Actinomycin-D / Vincristine in Pediatric Oncology Trials: COG Effort

1. Actinomycin-D / Vincristine in Pediatric Oncology Trials: COG Effort Jeffrey S. Barrett, Ph.D., FCPThe Children’s Hospital of PhiladelphiaDivision of Clinical Pharmacology and TherapeuticsThe University of Pennsylvania Medical SchoolDepartment of Pediatrics

2. Outline • Introduction • Clinical Setting for AMD / VCR in Pediatric Oncology • “Missing” Data and the Impact on Pharmacotherapy • Grant Overview • Objectives and Goals • Project Descriptions • Current Status • Project Plan Update • Overall Milestones Achieved to Date • By Project Review • Critical Activities • Next Steps

3. Introduction • In August of 2002, the Children’s Oncology Group (COG) suspended 3 active protocols for pediatric rhabdomyosarcoma after 4 chemotherapy-associated deaths from VOD. • No subsequent evaluation as to the cause of these devastating side effects or correlation between toxicity and drug exposure. • Primarily by the limited pharmacokinetic knowledge of AMD. • Because AMD is crucial to soft tissue sarcoma therapy, its use as an anti-neoplastic agent continues; clinical evaluation vital.

4. Introduction • June 24, 2004: NIH requests that the COG responds to an RFP focused on enhancing the safety and effectiveness of AMD and VCR administered to children with cancer. • July 21, 2004: COG provide LOI with 4 project proposals • August 11, 2004: Full proposal submitted to NIH / NCI • October 1, 2004: Award made to COG • March 31, 2005: Results of initial M&S activities presented to NIH/NCI at COG meeting – initial requirements gathered for Simulation Plan • October 20, 2005: Update on grant progress to FDA Pediatric Oncology Subcommittee

5. Study Sub study Study Dates Pediatric Indications N Treatment groups Duration VA, VAD ± XRT, NWTS-4 NA 1986-1989 2382 VA, VAD 24 to 66 wk VECD ± XRT NWTS-5 Relapse study 1995-2002 Wilms’ tumor - relapsed patients 203 VA ± XRT, VAD ± XRT 18 or 24 wk Biology study 1995-2002 Wilms’ tumor, kidney sarcoma, kidney rhabdoid 18 or 24 wk IRS-4 NA 1991-1997 RMS 883 VA, VAC, VAI, VIE 1 y except VA, 36wk IRS-5 D9602 1997-2004 Low risk RMS 367 VA ± XRT, VAC ± XRT 47 wk D9803 1999 - Intermediate risk RMS 518 VAC ± XRT , V/TOPO/C+XRT 39 wk IntroductionClinical Setting – Historical experience in children

6. IntroductionClinical Setting – Historical experience in children

7. IntroductionImpact of “Missing” Data on Pharmacotherapy • No analytical methodology for AMD • PK largely unknown – No idea about dose-exposure. • PD largely unknown. • AMD Dose-toxicity relationship qualitative at best • VCR PK not well defined in pediatric populations • Exposure-response (toxicity) not well defined. • PGx component to PK and/or clinical outcomes suspected but not defined. • Dose-limiting vs manageable toxicity unclear • Dose adjustments empirically based • No basis for age / size modification • No basis for special populations (e.g., renal impairment) • No guidance on drug interactions

8. Grant OverviewObjectives and Goals Project 1: To conduct a retrospective analysis of historical data from Wilms tumor (NWTS-IV and NWTS-V) and rhabdomyosarcoma (IRS-IV and IRS-V) studies in which vincristine and actinomycin-D were administered to various pediatric subpopulations in order to define exposure-toxicity relationships. Project 2: To develop a dosing and pharmacokinetic sampling procedure for actinomycin and vincristine utilizing a single lumen central venous catheter. Project 3: To construct PK/PD models based on actinomycin-D and vincristine exposure-response relationships that incorporate physiologic-based and mechanistic expression when possible, and simulation to extend such relationships into a clinical trial paradigm in which trial outcomes may be predicted. Project 4: To conduct a prospective PK/PD/outcome trial of vincristine and actinomycin-D in children, primarily less than 3 years of age, receiving these drugs as a component of their therapy.

9. Grant OverviewInterdependencies Overall success highly dependent on project management and communication

10. Grant OverviewProject Descriptions – Project 1 Aim 1: To describe vincristine and actinomycin D dosing for patients on NWTSG 4 and 5 and IRSG IV and V Aim 2: Correlate dosing data from Aim 1 with efficacy, particularly in children less than 3 years of age Aim 3: Correlate dosing data from Aim 1 with toxicity, particularly in children less than 3 years of age Aim 4: Analyze the combined NWTSG and IRSG datasets with classification and regression tree methodology to provide background data for the clinical trial simulation described in Project 3

11. Study Design and Analytic Methods Trial Design Data and Analysis Plan Aim 1 Aim 2 Aim 3 Aim 4 NTWS 4 Case cohort Individual dose description and analysis Standard univariate and multivariate analyses Standard univariate and multivariate analyses Classification and regression tree models on combined data set NTWS 5 IRS 4 Cohort Course dose description and analysis IRS 5 Cohort Individual dose description and analysis Grant OverviewProject Descriptions – Project 1

12. Grant OverviewProject Descriptions – Project 2 Aim 1: To examine the recovery of actinomycin-D and vincristine in common catheter configurations which would be utilized to administered these agents via a central venous line. Aim 2: To assess the in vitro equivalence of catheter configurations utilized for sampling purposes Aim 3: To develop procedures for dosing and sampling to ensure robust sampling equivalent to a separate sampling line Aim 4: To validate the procedure proposed in Aim 3 via clinical testing to the target patient population (children with cancer)

13. Grant OverviewProject Descriptions – Project 2 Develop and validate a single LC/MS/MS assay to quantify both Act-D and VCR Determine cytochrome P450s involved in the metabolism of Act-D Optimize plasma sampling techniques for PK studies in children Create a pilot PK study of Act-D and VCR in children

14. Grant OverviewProject Descriptions – Project 3 Aim 1: Develop PBPK models for actinomycin and vincristine from historical pharmacokinetic data for the prediction of plasma pharmacokinetics and exposure in organs and tissues. Aim 2: Incorporate dose/toxicity data from the historical literature and Project 1 into the PBPK models to associate specific organ exposures to toxicity outcomes. Aim 3: Conduct a pilot study in pediatric patients using extensive plasma sampling to further define AMD and VCR pharmacokinetics and inter-subject variability for model refinement. Aim 4: Perform Clinical Trial Simulations for the design of the prospective PK/PD trial proposed in Project 4.

15. Grant OverviewProject Descriptions – Project 3 Dose – Exposure Relationships Exposure – Response Relationships Data Sources • PBPK Model in the Dog • Define in NONMEM • Add precision estimate • Dose – AE Model • Pooled from Literature • Define response profile • Literature Priors • Animal and human PK • Variance in physiology • Scaling principals • In vitro binding data • Cellular partitioning • Clinical trial summaries (AE/SAE) • PBPK Model in the Adult • Scale Dog to Human • QC plasma exposure • Mechanistic PK/PD Model • Map transduction process • Biophase concentration • Correlate with in vitro data • PBPK Model in the Child • Scale CL allometrically • QC plasma exposure Individual AE Data (COG) • • Clinical Response Model • AE vs Pred. Exposure(dose) • Add variance components • Add covariate structure • Pilot PK Study • Dose Finding Trial • PBPK Pediatric Pop Model • Add variance components • Add covariate structure Dosing Guidance for Pediatric Cancer Patients

16. Grant OverviewProject Descriptions – Project 4 Aim 1: Develop and finalize a clinical protocol based on the observed toxicity-dose response (Project 1) and the clinical trial simulation results (Project 3) utilizing a single lumen catheter procedure defined by Project 2. Aim 2: Evaluate AMD/VCR dose-exposure relationships via nonlinear mixed effect modeling incorporating covariates that explain sources of variation including size, age, heritable and non-heritable sources. Aim 3: Create PK/PD models (based on Aim 2) that correlate toxicity findings and clinical outcomes from the prospective trial CTS results and catheter experiment results (procedures defined by Project 2) Aim 4: Propose dosing guidance for actinomycin-D and vincristine based on clinical utility (maximizing therapeutic outcome and minimizing therapeutic risk) suitable for label recommendations

17. Current StatusProject Plan

18. Current StatusMilestones Achieved • Analytical method for AMD/VCR quantification in pediatric plasma samples validated and published • Procedure for AMD/VCR dosing/sampling from central catheter has been developed (awaiting clinical validation) • Pilot PK study initiated; 3 (8 planned) enrolled • PBPK models for AMD and VCR developed and scaled to project pediatric exposures • PK models refined for CTS application • CTS Plan completed; CTS ongoing • Draft clinical protocol circulated to NIH and select COG phase 1 sites

19. Current StatusBy Project Review – Project 1 • NWTS database created • Data errors and inconsistencies continue to be an issue and are being resolved • Data entry of non-electronically available data delayed • SAP finalized

20. Current StatusBy Project Review – Project 2 AMD/VCR method validated, published and continues refinement (with LOD < 0.1 ng/mL probable)

21. Current StatusBy Project Review – Project 2 AMD/VCR method validated, published and continues refinement (with LOD < 0.1 ng/mL probable)

22. Current StatusBy Project Review – Project 2 In vivo performance of analytical method already demonstrated in pilot study patients

23. Current StatusBy Project Review – Project 2 Clinical procedure and apparatus for dosing / sampling from a central venous catheter developed Flush Volume: 1. Cook® 5 french 27cm catheter fragment 2. 200 µL pipette tip 3. Cook® catheter connector 4. Medex® 3-way stopcock 5. 3 mL syringe for sample collection 6. 5 mL syringe for waste collection

24. Current StatusBy Project Review – Project 3 PBPK Models developed for AMD and VCR – Scaled to pediatric populations PLASMA FLOW • Model Elements – AMD and VCR • Flow-limited PBPK models derived from dog • Human physiologic parameters inserted and rescaled allometrically for pediatric subjects • Moderate variation in physiologic and PK processes assumed to date • Models expressed in NONMEM and TS2 • Initial simulations agree with historical data in children based on plasma exposure PLASMA HEART HEPATIC ARTERY SPLEEN LIVER BILE KIDNEY URINE BONE MARROW MUSCLE CARCASS

25. Current StatusBy Project Review – Project 3 • Good agreement with Veal et. al. (n=31) and CHOP pilot PK study (n=2)

26. Current StatusBy Project Review – Project 3 Models refined based on pediatric data obtained from UKCCSG (Veal et. al.) • Model developed using the First-Order Conditional Estimation method in NONMEM • 165 plasma concentrations collected from 33 pediatric patients administered 0.70 to 1.50 mg/m2 AMD • A three-compartment model with first-order elimination was chosen as the structural model • Random effects to describe the inter-subject variability were included for V1 and CL

27. Current StatusBy Project Review – Project 3 Simulation plan completed (available for review) • Simulation Scenarios: • Previous IRS and NWTS Trials • Dosing Modifications in Infants • BSA vs BW Dosing • Dose Capping • Clinical Study Designs and Sampling Considerations • Adverse Event Rates for Prospective Study • Clinical response for Prospective Study

28. Current StatusBy Project Review – Project 3 Uncertainty in Var CL Novelty of M&S Approach Uncertainty in Mean CL Residual Variability Interindividual Variability: CL Ct = D/V*e-CLi/V*t + et

29. Current StatusBy Project Review – Project 3 Novelty of M&S Approach • Clinical Reality • Discrepancy across studies • Population, dosing, treatment diversity exists as well as compliance with targeted regimens / exposures • Correlation with toxicity difficult to assess from conventional analyses • Guidance for prospective study based on historical data difficult • Pharmacometric Solution • Global sensitivity analysis • Plot the MPE and RMSE against the population means (with uncertainty) for each simulation scenario • Identify study designs that produce minimal bias and high precision over the range of possible parameters

30. Current StatusBy Project Review – Project 4 Clinical Protocol Draft Circulated PROSPECTIVE PHARMACOKINETIC/PHARMACODYNAMIC AND OUTCOME TRIAL OF ACTINOMYCIN-D AND VINCRISTINE IN CHILDREN WITH CANCER

31. Critical Activities • Completion of pilot PK study and in vivo validation of central venous catheter dosing/sampling procedure • Completion of data entry / assembly for historical AE/tox data from IRS and MWTS trials • Correlation of tox with dosing metrics • Completion of key CTS scenarios

32. Critical Activities • Revision and finalization of clinical protocol • Investigator solicitation and education • Data collection strategy, data management plan for prospective trial • SAP for prospective study • Label exercise based on CTS output

33. References Barrett JS, Skolnik J, Gastonguay MR and Adamson PC. The Value of Priors and Prior Uncertainty in Clinical Trial Simulation: Case Study with Actinomycin-D in Children with Cancer. Presented, 2004 Population Approach Group Europe Meeting, Uppsala, Sweden, June 17-19, 2004. Skolnik J, Barrett JS, Shi H, and Adamson PC. Pre-clinical Studies in Support of the Clinical Pharmacologic Evaluation of Actinomycin-D in Children with Cancer. American College of Clinical Pharmacology Meeting, Phoenix, AZ, October 3-5, 2004. Mondick J and Barrett JS. A Physiologically-based Pharmacokinetic Model to Predict Tissue Distribution of Actinomycin-D in Humans. American College of Clinical Pharmacology Meeting, Phoenix, AZ, October 3-5, 2004. Skolnik JM, Paccaly DA, Barrett JS, Adamson PC. Mechanisms to enhance enrollment in pediatric trials: An in vitro procedure to clear residual chemotherapeutics from indwelling catheters. J. Clin. Pharmacol 2005; 45: 1085 (Abstr. 76). Barrett JS, Mondick JT, Skolnik J, Adamson PC. Clinical trial simulation in an academic research setting: Engaging the clinical team and generating the simulation plan. J. Clin. Pharmacol 2005; 45: 1087 (Abstr. 85). Skolnik, JM, Barrett, JS, Hsi, H, Adamson, PC; A liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of actinomycin-D and vincristine in children with cancer. Cancer Chemotherapy and Pharmacology; Sep 27;:1-7 [Epub ahead of print]