in the clinic as instructed by
the study nurse or the investigator. Drug should be taken at least 1 hour before or 2 hours after the
ingestion of any food or other medication.
Pts who are unable to swallow tablets may grind the tablets provided that the tablet powder (after
grinding) is collected quantitatively (by e.g. grinding in a mortar and collecting the whole powder) for
administration. This powder can then be mixed with marmalade or jelly (in order to mask the taste).
ERL will be administered on an outpatient basis. Doses should be taken at the same time each day.
If the patient vomits after taking the tablets, the dose is replaced only if the tablets can actually be seen
and counted.
If a patient misses a dose normally taken in the morning, the patient may take the dose any time during
the same day. However the missed dose should not be taken on a subsequent day. Pts will be instructed
to notify study site personnel of missed doses.
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ADMINISTRATION OF ERLOTINIB
Drug Dose Time
Erlotinib 150 mg per os (po), daily
dose
Daily dose should be taken in the morning at least 1 hour before or 2
hours after the ingestion of any food or other medication
6.3. Erlotinib dose adjustments
Interruption and/or reduction of dosing for adverse events (AEs) may take place at any time during the
study. In the event of any non�dose-limiting toxicity that is not controlled by optimal supportive care, or
not tolerated due to symptomatology, disfigurement, or interference with normal daily activities,
regardless of severity, the daily dose of ERL will be decreased according to the schedule displayed below.
ERLOTINIB DOSE LEVEL REDUCTIONS
Starting dose Dose at first reduction Dose at second reduction
150 mg 100 mg 50 mg
Within 2 weeks following a dose reduction, ERL related toxicity must improve by at least one National
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) grade and be NCI-CTCAE
grade ≤2, or further dose reduction by one level will be required. Dosing may be interrupted for a
maximum of 2 weeks, if clinically indicated and if the toxicity is not controlled by optimal supportive
medication. Once a patient has had a dose reduction for toxicity, the dose will not be re-escalated except
in the case of ERL related rash. In the event of a rash, dose can be re-escalated when rash is ≤ grade 2.
6.3.1. Erlotinib dose adjustments due to diarrhoea
Diarrhoea occurres in around 50% of pts, who receive ERL, is usually transient and, in most cases, can
be managed with loperamide. The recommended regimen is 4 mg loperamide at onset of symptoms,
followed by 2 mg every 2�4 hours, until the patient has remained free from diarrhoea for 12 hours. Pts
with diarrhoea that are unresponsive to loperamide, or those with associated dehydration, may require
dose reduction or interruption. Appropriate rehydration should be provided (particularly important for
elderly pts, who can rapidly become dehydrated, even with mild diarrhoea).
GUIDELINES FOR MANAGEMENT OF ERLOTINIB RELATED DIARRHOEA
Grade Study drug dosage
modification
Guideline for management
Grade 1 None Consider loperamide (4 mg at first onset, followed by 2 mg every 2-4 hours
until diarrhoea free for 12 hours) and appropriate rehydration
Grade 2 Interrupt Loperamide (4 mg at first onset, followed by 2 mg every 2-4 hours until
diarrhoea free for 12 hours) and appropriate rehydration
Grade 3 Interrupt Interrupt and give appropriate reyhdration, monitor electrolyte balance and
renal function until resolution to grade ≤ 1; restart at reduced dose
Grade 4 Discontinue study
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6.3.2. Erlotinib dose adjustments due to rash
A patient may develop several kinds of dermatological events (including rash) while being treated with
ERL. It is important to recognise that the rash typically seen during treatment with ERL is pathologically
and aetiologically distinct from acne (including steroid-induced acne) and therefore should be managed
differently. In clinical trials, rash was the most common side effect reported with ERL, in about 75% of
pts. Typically, the rash develops about 7�10 days after the start of treatment, and affects skin areas
above the waist. In most pts, the rash is mild (grade 1 or 2). For example, in the pivotal phase III trial
(BR.21), only 8% of pts had grade 3 rash, and less than 1% had grade 4 rash [6]. Mild or moderate rash
may be managed using topical emollients and corticosteroids, but in a few pts, the rash may be severe
enough to warrant dose reduction or withdrawal. There are also many reports of rash resolving
spontaneously (without treatment) and reappearing later (during the same treatment regimen).
Management of rash without secondary infections:
Consider using topical corticosteroids early in pts with mild rash (e.g. clobetasol propionate)
Analgesics may be of benefit: consider using before reducing the dose of ERL
Topical retinoids and other acne medications (e.g. benzoyl peroxide) are NOT recommended; their
skin-drying effects may exacerbate the rash
Evaluate treatment effectiveness after 1 week and continue for another week; discontinue if no
improvement after 2 weeks
Use topical agents cautiously, especially for severe rash: efficacy may be restricted if penetration of
deep layers of skin is poor
Systemic agents should be used with care as they may adversely affect beneficial processes in the
tumour
Consider using intranasal mupirocin applied once daily to each nostril to prevent secondary infection.
Management of rash with secondary infections:
Consider using topical antibiotics such as clindamycin
Short course of oral antibiotics; consider tetracyclines for their weak anti-inflammatory effects
If staphylococcus aureus infection is confirmed, or impetigo is diagnosed, consider topical mupirocin
If antibiotic resistance is suspected, culture to determine the infective bacterial strain and treat
accordingly.
GUIDELINES FOR MANAGEMENT OF ERLOTINIB RELATED RASH
Grade Study drug dosage modification
Grade 1 None
Grade 2 None
Grade 3 Dose reduction; dose can be re-escalated when rash is grade 2
Grade 4 Discontinue study
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Pts who require an interruption in dosing of >2 weeks (due to any ERL related AE not manageable with
optimal supportive medication) will discontinue ERL treatment and be taken off study. The reasons for
missed doses or ERL discontinuation must be recorded on the case report form (CRF).
Pts for whom ERL therapy is interrupted for <2 weeks for reasons other than ERL related AEs may restart
ERL therapy if the investigator agrees it is in the best interest of the patient to re-challenge and the
patient meets the following criteria to restart ERL therapy:
ECOG-PS must be 0�1, AND
ocular toxicity must improve to NCI-CTCAE Grade ≤ 1 (if appropriate).
6.4. Erlotinib administration warnings and precautions
ERL is protein bound (92% to 95% in humans) and metabolized by hepatic cytochromes CYP3A4 and
CYP1A2 and pulmonary cytochrome CYP1A1. Therefore, a potential for drug-drug interaction exists when
ERL is co-administered with drugs that are highly protein bound or that are CYP3A4 or CYP1A2
inhibitors/inducers. Substances that are potent inhibitors of CYP3A4 activity (e.g., ketoconazole)
decrease ERL metabolism and increase ERL plasma concentrations. This increase may be clinically
relevant as adverse experiences are related to dose and exposure. Therefore, for this study, caution
should be used when administering CYP3A4 inhibitors to patients who are on study drug.
Substances that are potent inducers of CYP3A4 activity (e.g., rifampin, phenytoin) increase ERL
metabolism and significantly decrease ERL plasma concentrations. This decrease in exposure may be
clinically relevant, as preclinical studies suggest that higher concentrations are more efficacious in vivo
animal tumour models. However, the relationship between exposure and efficacy in cancer pts has not
been adequately studied. Therefore, for this study, caution should be used when administering CYP3A4
inducers to pts who are on study drug. International normalised ratio (INR) elevations and/or bleeding
events have been reported in some cancer pts taking warfarin while on ERL. During this study, pts taking
warfarin or other coumarin-derived anticoagulants should be monitored as clinically indicated for changes
in prothrombin time or INR.
6.5. Ophthalmologic disorders caused by erlotinib
Based on results of Phase I studies in normal volunteers and the toxicological results in dogs dosed at 50
mg/kg/day, frequent ophthalmologic examinations were included in initial Phase I and II studies. Based
on the clinical experience to date and the rarity of significant ophthalmologic findings, these examinations
have been reduced or eliminated in more recent studies unless clinically indicated for ocular symptoms.
Infrequent occurrences of conjunctivitis and keratitis with associated facial rash have been observed
during ERL treatment. Isolated reports of corneal ulceration, uveitis, and orbital cellulites have been
reported in pts receiving ERL therapy, mostly as complications of mucocutaneous inflammation. However,
pts developing eye symptoms should promptly undergo ophthalmologic examination.
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6.6. Interstitial lung disease-like events caused by erlotinib
In the event of acute onset of new or progressive, unexplained pulmonary symptoms such as dyspnoea,
cough, and fever, ERL therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed,
ERL should be discontinued and appropriate treatment and close follow-up instituted as necessary.
6.7. Docetaxel administration
ADMINISTRATION OF 3-WEEKLY SCHEDULE DOCETAXEL
Drug Dose Time
Docetaxel 75 mg/m2 intravenous (iv) infusion Administered in either 0.9% sodium chloride or 5% dextrose
solution (the final concentration should be between 0.3 and 0.74
mg/mL), over 1 hour on day 1 every 21 days, until disease
progression or unacceptable toxicity developed.
Dexamethasone 8 mg iv or intramuscular (im),
every 12 hour or equivalent regimen
(-24, -12, 0, +12, +24, +36)
For 3 days starting the day before to each dose of DOC, unless
clinical contraindications exist, to reduce the severity of fluid
retention and hypersensitivity reactions
ADMINISTRATION OF WEEKLY SCHEDULE DOCETAXEL
Drug Dose Time
Docetaxel 35 mg/m2 iv infusion
Administered in either 0.9% sodium chloride or 5% dextrose
solution (the final concentration should be between 0.3 and
0.74 mg/mL), over 1 hour on day 1, 8, 15 every 28 days, until
disease progression or unacceptable toxicity developed.
Dexamethasone 8 mg iv or im, every 12 hours or
equivalent regimen (-12, 0, +12)
For 3 times starting 12 hours before to each dose of DOC,
unless clinical contraindications exist, to reduce the severity of
fluid retention and hypersensitivity reactions
6.8. Docetaxel dose adjustments
Any patient who requires a DOC dose reduction will continue to receive a reduced dose for the remainder
of the study. Any patient with two prior dose reductions who experiences a toxicity that would cause a
third dose reduction must be discontinued from study therapy. Treatment may be delayed for up to 42
days from day 1 of the current cycle to allow a patient sufficient time to recover from study drug-related
toxicity. A patient who cannot be administered study drug for 42 days from the time of last treatment
must be discontinued from study therapy unless continuation is approved by study coordinator.
6.8.1. Docetaxel dose adjustments due to haematological toxicity
6.8.1.1. 3-weekly schedule
Dose adjustments at the start of a subsequent course of therapy will be based on platelet and neutrophil
ANC nadir (lowest value) counts from the preceding cycle of therapy. ANC must be >1.5 x 109/L and
platelets >100 x 109/L prior to the start of any cycle. Treatment should be delayed to allow time for
recovery. Upon recovery, if treatment is resumed, it must be according to the guidelines reported in the
table below.
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ADJUSTMENTS OF 3-WEEKLY SCHEDULE DOCETAXEL DOSE FOR HAEMATOLOGICAL TOXIC EFFECTS
Platelets ( 109/L) Nadir ANC ( 10
9/L) Nadir Percent of Previous Dose
≥25 And ≥0.5 100%
≥25 And <0.5 for <7 days AND no fever 100%
≥25 And <0.5 for >7 days OR fever 75%
<25 And 0.5 75%
<25 And <0.5 for <7 days AND no fever 75%
<25 And <0.5 for >7 days OR fever 50%
6.8.1.2. Weekly schedule
It is possible only one dose reduction from 35 to 30 mg/m2 to discretion of physician, the start of a
subsequent course of therapy will be based on platelet and neutrophil value: ANC must be >1.5 x 109/L
and platelets >100 x 109/L prior to the start of any dose, in absence of other toxicity of grade 2, 3 or 4
(excluding alopecia). Treatment may be delayed for up to 42 days from day 1 of the current cycle to
allow a patient sufficient time to recover from study drug-related toxicity. A patient who cannot be
administered study drug for 42 days from the time of last treatment must be discontinued from study
therapy unless continuation is approved by study coordinator.
6.8.2. Docetaxel dose adjustments due to non haematological toxicity
6.8.2.1. 3-weekly schedule
For most grade 3 or 4 non haematological toxicities, including severe or cumulative cutaneous reactions,
but excluding grade 3 nausea or vomiting, treatment should be delayed until resolution of toxicity to the
patient�s original baseline grade. Treatment should resume at 75% of the previous dose level if deemed
appropriate by the treating physician [Do not forget to report any inpatient hospitalization as a serious
adverse event (SAE)]. If after two dose reductions, the patient still experiences grade 3 or 4 non
haematological toxicity (excluding grade 3 nausea and vomiting), discontinue the patient from study
therapy. Discontinue the patient if grade 4 vomiting occurs despite antiemetics and 2 dose reductions.
Exceptions to this dose adjustment scheme for non haematological toxicities are the following:
Clinically significant effusions
For pts who develop clinically significant pleural or peritoneal effusions (on the basis of symptoms or
clinical examination) during therapy, consideration should be given to draining the effusion prior to
dosing. However, if, in the investigator�s opinion, the effusion represents progression of disease,
patient should be discontinued from study therapy.
Fluid retention
Pts may be treated for symptomatic oedema (grade 2 or higher) with diuretics at the investigator
discretion. Spironolactone at a starting dose of 25 mg three times daily plus furosemide 20 � 40 mg
as needed is recommended.
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If fluid retention is grade 3 or 4, treatment should be delayed until resolution of toxicity to the
patient�s original baseline grade. Treatment should resume at 75% of the previous dose level if
deemed appropriate by the treating physician.
Grade 3 or 4 peripheral neuropathy
Pts who experience grade 3 or 4 peripheral neuropathy must stop receiving DOC. Pts will then enter
post-study follow.
Hypersensitivity reactions
If, despite the dexamethasone treatment regimen, patients experience hypersensitivity reactions,
treatment should be as indicated below.
MANAGEMENT OF HYPERSENSITIVITY REACTIONS FOR PATIENTS RECEIVING DOCETAXEL
Mild symptoms:
Localized cutaneous reaction such as
mild pruritus, flushing, rash
Consider decreasing the rate of infusion until recovery of symptoms; stay at
bedside. Then, complete DOC infusion at the initial planned rate.
Moderate symptoms:
Any symptom not listed as mild or
severe such as generalized pruritus,
flushing, rash, dyspnea, hypotension
with systolic blood pressure >80 mm
Hg.
Stop DOC infusion, give iv dexamethasone 10 mg and/or iv diphenhydramine
50 mg; resume DOC infusion after recovery of symptoms.
Severe symptoms such as
bronchospasm, generalized urticaria,
systolic blood pressure 80 mmHg,
angioedema.
Stop DOC infusion, give iv diphenhydramine 50 mg and/or epinephrine as
needed. Whenever possible, resume DOC infusion within 3 hours after
recovery, or reinfuse the patient within 72 hours, pretreating ½ hour prior to
infusion with dexamethasone 10 mg iv and/or diphenhydramine 50 mg iv. If
severe reaction recurs despite additional premedication, discontinue the
patient from study drug therapy.
Anaphylaxis (grade 4 reaction) No further study drug therapy
6.8.2.2. Weekly schedule
See section 6.8.2.1.
6.9. Pemetrexed administration
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ADMINISTRATION OF PEMETREXED
Drug Dose Time
Pemetrexed 500 mg/m2 iv infusion Administered in 0.9% sodium chloride approximately 100 mL
over 10 minutes (8 � 15 minutes) on day 1 of a 21-day cycle
Folic acid 1. 350 � 600 g folic acid
2. A multivitamin containing
folic acid in the range of 350
g to 600 g is acceptable if
option 1 is not available.
3. A dose of folic acid between
600 g and 1000 g is
acceptable only if neither
option 1 nor option 2 is
available.
Oral dose daily beginning approximately 1-2 weeks prior to the
first dose of PEM, and continuing daily until 3 weeks after the
last dose of PEM.
Vitamin B12 1000 µg im injection Approximately 1 � 2 weeks prior to the first dose of PEM, and
approximately every 9 weeks until 3 weeks after the last dose
of PEM.
Dexamethasone 4 mg, orally twice per day or
equivalent (-24, -12, 0, +12,
+24, +36)
Should be taken on the day before, the day of, and the day
after each dose of PEM, unless clinical contraindications exist.
Higher or additional doses are permitted for reasons (eg,
antiemetic prophylaxis).
6.10. Pemetrexed dose adjustments
Any patient who requires a PEM dose reduction will continue to receive a reduced dose for the remainder
of the study. Any patient with two prior dose reductions who experiences a toxicity that would cause a
third dose reduction must be discontinued from study therapy. Treatment may be delayed for up to 42
days from day 1 of the current cycle to allow a patient sufficient time to recover from study drug-related
toxicity. A patient who cannot be administered study drug for 42 days from the time of last treatment
must be discontinued from study therapy unless continuation is approved by study coordinator.
6.10.1. Pemetrexed dose adjustments due to haematological toxicity
Dose adjustments at the start of a subsequent course of therapy will be based on platelet and neutrophil
nadir (lowest value) counts from the preceding cycle of therapy. ANC must be >1.5 x 109/L and platelets
>100 x 109/L prior to the start of any cycle. Treatment should be delayed to allow time for recovery.
Upon recovery, if treatment is resumed, it must be according to the guidelines reported below.
DOSE ADJUSTMENTS FOR PEMETREXED BASED ON NADIR HEMATOLOGICAL VALUES FOR PRECEDING CYCLE
Platelets ( 109/L) Nadir ANC ( 10
9/L) Nadir Percent of Previous Dose
≥50 and ≥0.5 100%
≥50 and <0.5 75%
<50 and Any 50%
6.10.2. emetrexed dose adjustments due to non haematological toxicity
Clinically significant effusions
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For pts who develop clinically significant pleural or peritoneal effusions (on the basis of symptoms or
clinical examination) during therapy, consideration should be given to draining the effusion prior to
dosing. However, if, in the investigator opinion, the effusion represents progression of disease,
patient should be discontinued from study therapy.
Diarrhoea, mucositis, and other non haematological toxicities
In the event of diarrhoea requiring hospitalization (or of at least grade 3), treatment should be
delayed until diarrhoea has resolved before proceeding. Treatment should be resumed at 75% of the
previous dose level. For other non haematological effects greater than or equal to grade 3 (with the
exception of grade 3 transaminase elevations, nausea, or vomiting), treatment should be delayed
until resolution to less than or equal to the patient original baseline grade before proceeding.
Treatment should resume at 75% of the previous dose level if deemed appropriate by the treating
physician. (Do not forget to report any inpatient hospitalization as a SAE). Relevant dose adjustments
in case of mucositis are reported in the table below.
DOSE MODIFICATIONS FOR PEMETREXED FOR MUCOSITIS
NCI-CTCAE grade Percent of previous dose
Grade 0-2 100%
Grade 3-4 50%
Recurrence of grade 3 or 4 after treatment at 2 dose reductions Discontinue patient from study therapy
Creatinine clearance (CrCl)
If a patient develops a CrCl <45 mL/min, the next cycle will not begin until CrCl is 45 mL/min. Re-
testing is recommended at weekly intervals but will be conducted at the investigator discretion. If a
patient CrCl has not returned to 45 mL/min within 42 days of the last dose of PEM, the patient must
be discontinued from study therapy unless continuation is approved by study coordinator.
6.11. Pemetrexed treatment delays due to insufficient folic acid or vitamin B12
supplementation
Delay the first dose of PEM until the patient has taken folic acid for at least 5 of the 7 days immediately
preceding the first dose of PEM, and until the vitamin B12 injection has been administered. Delay
subsequent doses of PEM until the patient has taken folic acid for at least 14 of the 21 days before day 1
of the cycle.
6.12. Vinorelbine administration
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ADMINISTRATION OF VINORELBINE
Drug Dose Time
Vinorelbine 30 mg/m2 iv infusion* Administered in 0.9% sodium chloride or 5% glucose
approximately in 20-50mL in 6-10 minutes on days 1, 8, 15
every 28 days
* Suggested doses to be modified by the investigator on the basis of toxicities in previous lines of treatment
6.13. Vinorelbine dose adjustments
Any patient who requires a VNB dose reduction will continue to receive a reduced dose for the remainder
of the study. Any pts with two prior dose reductions who experiences a toxicity that would cause a third
dose reduction must be discontinued from study therapy. Treatment may be delayed for up to 42 days
from day 1 of the current cycle to allow a patient sufficient time to recover from study drug-related
toxicity. A pts who cannot be administered study drug for 42 days from the time of last treatment must
be discontinued from study therapy unless continuation is approved by study coordinator.
6.13.1. Vinorelbine dose adjustments due to haematological toxicity
DOSE ADJUSTMENTS FOR VINORELBINE BASED ON NADIR HEMATOLOGICAL VALUES FOR PRECEDING CYCLE
Platelets ( 109/L) Nadir ANC ( 10
9/L) Nadir Percent of Previous Dose
≥100 and ≥1.0 100%
50-100 and 0.5-1.0 75%
<50 and Any do not administer
6.13.2. Vinorelbine dose adjustments due to non haematological toxicity
The most common adverse events is stipsis, that rarely may induce also a paraliticus ileus.
Other adverse events are vomit, diarrohea, peripheral neurotoxicity, arthralgia, fever, mialgia, alopecia.
In the event of stipsis or paraliticus ileus requiring hospitalization (or of at least grade 3), treatment
should be delayed until stipsis has resolved before proceeding. Treatment should be resumed at 75% of
the previous dose level. For other non haematological effects greater than or equal to grade 3 (with the
exception of grade 3 transaminase elevations, nausea, or vomiting), treatment should be delayed until
resolution to less than or equal to the patient original baseline grade before proceeding. Treatment
should resume at 75% of the previous dose level if deemed appropriate by the treating physician. (Do
not forget to report any inpatient hospitalization as a SAE). Relevant dose adjustments in case of stipsis
are reported in the table below.
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DOSE MODIFICATIONS FOR VINORELBINE FOR STIPSIS
NCI-CTCAE grade Percent of previous dose
Grade 0-2 100%
Grade 3-4 50%
Recurrence of grade 3 or 4 after treatment at 2 dose reductions Discontinue patient from study therapy
6.14. Gemcitabine administration
ADMINISTRATION OF GEMCITABINE
Drug Dose Time
Gemcitabine 1000 mg/m2 iv infusion* Administered in 0.9% sodium chloride approximately 250 mL
over 30 minutes on days 1, 8, 15 every 28 days
Dexamethasone 4 mg, orally twice per day Higher or additional doses are permitted for reasons (eg,
antiemetic prophylaxis).
* Suggested doses to be modified by the investigator on the basis of toxicities in previous lines of treatment
6.15. Gemcitabine dose adjustments
Any pts who requires a GEM dose reduction will continue to receive a reduced dose for the remainder of
the study. Any pts with two prior dose reductions who experiences a toxicity that would cause a third
dose reduction must be discontinued from study therapy. Treatment may be delayed for up to 42 days
from day 1 of the current cycle to allow a patient sufficient time to recover from study drug-related
toxicity. A pts who cannot be administered study drug for 42 days from the time of last treatment must
be discontinued from study therapy unless continuation is approved by study coordinator.
6.15.1. Gemcitabine dose adjustments due to haematological toxicity
Dose adjustments at the start of a subsequent course of therapy will be based on platelet and neutrophil
nadir (lowest value) counts from the preceding cycle of therapy. ANC must be >1.5 x 109/L and platelets
>100 x 109/L prior to the start of any cycle. Treatment should be delayed to allow time for recovery.
Upon recovery, if treatment is resumed, it must be according to the guidelines reported below.
DOSE ADJUSTMENTS FOR GEMCITABINE BASED ON NADIR HEMATOLOGICAL VALUES FOR PRECEDING CYCLE
Platelets ( 109/L) Nadir ANC ( 10
9/L) Nadir Percent of Previous Dose
≥100 and 1.0 100%
50-100 and 0.5-1.0 75%
<50 and Any do not administer
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6.16. Concomitant therapies
Pts are allowed to receive full supportive care therapies concomitantly during the study. No other
chemotherapy, immunotherapy, hormonal cancer therapy, surgery for cancer, or experimental
medications, will be permitted while the patients are receiving study therapy. Palliative radiation therapy
is permitted for irradiating small areas of painful metastasis that cannot be managed adequately using
systemic or local analgesics. Any disease progression requiring other forms of specific anti-tumoral
therapy will be cause for early discontinuation of study therapy. The following concomitant therapies
warrant special attention:
Colony stimulating factors (CSFs)
Routine use of CSFs is not permitted during this study. Patients should not receive prophylactic
granulocyte colony stimulating factors (G-CSFs) in any cycle. G-CSFs should be considered only for
patients who have ANC <0.5 109/L, neutropenic fever, or documented infections while neutropenic.
Duration of uncomplicated neutropenia before initiation of G-CSF treatment is left to the investigator
discretion. G-CSF must be discontinued at least 24 hours prior to the start of the next cycle of
chemotherapy. If a patient develops hematological toxicities, chemotherapy dose reduction and
acute treatment of neutropenia are recommended, rather than chemotherapy dose maintenance and
pre-emptive treatment with G-CSFs.
Use of erythropoietin is allowed.
Use of stimulators of thrombopoiesis is not allowed
Nonsteroidal anti-inflammatory drugs (NSAIDs) (PEM only)
Pts taking NSAIDs or salicylates will not take the NSAID or salicylate 2 days before, the day of, and 2
days after receiving PEM. If a patient is taking an NSAID or salicylate with a long half-life (e.g.,
naproxen, piroxicam, diflunisal, or nabumetone), it should not be taken 5 days before, the day of,
and 2 days after receiving PEM
Diarrhea therapy
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: hydration,
octreotide, and antidiarrheals. If diarrhea is severe (requiring intravenous hydration) associated with
fever or severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Pts with
severe diarrhea (requiring intravenous hydration) associated with severe nausea or vomiting should
be managed according to local standard procedures for iv hydration and correction of electrolyte
imbalances. (Do not forget to report any in-patient hospitalization as a SAE)
Febrile neutropenia therapy
Patients experiencing febrile neutropenia, especially with diarrhea, should be managed according to
local standard procedures, with the urgent initiation of intravenous antibiotic therapy
Antiemetic therapy
Antiemetic therapy should be administered according to standard local practice
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Radiotherapy
If palliative radiotherapy will be judged necessary, the patient should be fully assessed for possible
progression. Because of possible interactions between cytotoxics and radiation in the study, it is
advised that palliative radiotherapy should not be given until at least one week after any previous
chemotherapy treatment, and subsequent chemotherapy should not be given until one week after the
end of radiation. As well, large single-dose radiotherapy (i.e. > 800 cGy) should not be used in this
study
Pregnancy
Fertile women must be instructed to avoid pregnancy. In case of pregnancy, ERL or chemotherapy
must be stopped. The investigator should counsel the patient; discuss the risks of continuing with the
pregnancy and the possible effects on the fetus. Monitoring of the patient should continue until
conclusion of the pregnancy
Other subsequent therapy
No chemotherapy other than that planned in the study design, or immunotherapy or experimental
medications will be permitted when patients have progressed after second-line treatment, third line
treatment, will be PEM or VNB or GEM depending on first line treatment (see section 6 �treatment
plan�) or the pts will enter in the follow-up phase.
7. CLINICAL EVALUATION, LABORATORY TESTS AND FOLLOW-UP
7.1. Registration
7.1.1. Patients with a new diagnosis of NSCLC
All pts referring to the centre with a new diagnosis of locally advanced or metastatic NSCLC should
preferentially be registered at this time in order to allow all the biological evaluations.
Before registration, results of the following assessments, performed at the time of diagnosis must be
available:
Demographics, medical history including diagnosis of lung cancer and prior response therapy
History of smoking habit
Physical examination including ECOG-PS. In the physical examination, particular care should be taken
with the cardiovascular treatment. A careful baseline evaluation should be done in such pts and they
can be considered eligible on the basis of an individual risk/benefit assessment by the investigator
with the patient
Existing signs, symptoms and toxicity evaluation
Concomitant medications
Laboratory assessment: white blood cell (WBC) count with granulocyte, lymphocyte and monocyte
counts, platelet count, haemoglobin, calcium, sodium, potassium, albumin, uric acid, glucose, blood
urea nitrogen, creatinine, alkaline phosphatase, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), total bilirubin, lactate dehydrogenase (LDH), gamma-GT, PT, PTT
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Tumour stage (TNM)
Radiology test assessment including: computer tomography (CT) scan of brain, chest and upper
abdomen, bone scan, plain chest X-ray. Other investigation(s) to document all sites of disease.
Written informed consent to allow the biological investigations on blood and tissue and written consent
to the management of personal data.
At the time of registration the blood sample is needed in order to perform pharmacogenomic analyses.
7.1.2. Patients relapsed or progressed after first line treatment
Pts relapsed after adjuvant treatment taxane free may be registered.
Pts progressed after first line platinum based, taxane free may be registered too, if this procedure has
not already done at diagnosis of NSCLC. For these category of pts it is important, providing that they are
eligible, to promptly send tissue and blood samples in order to avoid any delay in the detection of EGFR
19-21 mutations.
At the time of registration the blood sample is needed in order to perform pharmacogenomic analyses
REGISTRATION ASSESSMENTS
Procedure and Investigation Timing
History and Physical exam ECOG-PS, existing sign and symptoms, tumor stage (TNM) Within 14 days prior to
registration Diagnosis Pathological diagnosis of NSCLC
Smoking habit Number of cigarettes/day, duration of smoke
Haematology and
Biochemistry
White blood cell (WBC) count with granulocyte,
lymphocyte and monocyte counts, platelets count,
haemoglobin, calcium, sodium, potassium, albumin, uric
acid, glucose, blood urea nitrogen, creatinine, alkaline
phosphatase, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), total bilirubin, lactate
dehydrogenase (LDH), gamma-GT, PT, PTT
Within 21 days prior to
registration
Biomarker samples Biopsy and blood samples
Radiology CT scan of brain, chest and upper abdomen, bone scan,
plain chest X-ray. Other investigation(s) to document all
sites of disease
Informed consent for
biopsy and blood samples
Before any registration
procedure
7.2. Before randomization
Pts in which
- EGFR 19-21 mutations have been demonstrated will be treated with erlotinib
- EGFR 19-21 mutations have not been demonstrated can be randomized
All pts, irrespectively from their EGFR mutation status, will be monitored in the same way, according to
sections 7.3, 7.4 and 7.5.
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An eligibility screening form documenting the patient fulfilment of the eligibility criteria is to be completed
by the investigator before randomization.
Furthermore, before randomization, results of the following assessments, performed within a time
window of two or three weeks, must be available:
Demographics, medical history including diagnosis of lung cancer and prior response therapy
Physical examination including weight, height, calculated BSA, ECOG-PS, vital signs (body
temperature, blood pressure and pulse). In the physical examination, particular care should be taken
with the cardiovascular treatment. A careful baseline evaluation should be done in such patients and
they can be considered eligible on the basis of an individual risk/benefit assessment by the
investigator with the patient
Existing signs, symptoms and toxicity evaluation
History of smoking habit
Concomitant medications
Laboratory assessment: WBC count with granulocyte, lymphocyte and monocyte counts, platelet
count, hemoglobin, calcium, sodium, potassium, albumin, uric acid, glucose, blood urea nitrogen,
creatinine, alkaline phosphatase, AST, ALT, total bilirubin, LDH, gamma-GT and PT, PTT and CEA.
Additional laboratory tests should be performed as clinically indicated. Unexpected or abnormal results
must be reported in the CRF and should be explained by clinical assessment and investigation
Clinical tumour measurement (see section 9)
Radiology test assessment including : CT scan of brain, chest and upper abdomen, bone scan, plain
chest X-ray. Other investigation(s) to document all sites of disease. Baseline and subsequent
examinations must be performed using identical techniques
QoL assessment by EORTC QLQ-C30 and EORTC QLQ�LC13
Written informed consent must be obtained prior the patient undergoing any study specific procedures
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AT RANDOMIZATION
Procedure and Investigation Timing
History and Physical
exam*
Height, weight, BSA, ECOG-PS, body temperature, blood
pressure, pulse, existing sign and symptoms, concomitant
medications, medical history, response to prior therapy, clinical
tumour measurement
Within 14 days prior to
randomization.
Hematology* Hemoglobin, WBC, granulocyte lymphocyte and monocyte
counts, platelet count
Biochemistry* Serum bilirubin, alkaline phosphatase, AST, ALT, serum
creatinine, sodium, potassium, LDH, calcium, albumin, uric
acid, glucose, urea nitrogen, gamma GT, calculated PT, PTT,
CEA
Radiology* CT scan of brain, chest and upper abdomen, bone scan, plain
chest X-ray. Other investigation(s) to document all sites of
disease
Baseline and subsequent examinations must be performed
using identical techniques.
Within 21 days prior to
randomization.
To be performed only if
registration was made
more than 30 days
before.
Other Pregnancy test
Electrocardiogram (ECG)
Within 14 days prior to
randomization
Biomarker sample Status of EGFR and K-ras mutations Before start therapy
Toxicity Baseline evaluation (to document symptoms on entering study) Within 14 days prior to
randomization
Quality of Life EORTC QLQ - C 30 and EORTC QLQ � LC 13 Within 7 days prior to
randomization
Informed consent
signature
Before any study
procedure
*To be performed only if registration was made more than 30 days before
7.3. During second line treatment
7.3.1. Pts with 19-21 EGFR mutations
Pts with EGFR mutations will be treated with ERL and prospectively followed-up according to what
planned for randomized pts, as described in section 7.3.2.
7.3.2. Erlotinib arm
For baseline (BL) visit see section 7.2.
In this arm the dose of ERL is 150 mg daily, until disease progression.
Written informed consent must be obtained prior the patient undergoing any study specific procedures.
Before each cycles, every 28 days, is necessary to perform:
medical history and prior response therapy
Physical examination including weight, height, calculated BSA, ECOG-PS, vital signs (blood pressure
and pulse). In the physical examination, particular care should be taken with the cardiovascular
treatment
Existing signs, symptoms and toxicity evaluation
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Concomitant medications
Chemistry assessment within 4 days prior to each cycle: calcium, sodium, potassium, albumin, uric
acid, glucose, blood urea nitrogen, creatinine, alkaline phosphatase, AST, ALT, total bilirubin, LDH,
gamma-GT and CEA
For haematology weekly within 4 days prior to each cycle: WBC count with granulocyte, lymphocyte
and monocyte counts, platelet count, haemoglobin
Additional laboratory tests should be performed as clinically indicated. Unexpected or abnormal results
must be reported in the CRF and should be explained by clinical assessment and investigation
QoL assessment by EORTC QLQ-C30 and EORTC QLQ�LC13 must be administered prior to each cycle
After every 2 cycles is necessary a radiological and clinical revaluation:
Clinical tumour measurement (see section 9)
Radiology test assessment including: CT scan of brain, chest and upper abdomen, plain chest X-ray
(bone scan to discretion of investigator). Other investigation(s) to document all sites of disease and
examinations must be performed using identical baseline techniques
It is suggested a ECG control before radiology tumour assessment.
The schedule of events described in the table below should be followed.
ASSESSMENTS DURING SECOND LINE TREATMENT � ERLOTINIB ARM
BL During Therapy
Cycle/Visit 0 1 2 3 4 5- etc.
Day in a cycle 1 → → 28 1 → → 28 1 → → 28 1 → → 28 1 → → 28
Informed consent X
Physical exam X X X X X X
Medical history X X X X X
Response to prior therapy X
ECG X X X
Blood pressure and pulse X X X X X
BSA X X X X X
Concomitant medications X X X X X
ECOG-PS X X X X X
QLQ�C30,QLQ-LC13 X X X X X
Tumor assessment (palpable) X X X X X
Radiology tests X X X
Chemistry X X X X X
Hematology X X X X X
NCI-CTCAE grading X X X X X
CRF X X X X X X
ERL therapy X X X X X X X X X X X X X X X X X X X X
Tissue sample X
Blood samples X
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7.3.3. 3-weekly docetaxel
For BL visit see section 7.2.
In this arm docetaxel schedule is 75 mg/m2 iv on day 1 every 21 days, until disease progression or
unacceptable toxicity developed.
Written informed consent must be obtained prior the patient undergoing any study specific procedures.
Before each cycles is necessary to perform this control:
medical history and prior response therapy
Physical examination including weight, height, calculated BSA, ECOG-PS, vital signs (blood pressure
and pulse). In the physical examination, particular care should be taken with the cardiovascular
treatment
Existing signs, symptoms and toxicity evaluation
Concomitant medications
Chemistry assessment within 4 days prior to each cycle: calcium, sodium, potassium, albumin, uric
acid, glucose, blood urea nitrogen, creatinine, alkaline phosphatase, AST, ALT, total bilirubin, LDH,
gamma-GT and CEA
For haematology within 3 days prior to each infusion: WBC count with granulocyte, lymphocyte and
monocyte counts, platelet count, hemoglobin. It is strongly suggested to control WBC value weekly
Additional laboratory tests should be performed as clinically indicated. Unexpected or abnormal results
must be reported in the CRF and should be explained by clinical assessment and investigation
QoL assessment by EORTC QLQ-C 30 and EORTC QLQ�LC13 must be administered prior to each cycle
After every 3 cycles is necessary a radiological and clinical revaluation:
Clinical tumour measurement (see section 9)
Radiology test assessment including: CT scan of brain, chest and upper abdomen, plain chest X-ray
(bone scan to discretion of investigator). Other investigation(s) to document all sites of disease and
examinations must be performed using identical baseline techniques
It is suggested an ECG control before radiology tumour assessment
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ASSESSMENTS DURING SECOND LINE TREATMENT � 3-WEEKLY DOCETAXEL ARM
BL During Therapy
Cycle/Visit 0 1 2 3 4 5 6-etc.
Day in a Cycle 1 8 15 1 8 15 1 8 15 1 8 15 1 8 15 1 8 1
5
Inform Informed consent X
Physical examination X X X X X X X
Medical history X X X X X X
Response to prior therapy X
ECG X X X
Blood pressure and pulse X X X X X X
BSA X X X X X X
Concomitant medication X X X X X X
ECOG-PS X X X X X X
QLQ�C30, QLQ-LC13 X X X X X X
Tumor assessment
(palpable)
X X X X X X
Radiology test tumor X X X
Chemistry X X X X X X
Hematology X X X X X X X X X X X X X X X X X X
NCI-CTCAE grading X X X X X X
CRF X X X X X X X
DOC therapy X X X X X X
Tissue sample X
Blood samples X
7.3.4. Weekly docetaxel
In this arm docetaxel schedule is 35 mg/m2 iv on day 1, 8 and 15 every 28 days, until disease
progression or unacceptable toxicity developed. Written informed consent must be obtained prior the
patient undergoing any study specific procedures.
Before each cycles is necessary to perform this control:
medical history and prior response therapy
Physical examination including weight, height, calculated BSA, ECOG-PS, vital signs (blood pressure
and pulse). In the physical examination, particular care should be taken with the cardiovascular
treatment
Existing signs, symptoms and toxicity evaluation
Concomitant medications
Chemistry assessment within 4 days prior to each cycle: calcium, sodium, potassium, albumin, uric
acid, glucose, blood urea nitrogen, creatinine, alkaline phosphatase, AST, ALT, total bilirubin, LDH,
gamma-GT and CEA
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For hematology weekly within 3 days prior to each infusion: WBC count with granulocyte, lymphocyte
and monocyte counts, platelet count, hemoglobin. It is suggested to control WBC value weekly
Additional laboratory tests should be performed as clinically indicated. Unexpected or abnormal results
must be reported in the CRF and should be explained by clinical assessment and investigation
QoL assessment by EORTC QLQ-C30 and EORTC QLQ�LC 13 must be administered prior to each cycle
Complete additional measurements weekly
After every 2 cycles is necessary a radiological and clinical revaluation:
Clinical tumour measurement (see section 9)
Radiology test assessment including: CT scan of brain, chest and upper abdomen, plain chest X-ray
(bone scan to discretion of investigator). Other investigation(s) to document all sites of disease and
examinations must be performed using identical baseline techniques. It is suggested an ECG control
before radiology tumour assessment
ASSESSMENTS DURING SECOND LINE TREATMENT � WEEKLY DOCETAXEL ARM
BL During Therapy
Cycle/Visit 0 1 2 3 4-etc.
Day in a Cycle 1 8 15 21 1 8 15 21 1 8 15 21 1 8 15 21
Informed consent X
Physical exam X X X X X
Medical history X X X X
Response to prior therapy X
ECG X X X
Blood pressure and pulse X X X X
BSA X X X X
Concomitant medication X X X X
ECOG-PS X X X X
QLQ�C30, QLQ-LC13 X X X X X
Tumor assess (palpable) X X X X X
Radiology tests X X X
Chemistry X X X X
Hematology X X X X X X X X X X X X X X X X
NCI-CTCAE grading X X X X
CRF X X X X
DOC therapy X X X X X X X X X X X X
Tissue sample X
Blood samples X
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7.4. During third line treatment
After progression to the second line therapy, both pts with 19-21 EGFR mutations, included in the
randomized part of the study, and those with 19-21 EGFR mutations, treated with ERL, if judged by the
investigator, may receive a third line therapy.
Pts treated with a platinum-based first line chemotherapy with VNB or GEM will receive a standardized
third line therapy with PEM, 500 mg/m2 on day 1 every 21 days supplemented by folic acid and vitamin
B12, while pts treated with a platinum-based first line chemotherapy with PEM will receive either GEM
(1000 mg/m2 days 1, 8, 15 every 28 days)
or VNB (30 mg/m
2 days 1, 8, 15 every 28 days) until disease
progression or unacceptable toxicity developed.
Before each cycles is necessary to perform this control:
medical history and prior response therapy
physical examination including weight, height, calculated BSA, ECOG-PS, vital signs (blood pressure
and pulse). In the physical examination, particular care should be taken with the cardiovascular
treatment
existing signs, symptoms and toxicity evaluation
concomitant medications
chemistry assessment within 4 days prior to each cycle: calcium, sodium, potassium, albumin, uric
acid, glucose, blood urea nitrogen, creatinine, alkaline phosphatase, AST, ALT, total bilirubin, LDH,
gamma-GT and CEA
for hematology within 3 days prior to each infusion: WBC count with granulocyte, lymphocyte and
monocyte counts, platelet count, hemoglobin. It is strongly suggested to control WBC value weekly.
additional laboratory tests should be performed as clinically indicated. Unexpected or abnormal results
must be reported in the CRF and should be explained by clinical assessment and investigation.
QoL assessment by EORTC QLQ-C30 and EORTC QLQ�LC13 must be administered prior to each cycle
Complete additional measurements weekly
After every 3 cycles is necessary a radiological and clinical revaluation:
Clinical tumour measurement (see section 9)
Radiology test assessment including: CT scan of brain, chest and upper abdomen, plain chest X-ray
(bone scan to discretion of investigator). Other investigation(s) to document all sites of disease and
examinations must be performed using identical baseline techniques
It is suggested a ECG control before radiology tumour assessment
Vitaminic supplementation (only for PEM): folic acid po daily beginning approximately 1-2 weeks prior
to first dose of PEM and continuing daily until 3 weeks after the last dose of PEM or vitamin B12 given
as an intramuscular injection approximately 1 to 2 weeks prior to first dose of PEM and repeated
approximately every 9 weeks until 3 weeks after the last dose of PEM.
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ASSESSMENTS DURING PEMETREXED THIRD LINE TREATMENT
BL During Therapy
Cycle/Visit 0 1 2 3 4 5 6-etc.
Day in a Cycle 1 8 15 1 8 15 1 8 15 1 8 15 1 8 15 1 8 15
Physical exam X X X X X X X
Medical history X X X X X X
Response to prior therapy X
ECG X X X
Blood pressure, pulse X X X X X X
BSA X X X X X X
Concomitant medication X X X X X X
ECOG-PS X X X X X X
QLQ�C30, QLC-LC 13 X X X X X X
Tumor assessment (palpable) X X X X X X
Radiology tests X X X
Chemistry X X X X X X
Hematology X X X X X X X X X X X X X X X X X X X
NCI-CTCAE grading X X X X X X
CRF X X X X X X X
Folic acid X X X X X X X X X X X X X X X X X X X
Vitamin B12 X X X
PEM therapy X X X X X X
ASSESSMENTS DURING VINORELBINE OR GEMCITABINE THIRD LINE TREATMENT
BL During Therapy
Cycle/Visit 0 1 2 3 4 5
Day in a Cycle 1 8 15 21 1 8 15 21 1 8 15 21 1 8 15 21 1 8 15 21
Physical exam X X X X X X
Medical history X X X X X
Response to prior therapy X
ECG X X
Blood pressure, pulse X X X X X
BSA X X X X X
Concomitant medication X X X X X
ECOG-PS X X X X X
QLQ�C30, QLC-LC 13 X X X X X
Tumor assessment
(palpable)
X X X X X
Radiology tests X X
Chemistry X X X X X
Hematology X X X X X X X X X X X X X X X X
NCI-CTCAE grading X X X X X
CRF X X X X X X
VNB or GEM therapy X X X X X X X X X X X X X X X
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7.5. During follow-up
The patient that enter in follow-up are:
- those not suitable of third line after therapy with ERL or DOC
- pts that finished third line chemotherapy.
After each patient discontinues study therapy, the investigator should make every effort to continue to
evaluate the patient for delayed toxicity by clinical and laboratory evaluations as clinically indicated.
Every attempt should be made to obtain haematology and chemistry approximately 30 days after the last
dose of DOC or ERL or PEM or VNB or GEM. The pts must be followed approximately every 30 days until
toxicity resolves.
To obtain data on tumour responses, assessments of disease status will be made at regular intervals
throughout study therapy and until the patient is live. The timing of the assessment in post-therapy
follow-up will therefore be approximately every 3 months. Assessments will consist of clinical evaluation
(physical exam, medical history, blood pressure, pulse, BSA, PS, evaluation of toxicity), a plain x-ray and
CT same method used during study therapy to quantitatively assess tumor, chemistry, haematology, and
ECG.
After progression until death is necessary only clinical evaluation (physical exam, medical history, blood
pressure, pulse, BSA, PS, evaluation of toxicity).
During this post-therapy follow-up, information will be collected regarding date of disease progression or
death, and any additional supportive therapy or radiotherapy. Each patient�s assessments will continue
until death .
The QLQ�C30 and QLQ�LC13 should be completed at the time the patient discontinues from study
therapy. They should also be completed at any revaluation: every 3 months.
ASSESSMENTS DURING FOLLOW-UP
Months after last dose of drug 3 6 9 12 15 18-etc
Physical examination X X X X X X
Medical history X X X X X X
ECG X X X X X X
Blood pressure, pulse X X X X X X
BSA X X X X X X
Concomitant medication X X X X X X
ECOG-PS X X X X X X
QLQ�C 30, QLQ-LC13 X X X X X X
Tumor assessment (palpable) X X X X X X
Radiology tests X X X X X X
Chemistry X X X X X X
Hematology X X X X X X
NCI-CTCAE grading X X X X X X
CRF X X X X X X
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8. BIOLOGICAL EVALUATION
8.1. Specimen handling
8.1.1. Patients entering the study at diagnosis
Paraffin blocks and stained slides
Once the diagnosis of NSCLC of the lung is made, the physician in charge of the contributing centre
contacts the pathologist in order to organize the specimen submission. In particular, the samples
(paraffin block and stained slide) should be sealed within a proper container to avoid damages. They
should be sent along with the clinical report and a copy of the original diagnosis.
Collection is scheduled through TNT courier every two weeks. Whenever possible each centre should
select the time and the day of the week most appropriate for the picking up. This date is then generally
kept fixed unless special needs are required by the centre. In this case the person in charge for the
centre should contact the Istituto di Ricerche Farmacologiche �Mario Negri� (Massimo Broggini
[email protected] , or Marabese Mirko, [email protected] ) who will notify the
courier of the requested changes.
TNT courier will pick up the material directly at the centre and will deliver it to the Pathology Department
of Fatebenefratelli Hospital in Milan (S.C. di Anatomia e Istologia Patologica, Ospedale Fatebenefratelli e
Oftalmico, Corso di Porta Nuova 23, 20121, Milano; Tel. 02-63632581;
[email protected] ).
Each sample will be reviewed by the referring pathologist in order to confirm the diagnosis as well as to
verify specimen representativity and minimal criteria for enrolment in the study protocol. Diagnostic
confirmation may require additional immunostaining. Additional paraffin sections will be cut from the
paraffin block and sent to the Pathology Department, Niguarda Cà Granda Hospital, Milano, and to the
Mario Negri Pharmacological Institute for further biomolecular determinations. A minimal number of
sections will be retained at Pathology Department of the Fatebenefratelli Hospital which will act as the
central archive for the study.
Blood samples
Heparinized blood (3-5 ml) collected in plastic tubes must be stored at -20°c at each centre facility.
Blood collection from the TNT courier is scheduled every two-three months.
Each participating centre should notify the collection centre (Massimo Broggini
[email protected] , or Marabese Mirko, [email protected] ) if they do not have
the possibility to pack the samples with dry ice for the shipment. In this case a special delivery system
will be activated.
Blood samples will be delivered to the Laboratory of Molecular Pharmacology of the Istituto di Ricerche
Farmacologiche �Mario Negri�, Milan where DNA will be extracted from each sample.
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8.1.2. Patients entering the study at relapse
It is expected that in a limited number of cases a quick determination of the mutational status of EGFR is
needed to proceed with the treatment stratification. These cases will therefore follow a fast track
procedure.
Paraffin blocks and stained slides
The physician in charge of the contributing centre should contact immediately the coordinating people at
the Istituto di Ricerche Farmacologiche �Mario Negri� (Massimo Broggini
[email protected] , or Marabese Mirko, [email protected] ) who will organise a
quick delivery of the specimen from the participating centre to the Pathology Department of
Fatebenefratelli Hospital in Milan (S.C. di Anatomia e Istologia Patologica, Ospedale Fatebenefratelli e
Oftalmico, C.so di Porta Nuova 23 20121, Milano; tel. 0263632581; [email protected] ).
Each sample will be managed as for the procedures reported in section 8.1. Mutational status of the EGFR
will be determined in a short time to allow a quick determination of the treatment modalities necessary
for the patient.
Blood samples
Since analysis of mutations and polymorphisms in blood do not determine treatment modalities, this
material is treated exactly in the same way as reported in section 8.1.
FLOW CHART FOR THE BIOLOGICAL DETERMINATIONS
PATIENTS ENTERING THE STUDY AT DIAGNOSIS
Paraffin block/stainedslides
Stored at room temperature
Heparinized bloodStored at -20°C
Every two weeksE-mail message
to the Collection centrewhich organisesthe picking up of the material from
the centre.Pas
ticip
atin
gce
ntre
Paraffin block
/stained slides
Heparinizedblood
FbfSections
forbiological
studies
FBF FISH ANALYSIS
OSP NIGUARDADNA EXTRACTIONRAS AND EGFR MUT
molecularpharmacologymario negri institute
DNA EXTRACTIONEGFR MUT
DETECTION IN BLOOD
DNAPOLYMORPHISMS
PATIENTS ENTERING THE STUDY AT DIAGNOSIS
Paraffin block/stainedslides
Stored at room temperature
Heparinized bloodStored at -20°C
Every two weeksE-mail message
to the Collection centrewhich organisesthe picking up of the material from
the centre.Pas
ticip
atin
gce
ntre
Paraffin block
/stained slides
Heparinizedblood
FbfSections
forbiological
studies
FBF FISH ANALYSIS
OSP NIGUARDADNA EXTRACTIONRAS AND EGFR MUT
molecularpharmacologymario negri institute
DNA EXTRACTIONEGFR MUT
DETECTION IN BLOOD
DNAPOLYMORPHISMS
RANDOMISATION
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8.2. Minimal criteria for inclusion in the study
Specimens to be evaluated in the study will consist only of histological and/or cytological tumour
samples.
8.2.1. Histological specimens
- Samples should consist of tissue fragments from the primary tumour, or from any metastatic site of
disease, obtained by incisional or excisional biopsies, or by major surgical procedures. Following removal
the tissue should be immediately immersed in 10% buffered formalin, fixed for 12-48 hours at room
temperature, and embedded in paraffin as routine. It is strictly required that the paraffin be melted at
60 °C for 30-60 minutes.
- The paraffin block containing the tumour sample should be submitted with: a) a copy of the original
pathology report, b) a haematoxylin-eosin stained histological slide
- The paraffin block should contain enough tumour tissue as to allow additional cutting of at least 20 new
and representative 4 micron-thick paraffin sections; in particular, the neoplastic area should measure at
least 2mm2
on the tissue section. Tissue necrosis and/or artefacts should not obscure more than 30% of
the sample which should consist of a representative area of the tumour. Paraffin sections can be sent as
a substitute of the paraffin block provided that they fulfil the above requisites. The submitting pathologist
is encouraged to send additional slides with ancillary stains or immunostains that helped reaching the
primary diagnosis; evaluation of these slides by the referring pathologist is of help to reducing the extent
of the paraffin block sectioning of the residual material. These additional slides will be returned
immediately by express courier.
8.2.2. Cytological specimens
- Samples should be taken from the primary tumour and/or from any metastatic site of disease.
PATIENTS ENTERING THE STUDY AFTER RELAPSE
Paraffin block/stainedslides
Heparinized bloodStored at -20°C
Every two weeksE-mail message
to the Colection centre which organisesthe picking up of the material from
the centre.
Pa
stic
ipat
ing
cent
re
Heparinizedblood
FbfSections
for biological
studies
FBF FISH ANALYSIS
OSP NIGUARDADNA EXTRACTIONRAS AND EGFR MUT
molecularpharmacologymario negri institute
DNA EXTRACTIONEGFR MUT
DETECTION IN BLOOD
DNAPOLYMORPHISMS
RANDOMISATION
CONTACT IMMEDIATELYTHE COLLECTION CENTRE FOR
FAST TRACK DELIVERY AND MUTATION ANALYSIS
PATIENTS ENTERING THE STUDY AFTER RELAPSE
Paraffin block/stainedslides
Heparinized bloodStored at -20°C
Every two weeksE-mail message
to the Colection centre which organisesthe picking up of the material from
the centre.
Pa
stic
ipat
ing
cent
re
Heparinizedblood
FbfSections
for biological
studies
FBF FISH ANALYSIS
OSP NIGUARDADNA EXTRACTIONRAS AND EGFR MUT
molecularpharmacologymario negri institute
DNA EXTRACTIONEGFR MUT
DETECTION IN BLOOD
DNAPOLYMORPHISMS
RANDOMISATION
CONTACT IMMEDIATELYTHE COLLECTION CENTRE FOR
FAST TRACK DELIVERY AND MUTATION ANALYSIS
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- The following types of cytological specimens are suitable for the study: a) paraffin cell block sample
prepared from a serosal effusion fixed in 10% buffered formalin for 2-24 hours; b) paraffin cell block
sample prepared from needle rinsing following multiple passes by fine-needle (22 G) aspiration biopsy
and fixed in 10% buffered formalin for 2-24 hours; c) paraffin block of a solid core obtained by a 20 G
and 19 G cutting needle fixed in 10% buffered formalin for 2-24 hours. It is strictly required that the
paraffin be melted at 60 °C for 30-60 minutes. Other cytological preparations such as smears cannot
be considered for evaluation in the study.
- The paraffin cell block containing the tumour sample should be submitted with: a) a copy of the original
pathology report, b) a haematoxylin-eosin stained histological slide
- The paraffin cell block should contain enough tumour cellular component to allow additional cutting of at
least 20 new and representative 4 micron-thick paraffin sections. Tissue necrosis and/or artefacts should
not obscure more than 30% of the sample. Paraffin sections cannot be sent as a substitute of the paraffin
block. The submitting pathologist is encouraged to send additional slides with ancillary stains or
immunostains that helped reaching the primary diagnosis; evaluation of these slides by the referring
pathologist is of help to reduce the extent of the paraffin block sectioning of the residual material. These
additional slides will be returned immediately by express courier.
8.3. Analysis performed on tissues
8.3.1. Determination of mutational status of EGFR and K-ras genes
Formalin-fixed paraffin embedded tumour samples will be tested for the presence of EGFR exon 18-21
mutations and in the exon 2-4 of K-ras gene. DNA extraction will be performed on histological tumour
specimens, by using standard phenol-chloroform procedure, after macro/microdissection in order to
recovery most of cancer cells and to reduce the contamination by normal ones. DNA preparations will be
verified for their concentration and quality by spectrophotometric measurement.
Genomic DNA will be amplified by polymerase chain reaction (PCR) using high-fidelity Taq polymerase
and specific primers encompassing intronic regions for EGFR exon 18-21 and K-ras exon 2-4. PCR
products will then be analysed electrophoretically on agarose gel and automate bi-directional sequencing
will be performed using Big Dye Terminator chemistry (Applied Biosystems) and a 3130xl Genetic
Analyzer (Applied Biosystems) according to the manufacturer�s instructions. Sequences will then be
automatically compared with wild-type EGFR and K-ras gene profiles by appropriate software analysis
(SeqScape) in order to assess the presence of possible mutations.
Moreover, RFLP PCR for EGFR exon 19 and 21 will be performed on cases turned out negative at
sequencing to further confirm the absence of mutations. In order to define the presence of deletions in
the exon 19 of EGFR gene, an assay based on the difference in length analysis of fluorescently labelled
PCR products will be used, while for exon 21 the Sau96I restriction enzyme will be used to identify the
presence of L858R (T>G) point mutation. In both procedures digested and undigested fluorescently
labelled PCR products will be analysed by capillary electrophoresis.
In a small number of patients for which the material received will not be sufficient to precisely determine
the mutational status, a potentially more sensitive analysis will be applied. For these cases, Scorpion
primers, which are used in PCR for detection of fluorescent products, coupled with Amplified Refractory
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Mutation System (ARMS) will be used in a real time PCR-based method to detect EGFR and K-RAS
mutations. According to the literature this method is highly sensitive since it is supposed to detect
mutations in tumour DNA even if they are very sparse in relation to normal DNA possibly present. The
analysis will be performed using commercially available standardised kits (DxS, Manchester, UK).
Amplification reactions, using high fidelity taq polymerase, will be analysed on a 7900HT Fast real time
PCR system.
Whenever the material will be sufficient to be further processed, mutations in other genes relevant for
the signalling cascade associated with EGFR and K-RAS will be determined. The genomic regions that will
be analysed are: exon 15 of B-RAF gene, exon 20 of HER2 gene, and exons 9 and 20 of PIK3CA gene.
8.3.2. Immunohistochemistry for p-AKT, DDR1, FGFR
Tissue specimens embedded in paraffin are cut into sections of 4-6 ìm, collected on slides and then air-
dried. Sections are rehydrated through an ethanol scale. They are subjected to heat-induced epitope
retrieval procedure by microwaving for 15 minutes in a citrate buffer pH 6.0 then allowed to cool at room
temperature for additional 15 minutes. Incubations with primary specific anti-DDR1, anti-pAKT, anti-
FGFR monoclonal antibody solution, secondary biotinilated antibody and avidin-biotin complex are
performed by using an automated staining system (Benchmark XT, Ventana Medical Systems). Following
counterstaining the slides are examined under a routine light microscope.
8.3.3. Copy number determination of c-MET and FGFR1 genes
DNA extraction will be performed on histological tumour specimens, by using standard phenol-chloroform
procedure, after macro/microdissection in order to recovery most of cancer cells and to reduce the
contamination by normal ones. DNA preparations will be verified for their concentration and quality by
spectrophotometric measurement.
Genomic DNA will be used to determine the copy number and hence amplification of c-MET and FGFR1
genes using TaqMan® Real-Time PCR Assays on a 7900HT Fast real time PCR system. Analysis of the
results obtianed by Real Time PCR and determination of the number of copies of c-MET gene will be
performed using dedicated softwares available with the TaqMan assay.
8.3.4. EML4-ALK translocation
The EML4-ALK fusion protein results from a small inversion within the short arm of chromosome 2 in
which the N-terminal portion of echinoderm microtubule-associated protein-like 4 (EML4) is fused with
the intracellular kinase domain of anaplastic lymphoma kinase (ALK). ALK gene rearrangements will be
investigated by FISH analysis on tissue sections using a break-apart probe to ALK (Vysis) and cases will
be considered positive when tumor cells show a split signal in more than 20% of the cells.
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8.3.5. Analysis performed on blood
Evidence presented in a limited number of samples reported a good correlation between the detection of
EGFR and K-RAS mutations in the tumour tissue and in the circulating DNA extracted from total blood.
This would represent a valid alternative for the detection of mutations in those patients where the tumour
material is not available and, more generally, as a non-invasive method for the detection of genetic
alterations present in the tumour.
The possibility to detect mutations in circulating DNA needs however further confirmation and the present
study addresses this point by evaluating in approximately 300 patients (2035% of total accrual), the
presence of mutations in EGFR and K-RAS.
Analysis of EGFR and k-RAS mutations in circulating DNA will be performed for all the patients for which a
mutation in the tumour sample has been detected and in the same number of mutation-negative
samples.
Sample preparation and processing
DNA is extracted from total heparinized blood using Qiamp Blood kit from Qiagen and eluted in water.
Scorpion primers, which are used in PCR for detection of fluorescent products, coupled with Amplified
Refractory Mutation System (ARMS) will be used in a real time PCR-based method to detect single base
mutations. This method allows the detection of mutations in tumour DNA even if these are present in
small amounts relative to normal DNA. Specific alterations of EGFR and k-RAS will be evaluated. The
analysis will be performed using standardised kits available from dxs, Manchester, UK.
Amplification reactions, using high fidelity taq polymerase, will be analysed on a 7900HT Fast real time
PCR system.
Determination of single nucleotide polymorphism (SNP) in genes potentially relevant for the response to
erlotinib
Changes in a single nucleotide either inside or outside the coding region of several genes are known to be
associated to a differential response to treatment with anticancer agents.
These single changes, even if not associated to change in protein structure could lead to a differential
stability of the gene product. The search for SNPs potentially associated to ERL response is an attractive
possibility offered by this study along with the analysis of mutations and or amplification of EGFR and K-
ras genes.
The genes selected for this biological analysis are the EGF gene, the cyclin D gene, in the p53 degrading
gene mdm2, and in the DNA repair gene XPD. For these four genes genetic variance has been associated
to differential response to treatment in different tumour types. The possibility to analyse in a large
number of patients (as offered by the study) the relation between genetic variance in these genes and
response to ERL is likely to give useful information for the selection of patients to be treated.
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Sample preparation and processing
Genomic DNA will be extracted using commercially available preparative columns (Qiagen, Promega)
from total blood and purified DNA will be checked for purity and quantified by spectrophotometer
analysis. Analysis of polymorphisms will be performed using TaqMan SNP Genotyping assays. For each
analysis 10 ng of genomic DNA will be amplified using the TaqMan Universal PCR Master Mix
supplemented with the TaqMan SNP Genotyping assay of interest.
Genotyping will be conducted using the ABI PRISM 7900HT sequence detection
system (Applied
Biosystems) according to the manufacturer's protocol.
SNPs present in the Cyclin D gene (A870G), in the EGF gene (A61G), in XPD (312), in mdm2 (309) and
in K-RAS gene (3377) will be investigated.
The results obtained will be evaluated either as independent factors or as variables linked to the assays
performed in the tumoral tissue.
9. ASSESSMENT OF RESPONSE
Objective response will be categorized according to RECIST criteria�for a quick reference see
http://ctep.cancer.gov/guidelines/recist.html.
Objective response will be recorded both for first-line and second-line treatment.
Radiological examinations performed to assess and describe progression during or after first-line
treatment can be used as the baseline for the assessment of response to second line treatment. It is
strongly recommended that the interval between the date of radiological examinations and the date of
start of second line treatment is no longer than 6 weeks.
9.1. Definition of measurable and non-measurable
Measurable disease - the presence of at least one measurable lesion. If the measurable disease is
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.
Measurable lesions - lesions that can be accurately measured in at least one dimension with longest
diameter 20 mm using conventional techniques or 10 mm with spiral CT scan.
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm with
conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal disease,
ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic
lesions, and also abdominal masses that are not confirmed and followed by imaging techniques.
Please note that:
all measurements should be taken and recorded in metric notation, using a ruler or calipers;
the same method of assessment and the same technique should be used to characterize each identified
and reported lesion at baseline and during follow-up;
clinical lesions can be considered measurable only when they are superficial (e.g., skin nodules and
palpable lymph nodes).
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9.2. Baseline documentation of �target� and �non-target� lesions
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative
of all involved organs should be identified as target lesions and recorded and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their
suitability for accurate repeated measurements (either by imaging techniques or clinically).
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline
sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumour.
All other lesions (or sites of disease) should be identified as non-target lesions and should also be
recorded at baseline. Measurements of these lesions are not required, but the presence or absence of
each should be noted throughout follow-up.
EVALUATION OF TARGET LESIONS
Defined response as: If there is:
Complete Response (CR): Disappearance of all target lesions
Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the
baseline sum LD
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the
smallest sum LD recorded since the treatment started or the appearance of one or more
new lesions
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD,
taking as reference the smallest sum LD since the treatment started
EVALUATION OF NON TARGET LESIONS
Defined response as: If there is:
CR: Disappearance of all non-target lesions and normalization of tumor marker level
PR: At least a 30% decrease in the sum of the LD of target lesions, taking as reference the
baseline sum LD
NonCR/nonPD: Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker
level above the normal limits
PD: Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions
9.3. Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment until disease
progression/recurrence (taking as reference for PD the smallest measurements recorded since the
treatment started). In general, the patient's best response assignment will depend on the achievement of
both measurement and confirmation criteria.
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EVALUATION OF NON TARGET LESIONS
Target lesions Non-target lesions New lesions Overall response
CR CR No CR
CR Incomplete response/SD No PR
PR Non PD No PR
SD Non PD No SD
PD Any Yes or No PD
Any PD Yes or No PD
Any Any Yes PD
Symptomatic deterioration may occur in some patients. In this situation, disease progression is evident in
the patient�s clinical symptoms, but is not supported by the tumour measurements. Or, the disease
progression is so evident that the investigator may elect not to perform further disease assessments. In
such cases, the determination of clinical progression is based on symptomatic deterioration. These
determinations should be a rare exception as every effort should be made to document the objective
disease progression.
9.4. Confirmation and review of response
Confirmation and review of objective response, to avoid overestimating the observed response rate, are
not required in this study, because response rate is only a secondary end-point.
9.5. Reporting of results
All pts included in the study must be assessed for response to treatment, even if they are ineligible. Each
patient will be assigned one of the following categories: 1) CR, 2) PR, 3) SD, 4) PD, 5) early death from
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 8) unknown
(not assessable, insufficient data).
All pts will be included in the analysis of the response rate. Pts in response categories 3-8 will be
considered as failing to respond to treatment.
10. QOL ASSESSMENT
The EORTC QLQ-C30 [21], version 3.0, includes 30 questions, 28 with 4-category response, and 2 with
a 7-point scale for response. This questionnaire explores 5 multi-item functional subscales: physical, role,
emotional, social and cognitive functioning; three multi-item symptom scales: fatigue, pain, and emesis;
a global health status subscale; and six single items: financial impact and symptoms such as dyspnoea,
sleep disturbance, appetite, diarrhoea, and constipation.
The EORTC QLQ-LC13 [22] includes 12 questions with 4-category response exploring symptoms induced
by lung cancer and 1 question regarding the use of analgesics, with a binary response (no/yes) and, if
the latter response is yes, a further question on analgesic efficacy.
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10.1. Operative Procedures
- QoL questionnaires must be compiled by the pts
- QoL questionnaires must be compiled before clinical visit and before receiving treatment
10.2. QoL timing
- at baseline: before any study procedures AND within 2 weeks prior to randomization
- during treatment: before each cycle following the first during second and third line therapy
A cover sheet must be compiled by clinical assistants or physicians for all QoL questionnaires, annotating
eventual reasons for lack of questionnaires or lack of specific responses, or whether assistance was
required.
11. REMOVAL AND REPLACEMENT OF PATIENTS
Pts have the right to withdraw fully or partially from the study at any time and for any reason without
prejudice to his or her future medical care by the physician or at the institution.
Withdrawal of full consent for a study means that the patient does not wish to receive further
investigational treatment and does not wish to or is unable to continue further study participation. Any
patient may withdraw full consent to participate in the study at any time during the study. The
investigator will discuss with the patient the most appropriate way to withdraw to ensure the patient
health. Any patient who withdraws full consent to participate in the study will be removed from further
treatment and/or study observation immediately upon the date of request.
Withdrawal of partial consent means that the patient does not wish to take investigational product any
longer but is still willing to collaborate in providing further data by continuing on study (e.g., participate
in all subsequent study visits or procedures).
Pts may decline to continue receiving investigational product at any time during the study. These pts, as
well as those who have stopped receiving investigational products for other reasons (e.g., investigator
concern) should continue the schedule of study observations.
Reasons for removal from investigational product might include:
voluntary discontinuation by the patient who is at any time free to discontinue their participation in
the study, without prejudice to further treatment
safety reasons (e.g., AEs) as judged by the investigators
severe non-compliance to the protocol as judged by the investigator (unless the patient is benefiting
from protocol therapy)
incorrect enrolment or randomization of the patient (unless the patient is benefiting from protocol
therapy)
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radiological, objective progression of disease. If an investigator believes that a patient has convincing
evidence of �clinical progression� (for example worsening of PS that is clearly cancer related) but,
despite adequate imaging, it is not possible to document objective radiological progression, the
patient should be discussed with the investigators and a decision on discontinuation of study therapy
made on a case-by-case basis
Death
Patient lost to follow-up
An excessive rate of withdrawals can render the study uninterpretable; therefore, unnecessary
withdrawal of pts should be avoided. Should a patient decide to withdraw, all efforts will be made to
complete and report the observations as thoroughly as possible.
The investigator should contact the patient either by telephone or through a personal visit or a
responsible relative must be contacted to determine as completely as possible the reason for the
withdrawal. A complete final evaluation at the time of the patient�s withdrawal should be made with an
explanation of why the patient is withdrawing from the study. If the reason for removal of a patient from
the study is an adverse event, this must be reported as a SAE.
11.1. Replacement of patients
Pts who are removed or withdrawn from study following randomization will not be replaced.
12. REGISTRATION/RANDOMIZATION PROCEDURE
12.1. Registration
Once having received a copy of the site�s written independent ethics committee/institutional review board
(IEC/IRB) approval of the protocol, the coordinating center will provide each investigator of the site with
a personal username and a password.
Before registration eligible pts must provide his/her informed consent to the analysis of biological
markers. A validated system will be used accessible 24 hours a day at this address:
http://crc.marionegri.it/trials/tailor (Remember that the system is case sensitive, therefore username
and password should be entered always in compliance with the first capital/small letters format: e.g.
�ABC� is different from �abc�).
All registered pts will receive a unique patient identification number before any study specific procedures
are performed. This number will be used to identify pts throughout the clinical study and must be used on
all study documentation related to that subject. The patient identification number must remain constant
throughout the entire clinical study; it must not be changed at the time of randomization.
12.2. Randomization
After obtained informed consent to participate, eligible pts can be randomized. At that moment,
information regarding relevant demographic characteristics and stratification factors must be available
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and all randomization web page form should be completely filled in. The same system used for
registration will be used for random assignments of treatment groups.
At the end of the randomization process, the randomization web page can be printed. This document is
the notification form of patient randomization to be archived in the study folder. This printing operation is
important because this is the only opportunity to obtain the random notification form during the
randomization process. If this operation fails or has been omitted, please contact the Coordinating Centre
of the Istituto di Ricerche Farmacologiche �Mario Negri� to obtain a copy of the random notification form.
13. SAFETY DATA COLLECTION, RECORDING AND REPORTING
13.1. Definitions
13.1.1. Adverse event
An AE is defined in the International Conference on Harmonisation (ICH) Guideline for Good Clinical
Practice as � any untoward medical occurrence in a patient or clinical investigation subject administered a
pharmaceutical product and that does not necessarily have a causal relationship with this treatment�
(ICH E6 1.2).
This definition of AE is broadened in this study to include any worsening of a pre-existing medical
condition. Worsening indicates that the pre-existing medical condition has increased in severity,
frequency or duration of the condition or an association with significantly worse outcomes.
The term adverse event also applies to laboratory findings or results of other diagnostic procedures that
are considered to be clinically relevant (eg, that required unscheduled diagnostic procedures or treatment
measures, or result in withdrawal from the study.)
Surgical procedures themselves are not adverse events; they are therapeutic measures for conditions
that require surgery.
The investigator is responsible for reviewing laboratory test results and determining whether an abnormal
value in an individual study patient represents a change from values before the study. In general,
abnormal laboratory findings without clinical significance (based on the investigator�s judgement) should
not be recorded as AEs; however, laboratory value changes requiring therapy or adjustment in prior
therapy are considered AEs.
An adverse drug reaction (ADR) occurring in a clinical study is any untoward medical occurrence in a
patient or clinical investigation subject that is possibly or probably causally related to the administration
of a pharmaceutical product. Such ADRs are a subset of the adverse events defined above.
13.1.2. Serious adverse event
A SAE is defined as an adverse event that:
is fatal
is life threatening
requires in-patient hospitalisation or prolongation of existing hospitalization
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results in persistent or significant disability or incapacity
is a congenital anomaly or birth defect
is any other significant medical hazard
�Life-threatening" means that the patient was at immediate risk of death from event as it occurred. It
does not include an event that, had it occurred in a more serious form, might have been life threatening
(i.e. asymptomatic febrile neutropenia).
�Requires in patient hospitalisation or prolongation of existing hospitalisation" should be defined as
hospital admission required for treatment of the adverse event or occurred as a consequence of the
event. Hospital admission for scheduled elective surgery would not be a serious adverse event.
�Important medical events� are those which may not resulted in death or be immediately life-threatening
or result in patient hospitalisation, but may jeopardize patients and may require intervention to prevent
one of the other serious outcomes listed above. Examples of such events are intensive treatment in an
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result
in hospitalisation; development of drug dependency. A second malignancy or drug over dosage or abuse
may be considered serious by this criterion.
All adverse events, which do not meet any of the criteria for serious should be, regarded as non-serious
adverse events.
Events NOT considered to be SAEs are hospitalizations for:
- routine treatment or monitoring of the studied indication, not associated with any deterioration in
condition
- treatment, which was elective or pre-planned, for a pre-existing condition that did not worsen
- admission to a hospital or other institution for general care, not associated with any deterioration in
condition
- treatment on emergency, outpatient basis for an event not fulfilling any of the definitions of serious
given above and not resulting in hospital admission.
REMARK:
1) In this study death due to progression of disease will NOT be considered as an SAE and must therefore
NOT be reported as SAE.
2) Progression of a patient's underlying condition leading to one of the above should not be reported as a
serious adverse event.
Deaths occurring between the randomization and 30 days following the last infusion must be reported to
the Sponsor within 24 hours, as a SAE, regardless of the relation to study drug(s). Deaths occurring
during the study follow-up period (i.e. later than 30 days after the last infusion) need only to be reported
as serious adverse event if it is thought that there is a possible relation to the study drug(s) (possible,
probable). All deaths should be reported on the death report form section of the CRF regardless of cause.
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is any suspected adverse reactions related to
an investigational medicinal product (IMP) that are both unexpected and serious.
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13.2. Reporting of procedures for all adverse events
The investigator is responsible for ensuring that all AEs (as defined in section 13.1 and as further
specified below) observed by the investigator or reported by patients are collected and recorded in the
appropriate section of CRF. These AEs will include the following:
All SAEs (as defined in section 13.1.2) that occur after the patient has signed the informed consent
form
All non SAEs (as defined in section 13.1.1) that occur after randomization to investigational drugs.
The following AE attributes must be assigned by the investigator: adverse event diagnosis or
syndrome(s) (if known, signs or symptoms if not known); event description (with detail appropriate to
the event); dates of onset and resolution; severity; assessment of relatedness to investigational drugs;
and action taken. The investigator may be asked to provide follow-up information, discharge summaries,
and extracts from medical records or CRFs.
The assessment of causality is made by the investigator using the following definitions:
Relationship Description
Unrelated There is no evidence of any causal relationship
Unlikely There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within
a reasonable time after administration of the trial medication). There is another reasonable
explanation for the event (e.g. the patient�s clinical condition, other concomitant treatments).
Possible There is some evidence to suggest a causal relationship (e.g. because the event occurs within a
reasonable time after administration of the trial medication). However, the influence of other
factors may have contributed to the event (e.g. the patient�s clinical condition, other concomitant
treatments).
Probable There is evidence to suggest a causal relationship and the influence of other factors is unlikely.
Definitely There is clear evidence to suggest a causal relationship and other possible contributing factors can
be ruled out.
Not assessable There is insufficient or incomplete evidence to make a clinical judgement of the causal relationship.
NCI-CTCAE version 3.0 will be used to grade AEs.
Medically significant AEs considered related to the investigational drugs by the investigator or the sponsor
will be followed until resolved or considered stable.
It will be left to the investigator�s clinical judgement to determine whether an AE is related and of
sufficient severity to require the patient�s removal from treatment or from the study. A patient may also
voluntary withdraw from treatment due to what he or she perceives as an intolerable AE. If either of
these situations arises, the patient should be strongly encouraged to undergo an end-of-study
assessment and be under medical supervision until symptoms cease or the condition becomes stable.
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13.3. Serious adverse event reporting procedures
SAEs must be collected and recorded at least throughout the study period, beginning with the date of
registration through 30 days after the end of the treatment phase.
All SAEs occurring after the patient has been registered must be reported to the Coordinating center
within 1 working day of discovery or notification of the event. Initial SAE information and all amendments
or additions must be recorded on a SAE report form on e-CRF. Please fax or e-mail the report to:
Marlen Llerena
Laboratory of Clinical Trials
Istituto di Ricerche Farmacologiche �Mario Negri�
Phone: +39 02 39014638
Fax: +39 02 33200231
e-mail: [email protected]
SAEs occurring after conclusion of the study AND thought to be possibly related to investigation drugs will
be collected and reported within 1 working day of discovery or notification of the event.
Determination of expectedness will be based on the investigator� brochure for investigational drugs. It
should be recognized that SAEs and SADRs which have not been previously documented in the
Investigators� Brochure, or which occur in a more severe form than anticipated (i.e. they are
�unexpected�), are subject to rapid reporting to the Regulatory Authorities by the sponsor/promoter. This
also applies to reports from spontaneous sources and from any type of clinical or epidemiological
investigation, independent of design or purpose. The source of the report (investigation, spontaneous,
other) should always be specified.
If a patient is permanently withdrawn from the study because of a SAE, this information must be included
in the initial or follow-up SAE report form as well as the end of study CRF.
The sponsor will send the report to national authorities, Ethics Committees and investigators as
appropriate, according to local regulations.
To enable the Safety Desk/sponsor to comply with regulatory reporting requirements, completed
documentation of any reported serious adverse events or serious adverse drug reactions must be
returned within 10 calendar days of the initial report. If the completed form is not received within this
deadline, the safety desk will make a written request to the investigator.
Any question concerning SAE or SADR reporting can be directed to the Safety Desk.
14. STATISTICAL CONSIDERATIONS
14.1. Definition of endpoints
14.1.1. Efficacy/activity
OS is defined as the time from the date of randomization to the date of death from any cause.
Subjects who were not reported as having died at the time of the analysis will be censored at the date
they were last known to be alive.
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PFS is defined as the time from the date of randomization up to the date of first progression, second
primary malignancy or death from any cause, whichever comes first. Subjects who have not
progressed or died at the time of the analysis will be censored at the last disease assessment date
RR is defined as the proportion of randomized patients who will experience a complete or partial best
response according to RECIST criteria. Patients who will never achieve a CR or PR will be defined as
non-responders
QoL, assessed through EORTC QLQ-C30 and EORTC QLQ-LC13
14.1.2. Safety
Toxicity, graded according to the NCI-CTAE version 3.0
Frequency and nature of serious adverse reactions (SADRs)
Premature withdrawals
14.2. Sample size
According to the results of previous trials [10, 16-17], it is reasonable to hypothesize that DOC may
reduce mortality by 33% (HR 0.67) with respect to ERL. This effect translates in an increased probability
of surviving at 1 year from 20% with ERL to 34% with DOC. In order to detect with a 80% power such
an effect at the significance level of 5%, two-sided, 199 events must be observed overall.
Based on these assumptions, with a uniform accrual of 48 months, a minimum follow-up for each patient
of 12 months, a 5% lost to f-up pts, the total number of required pts is approximately 220.
As for PFS a difference of the same magnitude can be anticipated. Therefore, also for this secondary
endpoint, a comparison analysis between ERL and DOC will be performed at the occurrence of 199
events.
14.3. Efficacy analyses
Efficacy analysis will be performed on an intention to treat basis, therefore all randomized pts without
major protocol violations will be included in the analysis according to the randomization arm. Major
violations in the eligibility criteria and study conduction will be evaluated on a case by case basis in a
pre-analysis meeting in order to define the population to be analysed. CONSORT rules will be applied to
describe study flow and protocol deviations.
All time to event curves will be drawn with the Kaplan-Meier method. All comparisons between arms will
be performed by long-rank test. Statistical significance of difference will also be tested by a multivariable
Cox�s model including stratification variables and clinical/biological features as covariates. Results will be
presented as HRs and their 95% CIs.
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14.4. Response rate
Only patients with at least one target lesion will be considered eligible for response assessment.
Behaviour of patients with non target lesions only will be described.
Response rates in the two arms will be described with their 95% CIs and will be compared with chi-
square test in a 2x2 contingency table (responders/non-responders x treatment arms).
14.5. Safety analyses
All safety parameters will be presented and analysed in terms of listings and summary tables. The
analyses, will be conducted on the safety population, including all patients who received at least one
cycle of treatment. Patients will be assigned to treatment groups based on what they actually received.
The assessment of safety will be mainly based on toxicity and the frequency and nature of SADRs.
For each patient and for each type of toxicity, the worst degree ever suffered during second-line
treatment will be used for the analysis.
Two sets of statistical analyses will be performed to compare toxicity between the two arms. In the first
set the whole pattern of toxicity (all grades) will be considered for each item; analysis will be done by a
linear rank test. In the second set toxicity will be defined as severe (mostly including grade 3 or higher)
and not severe (mostly including grades up to 2) and analysis will be performed by Fisher�s exact test. In
both cases exact tests will be applied because it is foreseeable that (although the large sample size)
there will be uncommon toxic effects that will affect a small number of patients.
For each treatment arm, the number and percentage of patients having any SADR, will be presented.
Other information collected (e.g. severity or suspected relationship to study medication) will be listed as
appropriate.
The evaluation of number of cycles given, the modification of dose and reasons for ending the treatment
will be tabulated and described for each treatment arm.
14.6. Quality of life
QoL will be compared between the two arms only during the second line phase of treatment.
EORTC questionnaires will be managed according to standard rules for their analysis reported in the
EORTC manuals and the Guidelines of the Quality of Life Committee of National Cancer Institute of
Canada Cancer Treatment Group [23].
The pattern of missing data will be analyzed under different frames: rate of patients completing baseline
assessments and the assessments at designated time points over the total number of patients eligible
and entered onto the trial, rate of patients completing assessments at designated time points while
enrolled onto the study over the total number completing assessment at baseline, and rate of patients
completing assessments at designated time points over the number of patients still enrolled onto the
study that were expected to complete questionnaires at each of those time points.
Missing values will be described Multi-item scales are computed by calculating the mean raw scores of
single items and transforming them linearly so that all scales range from 0 to 100. For single items, only
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linear transformation is performed. For functioning scales (i.e. those exploring physical, role, emotional,
cognitive and social functioning and global health status), the higher the value the better the level of
function; for symptoms scales and items, the higher the value the worse the severity of symptoms.
Change scores (ie, differences from baseline) will be calculated and described at 3, 6 and 9 weeks for
each domain or symptom and within each arm.
The best response from baseline will be calculated for each domain or symptom as follows. A change
score of at least 10 points from baseline is defined as clinically relevant [23]. For each domain patients
will be considered improved if they will report a score >10 points better than baseline at any time of QoL
assessment. Conversely, patients will be considered worsened if they reported a score <10 points worse
than baseline at any time of QoL assessment without any improvement. Patients whose scores will be in
between 10-point changes from baseline at every QoL assessment will be considered to be stable. An
exact linear rank test will be used to test whether the two study arms will have the same underlying
multinomial distribution of the ordered QoL response. Because of the natural ordering of the response
categories (improved, stable, or worsened), multivariate analysis (including treatment arm and
stratification factors as covariates) will be performed by fitting a continuation ratio logistic regression
model for ordinal outcomes [24].
14.7. Interim analyses
After two years from the beginning of the study, and then on annual basis, interim analyses will be
conducted. In principle, no formal stopping rule will be applied, unless otherwise suggested by the DSMC.
Furthermore, the assumptions of the sample size calculation will be verified and if necessary adequate
sample size will be recalculated.
Safety reports will be drawn on annual basis.
In order to take into account the suggestions of the DSMC:
- an external statistician was asked to reformulate, if deemed necessary, the primary hypothesis of the
study. This led to the changes provided by the second amendment to the study protocol;
- since the decision to change the primary aim of the study was attributable only to evidences external
to the study, and not driven by the interim analysis results, it was not considered necessary to adjust
the overall type I error in order to make allowance for multiple analyses performed.
After the achievement of the required number of pts, the DSMC will be periodically informed on the
study progress in terms of data quality and number of events occurred;
- a statistician in charge of the interim analyses and not involved as a member of the Steering
Committee was identified.
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15. INDEPENDENT DATA & SAFETY MONITORING COMMITTEE
A DSMC will evaluate the results of interim analyses. Two expert clinicians and two statisticians, who are
not involved in the study and have no conflict of interest with respect of study results, will compose the
DSMC.
The role of the DSMC is to look at the data from an ethical standpoint, the safety, rights and well being of
the trial participants being paramount.
Specific tasks of DSMC are:
Evaluation of all the aspects concerning the study progress (i.e.: accrual rate, protocol compliance,
event rate)
Evaluation of treatment toxicity
Evaluation of efficacy data of interim analysis. It will be presented [unblinded] by the study
statistician to the DSMC. The DSMC may also ask for any additional information, if considered
appropriate
Drawing of a report to the Steering Committee summarising recommendations for study prosecution
and possible protocol modification.
16. DATA COLLECTING AND MONITORING
Data will be reported on the e-CRF connecting to: http://crc.marionegri.it/trials/tailor.
A data validation plan will be used in order to check the consistency, completeness and accuracy of the
data entered and data clarification forms (DCFs) will be sent to the investigators. Those DCFs must be
answered by the investigator (or an authorized staff member).
Each participating investigator will be responsible for ensuring data quality. Each reported information will
be systematically checked for consistency, completeness and accuracy by the Coordinating Data Centre
that will issue DCFs in case of inconsistent data.
Local quality control will be provided by coordinating center, which will be responsible of monitoring all
participating centres.
17. ETHICS AND GOOD CLINICAL PRACTICE
The responsible Investigator will ensure that this study is conducted in compliance with the protocol,
following the instructions and procedures described in it, adhering to the principles of Good Clinical
Practice and with current local legislation and in accordance with:
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996
Directive 2001/20/EEC of the European Parliament and of the Council
Declaration of Helsinki concerning medical research in humans (Helsinki 1964, amended Tokyo 1975,
Venice 1983, Hong Kong 1989, Somerset West 1996 and Edinburgh)
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17.1. Patient protection
The names of pts will not be recorded. A sequential identification number will be automatically attributed
to each patient registered in the trials. This number will identify the patient and must be included on all
CRFs.
In order to avoid identification errors, patient initials (maximum of 4 letters) and date of birth will also be
reported on the CRFs. Investigators will guarantee that all persons involved in this study will respect the
confidentiality of any information concerning the trial subject.
All parties involved in this clinical trial will maintain the strict confidentiality to assure that neither the
person nor the family privacy of the patient participating in the trial is violated; appropriate measures
shall be taken to avoid the access of non-authorized persons to the trial data. The processing of the
personal data of patients taking part in the trial, and in particular regarding data concerning consent,
shall comply with local law on the privacy (Legge delega 127/2001) and with the European Directive on
the Privacy of data (95/46/EC).
17.2. Informed consent
The investigator must explain to each patient (or legally authorised representative) the nature of the
study, its purpose, the procedures involved, the expected duration, the potential risks and benefits
involved and any discomfort it may entail. Each patient must be informed that participation in the study
is voluntary and that she/he may withdraw from the study at any time and that withdrawal of consent
will not affect her/his subsequent medical treatment or relationship with treating physician. The informed
consent will be given by means of standard written statement, using non-technical language. The patient
should read and consider the statement before signing and dating it, and should be given a copy of the
signed document. If the subject cannot read or sign the document, oral presentation may be made or
signature given by the subject�s legally appointed representative, if witnessed by a person not involved in
the study, mentioning that the patient could not read or sign documents. No patient can enter the study
before her informed consent has been obtained. The informed consent is part of the protocol and must be
submitted by the investigator to the local ECs.
18. TRIAL SPONSORSHIP AND FINANCING
The study is sponsored by Ospedale Fatebenefratelli Oftalmico, Milano which plays the role of not-for-
profit Sponsor.
The trial is financially supported by the AIFA with a grant for independent clinical researches (grant no.
FARM6F5JER). All study drugs are already included in the Italian national formulary and reimbursed by
the Italian National Health System.
No funds will be provided to ECs in accordance to the D.Lgs 24-06-2003 and DM 17-12-2004
Results derived from the trial are property of the Dipartimento di Oncologia, Ospedale Fatebenefratelli
Oftalmico, Milano which shares it with all participating investigators.
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19. PUBLICATION POLICY
Publications will be decided by the Steering Committee of the study. Other co-authors to be reported in
the front page will be selected on the basis of the specific contribution or the number of enrolled patients
and on the consistency, completeness and accuracy of the data. All papers will report the statement ��
on behalf of the TAILORAIFA Investigators�, as well as those investigators, who mostly contributed to
study recruitment. Furthermore, all manuscripts will include an appropriate acknowledgment section,
mentioning all investigators who have contributed to the trial, as well as supporting bodies.
Rules for abstract presentation will be the same as for extended papers.
20. REFERENCES
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