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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

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Page 1: Fase I para moléculas sintéticas e biológicas para o ...sbmf.org.br/pdf_eventos/medicamentos-oncologicos/Gilberto_Denucci... · Fase I para moléculas sintéticas e biológicas

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

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Objetivos da Fase I

• Farmacocinética

• Tolerabilidade

• Toxicidade (MTD e OBD)

• Escalonamento de dose para Fase II

• Avaliar aspectos Farmacodinâmmicos

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Invest New Drugs (2011) 29:996–1003.

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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.

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Avaliação de produtos

oncológicos em voluntários

sadios

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• 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

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• 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

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Metabolic activation of capacitabine in humans

Reiner et al, 1998

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Adverse effects

• Asthenia/ fatigue

• Diarrhea

• Lymphopenia

• Leukopenia

• Mucositis

• Nausea

• Neutropenia

• Thrombocytopenia

• Vomit

• Hand Foot Syndrome

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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

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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

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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)

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- 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.

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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

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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

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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

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To evaluate bioequivalence between two

formulations of capecitabine (test and reference)

in healthy male volunteers

Objective

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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.

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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It is safe to perform capicetabine (150mg) bioequivalence

study in healthy male volunteers.

Conclusion

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• Fase 0 para produtos

oncológicos – pode ser

realizado tanto em

voluntários sadios como

pacientes

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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.

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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.

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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.

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Int J Pharm Med (2006) 20:159-165.

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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