Fase I para moléculas sintéticas e biológicas para o tratamento do câncer Gilberto De Nucci http://www.gilbertodenucci.com/faseItratamentodocancer.ppt Departamento de Farmacologia, USP e Unicamp
Fase I para moléculas sintéticas e biológicas para o
tratamento do câncer
Gilberto De Nucci
http://www.gilbertodenucci.com/faseItratamentodocancer.ppt
Departamento de Farmacologia, USP e Unicamp
Objetivos da Fase I
• Farmacocinética
• Tolerabilidade
• Toxicidade (MTD e OBD)
• Escalonamento de dose para Fase II
• Avaliar aspectos Farmacodinâmmicos
A first-in-class, first-in-human, phase I trial of p28, a non-
HDM2-mediated peptide inhibitor of p53 ubiquitination in
patients with advanced solid tumoursM A Warso, J M Richards, D Mehta, K Christov, C Schaeffer, L Rae Bressler, T
Yamada, D Majumdar, S A Kennedy, C W Beattie and T K Das Gupta.
Methods: A total of 15 patients were administered p28 i.v. as a short
infusion three times per week for 4 weeks followed by a 2-week rest
under an accelerated titration 3 + 3 dose escalation design until either a
grade 3-related adverse event occurred or the maximum tolerated dose
(MTD) was reached. Single-dose and steady-state serum
pharmacokinetics were characterized. Assessments included toxicity, best
objective response by RECIST 1.1 Criteria, and overall survival.
British Journal of Cancer (2013) 108, 1061–1070.
A first-in-class, first-in-human, phase I trial of p28, a non-
HDM2-mediated peptide inhibitor of p53 ubiquitination in
patients with advanced solid tumours
The first group of three subjects received the starting dose of 0.83 mg/kg
which was chosen to provide a 12-fold safety margin based on the highest
dose tested in Cynomolgous sp. monkeys and exhibited significant
preclinical efficacy against p53-positive xenograft tumours of similar type
(Jia et al, 2011).
British Journal of Cancer (2013) 108, 1061–1070.
A Phase I Study of an Anti-GD3 Monoclonal Antibody,
KW-2871, in Patients with Metastatic MelanomaAndres Forero, Jatin Shah, Ronda Carlisle, Pierre L. Triozzi, Albert F. LoBuglio, Wen-
Quan Wang, Matt Fujimori, and Robert M. Conry.
This trial was an open-label, single-center, dose-escalation, phase I study
to determine the MTD, safety, immunogenicity, and pharmacokinetic
profile of repeated doses of KW-2871 administered intravenously (i.v.) in
patients with metastatic melanoma. Patients received an initial test dose of
10 mg/m2 of KW-2871 (infused over a 1-hour period). Two weeks after
the test dose, patients were entered into a specified dose cohort and
received 4 doses given at 2-week intervals or until dose-limiting toxicity
(DLT) was encountered.
17 patients enrolled.Cancer Biother Radiopharm (2006) 21:561-568.
A phase I trial of the bombesin/gastrin-releasing peptide
(BN/GRP) antagonist RC3095 in patients with advanced
solid malignanciesG. Schwartsmann, L. P. DiLeone, M. Horowitz, D. Schunemann, A. Cancella, A. S.
Pereira, M. Richter, F. Souza, A. Brondani da Rocha, F. H. Souza, P. Pohlmann,
G. De Nucci.
Purpose: To determine the safety and feasibility of the administration of
RC-3095 by daily subcutaneous injections in patients with advanced and
refractory solid malignancies.
Methods: 25 patients received RC-3095 once or twice-daily at doses
ranging from 8 to 96 ug/kg. Dose was escalated in groups of 3–5 patients
per dose level.
Invest New Drugs (2006) 24:403–412.
A Phase I Trial and Pharmacokinetic Study of a 24-Hour Infusion of Trabectedin (YondelisW, ET-743) in Children
and Adolescents With Relapsed or Refractory Solid TumorsMeredith K. Chuk, Alberta Aikin, Trish Whitcomb, Brigitte C. Widemann,
Peter Zannikos, Eliel Bayever, Frank M. Balis and Elizabeth Fox.
Several doses and schedules have been studied in adults, and therecommended dose and schedule for sarcomas in adults is 1.5 mg/m2infused over 24 hours every 21 days.
Trabectedin (supplied by J&J PRD, LLC) was administered via a centralvenous catheter by continuous infusion over 24 hours every 21 days. Thestarting dose was 1.1 mg/m2 with escalation to 1.5 and 1.7 mg/m2 insubsequent cohorts of three to six patients. For patients enrolled at the 1.1mg/m2 dose level, intrapatient dose-escalation to 1.5 mg/m2 was permittedin subsequent cycles in patients who did not experience dose-limitingtoxicity and had recovered from toxicity by day 21 of the prior cycle.
12 patients enrolledPediatr Blood Cancer 2012;59:865–886.
A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A
Children's Oncology Group Phase I Consortium ReportJulia G. Bender, Susan M. Blaney, Scott Borinstein, Joel M. Reid, Sylvain Baruchel, Charlotte Ahern, Ashish M. Ingle, Darrell J. Yamashiro, Alice Chen, Brenda Weigel,
Peter C. Adamson and Julie R. Park.
The adult recommended phase II dose of aflibercept administered as asingle agent is 4.0 mg/kg intravenously every 2 weeks, based on toxicity,pharmacokinetic (PK) profile, biomarker analysis, and antitumor activity.Proteinuria and rectal ulceration, occurring at 7.0 mg/kg, were the dose-limiting toxicities (DLT) in adults with refractory solid tumors.
Clin Cancer Res 2012;18:5081-5089.
A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A
Children's Oncology Group Phase I Consortium Report
The starting dose was 2.0 mg/kg/dose, the lowest dose at which completeVEGF ligand sequestration could be achieved in adults. Planned dose-escalations were to occur in increments of 1.0 mg/kg/dose. No intrapatientdose-escalation was allowed. A conventional 3 by 3, phase I dose-escalation scheme was used wherein the MTD was exceeded if either 2 of3 or 2 of 6 subjects encountered DLTs. When this occurred at the seconddose level (3.0 mg/kg), the study plan was modified to investigate anintermediate dose of 2.5 mg/kg (Amendment 4).
22 patients enrolled.
Clin Cancer Res 2012;18:5081-5089.
A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report
Purpose: To determine the dose-limiting toxicities (DLT), maximumtolerated dose (MTD), pharmacokinetics, and pharmacodynamics ofsorafenib in children with refractory extracranial solid tumors andevaluate the tolerability of the solid tumor MTD in children withrefractory leukemias.
Clin Cancer Res 2012;18:6011-6022.
A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report
Methods: Sorafenib was supplied 50- and 200-mg tablets by the CancerTherapy Evaluation Program (NCI, Bethesda, MD) and administeredorally, twice daily, continuously for 28- day cycles. The starting dose was150 mg/m 2 /d with planned escalations to 200, 250, and 325 mg/m2/dose.Doses were prescribed using a dosing nomogram with a maximum doseof 600 mg dose, as higher doses were intolerable in adults. Patientsmaintained a diary to document drug intake. A traditional 3 + 3 phase 1dose-escalation scheme was used. Intrapatient dose-escalation was notpermitted.
60 patients treated.
Clin Cancer Res 2012;18:6011-6022.
A dose-escalation phase I trial of nimotuzumab,
an antibody against the epidermal growth factor receptor,
in patients with advanced solid malignancies Benoit You, Anthony Brade, Joao M. Magalhaes, Lillian L. Siu, Amit Oza, Sonya
Lovell, Lisa Wang, David W. Hedley, Leonardo V. Nicacio, Eric X. Chen.
Objective: The primary objective of the trial was to assess the pharma-
codynamic effects of nimotuzumab in tumor and skin tissues. Hence, no
dose escalation above 800 mg was planned. This study did not aim at
determining a recommended dose for phase 2 trial.
Invest New Drugs (2011) 29:996–1003.
A dose-escalation phase I trial of nimotuzumab,
an antibody against the epidermal growth factor receptor,
in patients with advanced solid malignancies
Eligibility: The 17 patients enrolled onto this study had histologically or
cytologically documented solid tumors either refractory to standard
therapy or for which no curative therapy exists.
Administration: Nimotuzumab was administered intravenously every
week over 30 min after administration of 50 mg of diphenhydramine on
an outpatient basis. Each cycle was defined as 6 weeks and treatment was
continued until disease progression, occurance of intolerable toxicity, or
patient’s withdrawal of consent. No routine antiemetic prophylaxis was
mandated.
Invest New Drugs (2011) 29:996–1003.
Invest New Drugs (2011) 29:996–1003.
A phase I trial of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer
Brigitte C. Widemann, AeRang Kim, Elizabeth Fox, Sylvain Baruchel, Peter C. Adamson, Ashish M. Ingle, Julia G. Bender, Michael Burke, Brenda Weigel, Diana
Stempak, Frank M. Balis and Susan M. Blaney.
This was a Phase I, dose escalation trial of imatinib plus mFOLFOX6–bevacizumab across four oncology centres within the Cancer TrialsAustralia consortium (Peter MacCallum Cancer Centre, Austin Health,Royal Mel- bourne and Western Hospitals).Overall 10 patients were accrued, 3 patients in DL1 (400 mg imatinib) and 7in DL2 (600 mg).Dose level 1 comprised of 3 patients who received imatinib 400 mg. Nopatient in DL1 had experienced a DLT, hence DL2 (imatinib 600 mg) wasopened. In total, 7 patients were accrued to DL2, 1 patient had progressivedisease during the induction phase and was therefore replaced.
10 patients enrolled.
Cancer Chemother Pharmacol (2013) 71:321–330.
Avaliação de produtos
oncológicos em voluntários
sadios
• Capecitabine is an adjuvant treatment for colon cancer and for
the treatment of metastatic breast cancer in patients whose
pathology did not improve during treatment with other
therapeutic agents.
• Capecitabine is a prodrug, and it is selectively activated by
tumor cells to its cytotoxic moiety, 5-fluorouracil, by thymidine
phosphorylase, which is generally expressed at high levels in
tumors.
Capecitabine
• Clinical and pharmacokinetics studies for capecitabine are
performed in patients with cancer.
• Standard dosing is 1,250 mg/m2 orally twice daily, morning
and evening, for 14 consecutive days in 3-week cycles.
• For an average healthy male volunteer weight (70 kg) and
height (170 cm) this would mean 2150 mg per dose (4300 mg
per day). Corporal Area = 1,809 m2
Capecitabine
Metabolic activation of capacitabine in humans
Reiner et al, 1998
Adverse effects
• Asthenia/ fatigue
• Diarrhea
• Lymphopenia
• Leukopenia
• Mucositis
• Nausea
• Neutropenia
• Thrombocytopenia
• Vomit
• Hand Foot Syndrome
Committee of Ethics in Research approval the pilot study protocol
Item V- CER evaluation
The Committee of Ethics in Research of the Faculty of Medical Sciences of
UNICAMP, obeying the evaluations of the previously designated members
for the present case and attending all of dispositions of Resolutions
196/96 and complementary, decided to approve without restrictions the
Research Protocol, the informed consent, as well as all the attached files
included in the research proposal.
April 10th, 2010
2nd World Congress on Bioavailability
& Bioequivalence 2011 (BABE 2011)
Presentation of the results of the two pilot studies of
capecitabine on 16 healthy male volunteers
June 6th 2011
August 10th 2011
CONEP had received from the National Agency of Sanitary Vigilance
(ANVISA) a note warning about the approval from the Committee of
Ethics in Research of clinical studies that violated the ethical concepts of
resolution CNS 196/96.
In response, CONEP released a note stating the following:
“Healthy individuals should not enroll on bioequivalence studies of drugs
with high toxic potential (chemotherapeutics); Studies with these agents
should only be performed on patients that may benefit from the studied
drug.”
National Commission on Ethics in Research (CONEP)
- Evaluated the safety of a capecitabine bioequivalence study (150 mg tablet) using 8
healthy male volunteers under fasting and non-fasting conditions.
- The study was initially conducted with an open, randomized, two-period crossover
design in a 2-week washout with fasted volunteers.
- After the fasted study a new protocol was submitted to the Ethics Committee to
evaluate the non-fasted study.
- The volunteers were selected for the study after having their health status previously
assessed by a clinical evaluation and laboratory tests .
- A single capecitabine tablet (150mg) was given in each interment.
- The drug was well tolerated by the volunteers, and they presented no adverse
reactions. The biochemical and hematological parameters presented no clinically
relevant alterations.
- Results indicate that it is safe to perform capecitabine bioequivalence studies in
healthy male volunteers.
Item 2 – Relative bioavailability/ bioequivalence studies with drugs present on attachment Imust respect the general measures described on this note as well as specific measures to eachdrug described on the same attachment.
Item 3.1 – Based on the toxic potential of these drugs the investigators must decide on theparticipation of patients or healthy volunteers, as well as the most adequate dose to use in thestudy.
Attachment I – Drugs that must have bioavailability/ bioequivalence studies conducted accordingly to this note
Technical Note 05/2012
Capecitabine
Study populationMale volunteers
Female volunteers with definitive sterilization
Oral dose 150 mg
Item 2 – Relative bioavailability/ bioequivalence studies with drugs present on attachment Imust be conducted on patients of the target population of the studied drug; patients must bereceiving treatment to a pathology to which the reference drug is indicated. These studiesmust respect the technical aspects depicted on this note.
Attachment I – Drugs that must have bioavailability/ bioequivalence studies conducted on patients.
Technical Note 06/2012
Azacitidine Ganciclovir Temozolomide
Chlorambucil Goserelin Testosterone
Clozapine Leuprorelin Topotecan
Doxorubicin Melphalan Triptorelin
Etoposide Mercaptopurine Vorinostat
Everolimus Nabilone
Felbamate Nilutamide
December 13th, 2012
6.2.1. Phase I, single agent dose and schedule finding trials
– Non-clinical data and, when available, data from healthy volunteers
should be used to design the studies to be conducted in patients
– Based on preclinical tolerability and toxicology findings and the
assumed pharmacology of the compound, early trials may sometimes
be conducted in healthy volunteers.
European Medicines Agency
To evaluate bioequivalence between two
formulations of capecitabine (test and reference)
in healthy male volunteers
Objective
Why evaluate on healthy volunteers?
Capecitabine is employed for the treatment of metastatic
cancer, therefore the prognosis of these patients is usually
reserved. To expose these critical patients to either
ineffective or toxic doses of the drug (due to unforeseen
infra or supra-bioavailability of the test formulation), to
experimental procedures such as internment, venous
puncture and blood collection to evaluate bioequivalence
should be ethically re-evaluated. Furthermore, studies
performed in patients are with therapeutic doses, using
several tablets for each administration (generally a
combination of both 150 and 500 mg tablets), a procedure
that limits the discrimination between dosage forms.
• The clinical protocols were approved by the university IRB.
• The studies were conducted using an open, randomized, two-
period (150 mg single administration of Xeloda; F. Hoffmann-La
Roche Ltd., vs a test formulation) crossover design with a one-
week washout interval, in two groups, with food.
• All male subjects were negative for HIV, HCV and HBV. The
laboratory tests (biochemical and hematological parameters) were
performed on average three days after the first confinement, and
7 days after the second confinement.
Methods
• Subjects: Seventy-two healthy male volunteers were recruted
• Hematological evaluation: Hemoglobin, Hematocrit,
Erythrocyte Count, VCM, HbCM, White Cell and Platelet
Count
• Biochemistry: Total Cholesterol, Triglycerides, Total Proteins,
Albumin, Uric Acid, Total Bilirubins (Direct and Indirect),
Alkaline Phosphatase, SGOT (AST), SGPT (ALT), Urea,
Creatinine, Fasting Blood Glucose
• Physical exam and EKG.
Methods
• Dose: 150mg single-dose on each treatment with a one-week
washout period between treatments.
• Volunteers had a standardized breakfast 30 minutes before drug
administration.
• Blood samples were collected at 0:10, 0:15, 0:20, 0:30, 0:40, 0:50,
1:00, 1:10, 1:20, 1:30, 1:40, 1:50, 2:00, 2:30, 3:00, 3:30, 4:00,
5:00, 6:00 and 7:00h after drug administration
Methods
• HPLC coupled to tandem mass spectrometry
• Deuterated capecitabine
Determination of Capecitabine
Capecitabine
M.W. 359.93 g/mol
Capecitabine-d11
M.W. 371.08 g/mol
• Three drop-outs due to time unavailability.
• The drug was well tolerated by the 69 volunteers that
concluded the study.
• One volunteer had a mild headache.
• Three individuals presented hypertriglyceridemia.
Results
• To determinate if hypertriglyceridemia was due to capecitabine,
plasma samples remaining from the analitical study were evaluated for
triglycerides.
• Two out of the 3 volunteers had hypertriglyceridemia before the first
and the second dose of capecitabine, and did not have significant
variation through out the treatment day.
• The volunteer that had normal triglycerides before treatments only
presented mildly elevated levels (273 mg/dL) 8 days after the second
dose (discharge evaluation). It resolved without treatment, as
evaluated 30 days after the last dose.
Results
It is safe to perform capicetabine (150mg) bioequivalence
study in healthy male volunteers.
Conclusion
• Fase 0 para produtos
oncológicos – pode ser
realizado tanto em
voluntários sadios como
pacientes
Review of Human Phase 0 (Microdosing) Clinical Trials Following the US Food and Drug Administration
Exploratory Investigational New Drug Studies GuidanceGraham Lappin and R. Colin Garner
Microdosing, or human phase 0 clinical trials, is a technique wherebysubpharmacological doses of prospective drug candidates areadministered to human volunteers. A microdose study provides earlypharmacokinetic data in humans and only requires minimal preclinicaltoxicology safety testing. A microdose is defined as 100th of thepharmacological dose (or predicted pharmacological dose) or a maximumof 100 µg.
Int J Pharm Med (2006) 20:159-165.
Metabolism and disposition of imatinib mesylate in healthy volunteers
Hans-Peter Gschwind, Ulrike Pfaar, Felix Waldmeier, Markus Zollinger, Claudia Sayer, Peter Zbinden, Michael Hayes, Rolf Pokorny, Michael Seiberling, Monique Ben-
Am, Bin Peng and Gerhard Gross
Purpose: To investigate the disposition and biotransformation of imatinibmesylate in 4 male healthy volunteers after a single oral dose of 239 mg of14C-labeled imatinib mesylate. Biological fluids were analyzed for totalradioactivity, imatinib, and its main metabolite CGP74588.
Int J Pharm Med (2006) 20:159-165.
Advantages of Microdosing
First of all, microdosing requires minute quantities of the drug for safety
testing. A microdose is so small that when administered to human
subjects, it is not intended to produce any pharmacologic action; hence,
the risk of adverse events is less.
A smaller toxicology package is required. As per the regulatory
requirement, animal studies, at least in one species, are required to
establish microdose in humans, but at a much reduced level. Further, if
human screening of compounds is done earlier in the drug development
process, fewer animal studies are required before Phase I clinical trials.
Thus, further animal studies can be avoided with compounds having
unsuitable pharmacokinetic profiles.
Int J Pharm Med (2006) 20:159-165.
Conclusões
• Realização de estudos fase I para
produtos oncológicos não apresenta
maiores dificuldades técnicas
• Para ganho de tempo seria interessante
investir mais em estudos fase 0.
• Uso de voluntários sadios é possível para
avaliação de parâmetros
farmacocinéticos