A model applicable to other disciplines?

Transcription

1 Conducting Phase 1 studies in Pediatric Oncology A model applicable to other disciplines? Sylvain Baruchel MD New Agent and Innovative Therapy Program Toronto Hospital For Sick Children

2 MILESTONES IN PEDIATRIC ONCOLOGY 1940s Remission achieved in pediatric leukemia patients 1950s 6-mercaptopurine treats pediatric acute lymphoblastic leukemia (ALL) NCI begins funding pediatric cooperative clinical trials 1960s Dactinomycin first used to treat Wilms tumor 1970s First successful bone marrow transplant (BMT) for leukemia 1980s Adjuvant chemotherapy improves relapse-free survival for pediatric osteosarcoma 1990s Autologous BMT and 13-cis-retinoic acid improve event-free survival for high-risk neuroblastoma Combined ifosfamide and etoposide improve outcomes for non-metastatic Ewing sarcoma 2000s Imatinib added to intensive chemotherapy improves early outcomes for Ph+ ALL and infant leukemia AntiGD2 maintenance in stage 4 neuroblastoma increase survival by 20% 5-year survival rates for children with cancer (age 0-14 years) approach 80%

3 Pediatric Clinical Trial Enrollment By Age Today more than 40,000 children are treated on as part of COG clinical Trials at hundreds of hospitals around The world. In the U.S., "the majority Of children for whom there are clinical trials, and who are eligible for those trials, are actually enrolled on clinical trials 5 and younger: greater than 90% 10 and younger: 75-90% 10 to 15: 50% Adolescents aged 15 to 19: 15-25%

4 Challenges in Pediatric Drug Development Limited patient numbers due to the success of front-line therapy cure rate 80% Integration of new agents into standard curative but toxic regimens Application of molecularly targeted drugs to childhood cancer (preclinical pediatric oncology platforms)

5 Building on 50 Years of Cooperative Research But Only 21 Phase 1 centres accredited to conduct phase I

6 COLLABORATIVE NETWORKS COG PHASE 1 CONSORTIUM US and Canada NANT US and Canada NEUROBLASTOMA TACL US and Canada LEUKEMIA POETICS US and Canada PBTC US BRAIN TUMORS SIOP EU US Canada C17 /NCIC CTG Canada INDUSTRY Investigator Initiated studies

7 The distribution of patients (n = 1,807) enrolled onto pediatric phase I trials Lee, D. P. et al. J Clin Oncol; 23: Copyright American Society of Clinical Oncology

8 Pediatric Development Plan First Stage Phase 1 studies to determine dose, pharmacokinetics, and toxicities Planned for about 25 patients If unacceptable toxicity occurs, the development would stop If toxicity is acceptable, proceed to second stage (anticipated general case)

9 Pediatric Development Plan Second Stage Phase 2 studies (single agent or add comparative design) and/or pilot studies (combinations) to demonstrate an agent s characteristics and contribution to efficacy, perhaps using surrogate endpoints such as response rate justification for further development to examine clinical benefit

10 Goal of Phase 1 designs Estimate the maximum tolerated dose (MTD) of a new agent for further study As accurately and reliable as possible As quickly as possible Exposing as few patients to dose limiting toxicities (DLT) as possible Treating as many patients at therapeutic doses as possible Initiate pediatric evaluations of pharmacokinetic (and sometimes pharmacodynamic) behaviour of agent

11 Children s Oncology Group Disease Committees Discipline Committees Scientific Committees Developmental Therapeutics Committee Phase 1 Phase 2 Phase 3 COG Phase 1 Pilot Consortium

12 Expertise Drug development expertise Pharmacology Biological correlates Phase 1 & 2 trial design & performance Monitoring Toxicity Reporting requirements Specimen acquisition Pharmacology Labs Biology Labs Regulatory oversight FDA/OHRP/NIH IND requirements Industry requirements

13 Quality Control/Quality Assurance Integrated throughout protocol design operations Clear and complete protocols Careful design of data collection screens Remote Data Entry system Formal study/data review by committee and DSMC Audits by OC/SDC/Theradex

14 Study Coordination and Monitoring Detailed reports of accrual and toxicity Distributed weekly to study chair & DVL chair/co-chair Reviewed on weekly leadership call At key decision points e.g. escalation, de-escalation, expansion Conference call between study chair, DVL chair/co-chair, SDC Coordinator, staff Make decision, or identify deficiencies that prevent decision

15 Phase 1 Consortium Accrual COG Year 1 Year 2 Year 3 Year 4 Year 5 Overall Consortium Accrual By Grant Year 24 studies 603 patients 54 patients from Canada

16 Can Early Phase Trials in Pediatric Cancers be Done in Canada outside other consortia? 2005 Survey: 241 children relapsing/ 85 eligible for phase I 5/1 40/10 22/8 2/1 8/3 102/38 52/21 10/3 Can J Pharmacol, 2005

17 Standard 3+3 Design for Pediatric Phase 1 Trials Smith M, Bernstein M, Bleyer WA, et al. Conduct of phase 1 trials in children with cancer. J. Clin Oncol 1998:16: Begin at 70-80% of adult MTD Dose level escalations of approximately 30% Patients dose escalated in cohorts of 3 until DLT is observed One DLT leads to treatment of 3 additional patients at the current dose level Escalation continues if no additional DLT is observed Two instances of DLT, at a dose level, leads to a halt in dose escalation De-escalation continues until such a dose level is determined

18 Problems with Standard 3+3 Design for Pediatric Phase 1 Trials Imprecision in estimate of MTD Relatively time-consuming Limited pharmacokinetic and pharmacodynamic data may be obtained across all dose levels

19 BENEFIT RESPONSES MEANINGFUL STABLE DISEASE NOT WELL DOCUMENTED PAIN CONTROL and QUALITY OF LIFE Access to skilled physician HOPE,psychological benefit Does not exclude access to palliative care

20 RISKS in Pediatric Phase 1 Trials Risks associated with pediatric phase 1 study are small The likelihood of developing a DLT once enrolled onto a study is 24%. The toxic death rate is 0.5% Median number of dose levels = 4, MTD defined at 3 rd dose level Median time to dose level completion = 77 days Median time to study completion = 452 days Pediatric MTD closely related to adult MTD Lee et al. J Clin Oncol. 2005

21 Rolling Six Design: Predications Concurrently enroll up to six patients onto a cohort Will allow the majority of phase 1 studies to be completed in less than one year A higher fraction of eligible patients will be able to enroll onto phase 1 studies There will be an increase in the number of new agents concurrently available for (randomized) phase 2 studies Mean ± SD of 3.3 ± 1.1 participants developed a DLT in the rolling six design, and 3.2 ± 1.1 participants developed a DLT in the design Skolnik JM, Barrett JS, Jayaraman B, et al. Shortening the timeline of pediatric phase 1 trials: the rolling six design. J Clin Oncol 2008:26:

22 Pharmacokinetics Scaling adult doses based solely on BSA ignores developmental changes Volume of distribution Drug clearance & metabolism Define drug disposition in children Correlate pharmacokinetic parameters with demographics and outcomes Develop limited sampling methods to allow for ongoing phenotyping in phase 2 and 3 trials

23 PHASE 1 Celecoxib STUDY Targeted PK STUDY Targeted Exposure to Celecoxib Concentration (ug/l) 1000 Original Modified 300 AUC 0-12 = 9410ug/L*h AUC 0-12 = ug/L*h Time (h)

24 Celecoxib: Steady State PK Steady State Plasma Concentration Time Curve Plasma concentration (ug/l) Without high fat food (n=16) With high fat food (n=7) Time post celecoxib dose (h)

25 Celecoxib Excessive exposure: An observation of safety Single Dose Plasma Concentration Time Curve Steady State Plasma Concentration Time Curve Plasma concentration (ug/l) Without food (n=20) With food (n=7) CYP2C9 *3/*3 Plasma concentration (ug/l) Without food (n=16) With food (n=7) CYP2C9 *3/*3 Time post celecoxib dose (h) Time post celecoxib dose (h)

26 Introduction to the Problem Some new agents may be difficult to evaluate in a standard phase 2 trial May not cause tumor shrinkage May have limited effect as single agents while contributing to a multi-drug regimen Resource and ethical concerns prevent immediate introduction of such new regimens into phase 3 Current pediatric phase 2 trials use 2- stage designs with total patients for stratum of 20-35

27 Phase 1 Trials with Escalation Based on Pharmacodynamic Endpoints Goal of determining: Optimum Biological Dose Biologically Adequate Dose [e.g., defined as either a dose that yields a specific (high) biological response rate or alternatively a dose in the plateau region] Driving force for these designs: There may be a plateau on the dose-efficacy curve so that higher doses may not improve clinical benefit Toxicity does not necessarily increase with increased doses, and toxicity may occur beyond doses that are yielding sufficient clinical benefit.

28 SEARCH FOR PHARMACODYNAMIC MARKERS A Phase I Study of Bevacizumab in Children with Refractory Solid Tumors: A Children s Oncology Group Study Julia Glade Bender, 1 Peter C. Adamson, 2 Sylvain Baruchel, 3 Yuval Shaked, 4 Helen Chen, 5 Joel Reid, 6 Ashish Ingle, 7 Susan M. Blaney, 8 Jessica Kandel, 1 Darrell Yamashiro 1 J Clin Oncol Jan 20;26(3):

29 Asymptomatic rise in BP Systolic BP Diastolic BP

30 Stable disease and Circulating Endothelial Cells (CECs) There were no partial or complete responses 3 pts with Ewing and 2 with soft tissue sarcoma had stable disease > 3m p=0.04* Enumerated using 4-color FACS including anti-cd45 to exclude hematopoietic cells, CD31, CD146, CD133 (progenitor marker), 7AAD (apoptosis marker) *by proportional hazards regression analysis relating logarithm of the acec/tcec ratio at day 28 of cycle 1 to risk for progression

31 Phase 1 COG SUNITINIB biomarkers P=0.70 P=0.51 P-0.09 P=0.11

32 Expansion at the MTD in Pediatric Phase 1 Studies Cohort of 6-12 patients Additional PK Confirmation of toxicity profile Ensure inclusion of sufficient younger children Formal phase 2 cohort Preclinical data may highlight specific histotype for priority evaluation Delays between phase 1 study completion and phase 2 study opening particularly concerning in this setting Consider including expansion at MTD for histotype of interest using standard 2-stage design Distinguishing 5% versus 25% response rates Enroll 10 patients and stop if no responses If 1 or more response, enroll additional 10 patients and declare success for 3 or more responses

33 Number of randomized phase II cancer studies published from 1986 to 2002 Lee, J.J. et al. J Clin Oncol; 23:

34 Prioritization - Future Goal To move toward a more rational method of drug prioritization through an improved understanding of tumor biology and the molecular mechanism(s) of drug action. Preclinical drug testing PPTP NCI funded SickKids Preclinical testing program Comprehensive Cancer center

35 From Tumor Initiating Cells to personalize medecine Rapid translation to clinical trial α

36 Phase 1 Trials with Escalation Based on Pharmacodynamic Endpoints Pediatric Applications Phase 1 study of Vinblastine Rapamycin Multicenter phase 1 study US and Canada Confirm preclinical testing program findings from patients back to mice models targeted rapamycin drug level and biomarker studies

37 Conclusions Several reasonable options exist for conducting first in children studies for anticancer agents Selection for specific option depends upon agent characteristics and target pediatric population This should apply to any other pediatric disease What is needed is expertise and infrastructure : translational research platform ( Preclinical PK PD) and clinical trial operation Operational funding

38 The emerging risk no open studies when needed Lab Rat? Sam Hutchison has cancer. His father is seeking a cure beyond the edge of medicine. By GEETA ANAND December 15, 2007 "When your kids have run out of options, you have to think outside the box," Mr. Hutchison says. "It's terrifying, but it's our only hope.

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