Challenges of Pharmacokinetic/Pharmacodynamic Assessments in Pediatric Oncology

Challenges of Pharmacokinetic/Pharmacodynamic Assessments in Pediatric Oncology Clinton F. Stewart, Pharm.D. St. Jude Children’s Research Hospital Memphis, TN

Outline • Summary of results of early clinical pharmacokinetic studies with topoisomerase I inhibitors • Application of results from nonclinical studies of topoisomerase I inhibitors to design of clinical trials (Phase Ib/IIa) • Summary results of later clinical drug development with topoisomerase I inhibitors (Phase Ib/Phase IIa) • Thoughts regarding design of clinical pharmacokinetic studies of “targeted” drug therapy

Phase I Clinical Trials Nonclinical PK/PD Studies Pharmacology Studies EnhanceDevelopment of Anticancer Drugs • Additional PK/PD (efficacy) studies • Evaluate different schedules Phase IV Clinical Trials Phase II Clinical Trials Phase III Clinical Trials MARKET • Evaluate clinical safety of new schedules, dosage, or combinations • Comparative studiesof efficacy

Two Commercially Available Topoisomerase I Inhibitors For Use In Pediatric Oncology:Topotecan and Irinotecan

TOPO-L Oncolytic Response Mucositis Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer • Topotecan 72-hour CI in children with recurrent solid tumors (Pratt, JCO, 1994) • Antitumor activity* • DLT myelosuppression • Preliminary data for LSM • Topotecan 120-hour CI in children with recurrent leukemia (MTSE) (Furman, JCO, 1996) • Antileukemic effect* • DLT mucositis • PK/PD observations

0.5-hr 24-hr 72-hr Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer • Oral topotecan (15 or 21-days) in children with refractory solid tumors (Zamboni, CCP, 1999) • Well absorbed • Wide interpatient variability but less than intrapatient • Topotecan CSF penetration studied in children with primary brain tumors (Baker, CCP, 1996) • Extensive penetration, wide interpatient variability, no difference among infusion rates

Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer • Topotecan 30-min infusion (dx5) in children with recurrent solid tumors (POG-9275; Tubergen, Stewart JPHO, 1996) • Antitumor activity • DLT myelosuppression • Validation of LSM • Wide interpatient variabilityin clearance with small (~20%) dosage increments, overlap in topotecan exposure across dose levels

Initial Clinical Trials with Topoisomerase I Inhibitors in Children with Cancer • Irinotecan 60-min infusion (dx5x2) in children with recurrent solid tumors (Furman, JCO, 1999) • Antitumor activity • DLT diarrhea • Pharmacokinetics complex with metabolism to active (SN-38) and inactive metabolites • SN-38 highly protein bound • Role for pharmacogenetics

Comparison of Results from Adult and Pediatric Phase I Studies for the Topoisomerase I Inhibitors • Pharmacokinetics • Topotecan lactone systemic clearance similar between adults and children, in early studies* • Limited pediatric population (ages, drug-drug intxn) • Pharmacodynamics • Relation between TPT lactone systemic exposure and %decrease ANC similar between two groups • MTD • Pediatric MTD higher for comparable schedules; problematic comparison (dx5x2) • DLT (no difference)

Outline • Summary of results of early clinical pharmacokinetic studies with topoisomerase I inhibitors • Application of results from nonclinical studies of topoisomerase I inhibitors to design of clinical trials (Phase Ib/Iia) • Summary results of later clinical drug development with topoisomerase I inhibitors (Phase Ib/Phase Iia) • Thoughts regarding design of clinical pharmacokinetic studies of “targeted” drug therapy

Phase IV Clinical Trials Phase III Clinical Trials Phase I Clinical Trials Nonclinical PK/PD Studies MARKET • Comparative studiesof efficacy Application of Nonclinical PK/PD StudiesEnhance Anticancer Drug Development • Additional PK/PD (efficacy) studies • Evaluate different schedules Phase II Clinical Trials • Evaluate clinical safety of new schedules, dosage, or combinations

Role of Pharmacokinetics in Xenograft Model Topoisomerase I Inhibitors

Summary of Topoisomerase I Antitumor Efficacy Studies Conducted in the Xenograft Model • Schedule-dependent • Duration of therapy critical • Administration interval important • Protracted dosing schedule associated with antitumor activity • Dose-dependent • Self-limiting antitumor activity at high doses • Critical threshold drug exposure for antitumor activity • Clinical dosing schedule: low-dose, protracted (dx5x2)

Objectives Use of the Nonhuman Primate Model Topotecan in CNS Malignancies • To evaluate effect of TPT infusion rate on TPT CSF concentration throughout the neuraxis (ventricular & lumbar) • To generate a PK model to describe plasma and CSF TPT disposition, which could be used to design clinical trials of TPT to treat CNS tumors

Dose intensity Clinical Response Rationale for Pharmacokinetically Guided Dosing of Anticancer Drugs • Considerations for this relationship • Preclinical models • Clinical studies • Drug sensitive tumor • Systemic-intensity not same as dose intensity • Medication errors • Patient tolerance • Patient compliance Dose intensity Clinical Response Systemic Exposure

7-Fold Range In TPT Clearance # Courses of Therapy 10 20 30 40 50 60 70 Topotecan Systemic Clr (L/hr/m2) Rationale for Pharmacokinetically Guided Dosing in Children with Cancer • Pharmacokinetic variability • Drug absorption, distribution, metabolism, & elimination • Inter-patient variability greater than intrapatient • Other sources of variability • Maturational changes • Renal & hepatic impairment • Inherited difference in drug metabolism & disposition • Drug-drug intxns

Selected Criteria for Pharmacokinetically Guided Dosing • General considerations • Narrow therapeutic index • Drug effect delayed • Relation between drug effect & drug exposure • Logistical considerations • Drug regimen amenable to dosage adjustment (e.g., > 24 hr CI, > 1 d regimen [dx5x2], etc.) • Assay method available • Pharmacokinetic considerations • Well-characterized pharmacokinetics (PK model) • Population priors for available for Bayesian analysis • Limited sampling model

Area under the concentration- time curve (AUC) in plasma Time Above Threshold Exposure in CSF Application of Pharmacokinetic Studies to Optimize Topotecan Therapy: Design Considerations • Selection of initial systemic exposure and dose • Pharmacokinetic metric to express drug exposure

1 2 3 4 5 6 7 8 9 10 11 12 Day X X Dose Topotecan Dosage Adjustment Schema TOPO5x2 PK Studies Adjust Dose Topotecan i.v. over 30 minutes daily x 5 for two consecutive weeks Target topotecan systemic exposure 100 ± 20 ng/ml-hr

Lessons Learned from Pharmacokinetically Guided Topotecan Clinical Trials • Phase I Feasibility Study (TOPO5x2) • Antitumor activity noted • Achieve target systemic exposure and reduce interpatient variability in topotecan exposure • Pharmacokinetically guided TPT in combination with vincristine (Phase I) • Some antitumor responses • However, significant myelosuppression (platelets) • Used lower topotecan target (80 ± 10 ng/mL) • Pharmacokinetically guided TPT in combination with CTX (Phase I) • Used as a conditioning regimen followed by AHSCT • Toxicities manageable • ~90% patients were within “target”

Lessons Learned from Pharmacokinetically Guided Topotecan Clinical Trials • PK guided TPT dosing: upfront window therapy (Phase II) in children with high-risk neuroblastoma (SJNB97) • No progressive disease noted (> 50% PR) • Achieve target exposure (>90%) &  interpt var. TPT AUC • Studied 10 infants (< 2 yr), noted TPT lactone systemic clearance significantly < than in other pts (12 vs 21 L/hr) • PK guided TPT dosing: upfront window therapy (Phase II) in children with high-risk medulloblastoma (drug exposure in a “minor” exposure compartment, i.e., CSF) • Significant antitumor response (target plasma~target CSF) • Manageable toxicities • Drug-drug interactions • Enzyme-inducing anticonvulsants (DPH) increase TPT clr • Dexamethasone increases TPT clr

Design Issues for Molecular Target-Based Anticancer Drugs in Children • Definition of “target” • Expression of protein in vivo • Expression of protein and data from in vitro studies • Expression of protein, data from in vitro studies, and prognostic significance • Emphasizes the need for a “relevant” model in which to evaluate the “target” • In vitro, xenograft, transgenic • Requires a complete understanding of pathway(s) • Pharmacologic metric (as with PK guided dosing) • IC50 vs AUC vs some other measure of drug exposure • Important to consider that pediatric tumors likely have different biological pathways and therefore targets

Challenges in Pharmacokinetic/Pharmacodynamic Assessments in Pediatric Oncology • Haven’t really talked a lot about “challenges” per se because: • Resources and infrastructure of St. Jude have made these studies possible • Also, the infrastructure present in the DT Committee, COG • Challenge for the future to apply what we have learned to Phase IIb/III clinical trials of topotecan used in combination • COG study of topotecan in combination with CTX in NB • How to dose topotecan? • Topotecan population pharmacokinetic study, where we’ve found that covariates for TPT clearance included BSA, concomitant phenytoin therapy, serum creatinine, and age • PK studies provide insight into differences in drug disposition (phenotype) which can then be explained in many cases by genetic variations in drug metabolism or transport (genotype)

Challenges of Pharmacokinetic/Pharmacodynamic Assessments in Pediatric Oncology