Michele Milella Istituto Nazionale Tumori Regina Elena 7 maggio 2016/02... · Istituto Nazionale Tumori Regina Elena. 2 • Adjuvant Gem has been evaluated in multiple phase III trials1,2

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• Adjuvant Gem has been evaluated in multiple phase III trials1,2

• Adjuvant 5-FU/leucovorin is equally effective, but more toxic

a Gem was administered for only three 28-day cycles in the JSAP-02 trial vs six 28-day cycles in CONKO-001 and ESPAC-3.b Although they had similar efficacy, Gem had fewer treatment-related serious toxicities (7.5% vs 14%) than 5-FU.5-FU, 5-fluorouracil; DFS, disease-free survival; Gem, gemcitabine; HR, hazard ratio; nab-P, nab-paclitaxel; NCCN, National Comprehensive Cancer Network; Obs, observation; OS, overall survival; PC, pancreatic cancer. 1. Neoptolemos JP, et al. JAMA. 2010;304:1073-1081. 2. Neoptolemos JP, et al. Lancet. 2001;358:1576-1585. 3. Oettle H, et al. JAMA. 2007;297:267-277. 4. Oettle H, et al. JAMA. 2013;310:1473-1481. 5. Ueno H, et al. Br J Cancer. 2009;101:908-915. 6. The National Comprehensive Cancer Network. NCCN Guidelines in Oncology: Pancreatic Adenocarcinoma, v1.2013.

Adjuvant Weekly Gem at 1000 mg/m2 in Phase III Trials3-7

Trial Comparisona Primary Endpoint Median, mo HR P Value

CONKO-001 Gem vs Obs DFS 13.4 vs 6.7 0.55 < 0.001JSAP-02 Gem vs Obs OS 22.3 vs 18.4 0.77 0.19

ESPAC-3 (v2) Gem vs 5-FU/leucovorin OSb 23.6 vs 23.0 0.94 0.39

Available evidence supports adjuvantchemotherapy in operable PDAC

Adjuvant CHT

Available evidence supports adjuvantchemotherapy inoperable PDAC

Andit’s probably your (andpatient’s)bestbetinroutineclinical practice too…

USregistrydata(confidential information)

5nab® is a registered trademark of Celgene Corporation.

ABI-007-PANC-003A Phase III, Multicenter, Open-Label, Randomized Study of nab®-Paclitaxel Plus Gemcitabine Versus Gemcitabine Alone as Adjuvant Therapy in Subjects With Surgically Resected Pancreatic Adenocarcinoma

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ABI-007-PANC-003 (APACT): Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC TreatmentPrimary Objective

• To compare disease-free survival between patients randomized to nab-P + Gem vs Gem alone

Gem, gemcitabine; nab-P, nab-paclitaxel; PC, pancreatic cancer.ClinicalTrials.gov: NCT01964430.

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ABI-007-PANC-003 (APACT): Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC TreatmentSchema

DFS, disease-free survival; EORTC, European Organisation for Research and Treatment of Cancer; Gem, gemcitabine; LN, lymph node; nab-P, nab-paclitaxel; OS, overall survival; PC, pancreatic cancer; QLQ, quality of life questionnaire; qw 3/4, first 3 of 4 weeks. 1. Celgene Data on File. Protocol ABI-007-PANC-003. 2. ClinicalTrials.gov: NCT01964430.

nab-P 125 mg/m2 qw 3/4 + Gem 1000 mg/m2 qw 3/4

× 6 cycles

Gem 1000 mg/m2 qw 3/4× 6 cycles

Confirmed resected PC with macroscopic

complete resection (R0 and R1) and no

evidence of metastases

Planned N ≈ 800

Treatment should begin within 12 weeks of surgery

Randomized 1:1

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ABI-007-PANC-003 (APACT): Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC TreatmentDose Reductions

• Two dose reductions are allowed for toxicities• Patients will be discontinued from the study if further dose reductions

are required

a Dose reductions may or may not be concomitant in the nab-P + Gem arm.Gem, gemcitabine; nab-P, nab-paclitaxel, PC, pancreatic cancer.1. Celgene Data on File. Protocol ABI-007-PANC-003.

Dose Levela nab-P, mg/m2 Gem, mg/m2

Starting dose 125 1000−1 100 800−2 75 600

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ABI-007-PANC-003 (APACT): Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC TreatmentSelect Inclusion Criteria

• Histologically confirmed resected PC with macroscopic complete resection (R0 and R1)

– No neuroendocrine tumors• Stage T1-3, N0-1, M0• Able to begin treatment ≤ 12 weeks after resection• Age ≥ 18 years• ECOG PS 0 or 1• Adequate hematologic and blood chemistry parameters, including

– Absolute neutrophil count ≥ 1500 cells/mm3

– Total bilirubin ≤ ULN (patients with Gilbert syndrome, ≤ 1.5 ×ULN)• CA19-9 < 100 U/mL assessed within 14 days of randomization

CA19-9, carbohydrate antigen 19-9; ECOG PS, Eastern Cooperative Oncology Group performance status; Gem, gemcitabine; nab-P, nab-paclitaxel; PC, pancreatic cancer; ULN, upper limit of normal. 1. Celgene Data on File. Protocol ABI-007-PANC-003. 2. ClinicalTrials.gov: NCT01964430.

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ABI-007-PANC-003 (APACT): Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC TreatmentSelect Exclusion Criteria• Prior neoadjuvant treatment or radiation therapy or systemic therapy

for PC• Presence or history of metastatic PC• Any other malignancy within 5 years of randomization, excluding

adequately treated in situ cervical, uterus, or nonmelanomatous skin cancer

– Treatment should have been completed 6 months before randomization• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring

systemic therapy• Known infection of active Hepatitis B or C• Known history of HIV or use of immuno/myelosuppressive

medications that could increase the risk of neutropenia

Gem, gemcitabine; HIV, human immunodeficiency virus; nab-P, nab-paclitaxel; PC, pancreatic cancer. 1. Celgene Data on File. Protocol ABI-007-PANC-003. 2. ClinicalTrials.gov: NCT01964430.

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ABI-007-PANC-003 (APACT): Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC TreatmentStatistical Design1,2

• Assumption based on 2 previous phase III trials: Gem will result in a median DFS of 14 months1,3,4

• The estimated enrollment of this trial is 800 patients1,2

– If nab-P + Gem results in a median DFS of 19 months, this would represent an HR of 0.74

– At least 489 DFS events from 800 patients would allow 90% power to detect the HR of 0.74 at a 2-sided significance level of 0.05

DFS, disease-free survival; Gem, gemcitabine; HR, hazard ratio; nab-P, nab-paclitaxel; PC, pancreatic cancer. 1. Celgene Data on File. Protocol ABI-007-PANC-003. 2. ClinicalTrials.gov: NCT01964430. 3. Oettle H, et al. JAMA. 2007;297:267-277. 4. Neoptolemos JP, et al. JAMA. 2010;304:1073-1081

Enrollment has been completed inMarch2016

Italy is thetopenroller…

Italian enrollment

Dataanalysis is ongoing…

APACTincontext

• ThegoalsofadjuvanttherapyaretoreducerecurrenceandimproveDFSandOSfollowingsurgeryforresectable PC

• TherearefewongoingphaseIIItrialsofadjuvanttherapyinPC

Trial No. Treatment Estimated Enrollment

NCT01013649 Gem ± radiotherapy with Cape or 5-FU N ≈ 950NCT01526135 Gem vs mFolfirinoxa N ≈ 490

NCT01150630b Neoadjuvant and adjuvant Gem ± Cis, Epi, and Cape vs adjuvant Gem N ≈ 370

Tempero MA, Cardin D, Biankin A, et al. APACT: a phase III, multicenter, open-label, randomized study of nab® -paclitaxel plus gemcitabine vs gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Poster presented at: American Society of Clinical Oncology Annual Meeting; May 30 - Jun 3, 2014; Chicago, IL [abstract TPS4162].

a Modified: oxaliplatin 80 mg/m2, irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-fluourouracil 1200 mg/m2/day (no bolus), q2w × 24 weeks.b Phase II/III.

5-FU, 5-fluourouracil; Cape, capecitabine; Cis, cisplatin; DFS, disease-free survival; Epi, epirubicin; Gem, gemcitabine; nab-P, nab-paclitaxel; OS, overall survival; PC, pancreatic cancer; q2w, every 2 weeks.