Jeffrey M. Skolnik

Pediatric Phase I Trials in Oncology: An Analysis of Study Conduct Efficiency

PURPOSE To determine the efficacy and safety of pediatric phase I oncology trials in the era of dose-intensive chemotherapy and to analyze how efficiently these trials are conducted. METHODS Phase I pediatric oncology trials published from 1990 to 2004 and their corresponding adult phase I trials were reviewed. Dose escalation schemes using fixed 30% dose increments were studied to theoretically determine whether trials could be completed utilizing fewer patients and dose levels. RESULTS Sixty-nine pediatric phase I oncology trials enrolling 1,973 patients were identified. The pediatric maximum-tolerated dose (MTD) was strongly correlated with the adult MTD (r = 0.97). For three-fourths of the trials, the pediatric and adult MTD differed by no more than 30%, and for more than 85% of the trials, the pediatric MTD was less than or equal to 1.6 times the adult MTD. The median number of dose levels studied was four (range, two to 13). The overall objective response rate was 9.6%, the likelihood of experiencing a dose-limiting toxicity was 24%, and toxic death rate was 0.5%. CONCLUSION Despite the strong correlation between the adult and pediatric MTDs, more than four dose levels were studied in 40% of trials. There appeared to be little value in exploring dose levels greater than 1.6 times the adult MTD. Limiting pediatric phase I trials to a maximum of four doses levels would significantly shorten the timeline for study conduct without compromising safety.

Dactinomycin and Vincristine Toxicity in the Treatment of Childhood Cancer: A Retrospective Study from the Children’s Oncology Group

Dactinomycin (AMD) and vincristine (VCR) have been used for the treatment of childhood cancer over the past 40 years but evidence‐based dosing guidance is lacking.

Population Pharmacokinetic Investigation of Actinomycin‐D in Children and Young Adults

Actinomycin‐D is an antineoplastic agent that inhibits RNA synthesis by binding to guanine residues and inhibiting DNA‐dependent RNA polymerase. Although actinomycin‐D has been used to treat rhabdomyosarcoma and Wilms tumor for more than 40 years, the dose/exposure relationship is not well characterized. The objective of this study was to develop an initial population pharmacokinetic model to describe actinomycin‐D disposition in children and young adults from which a prospective study could be designed. A total of 165 actinomycin‐D plasma concentration measurements from 33 patients, aged 1.6 to 20.3 years, were used for the analysis. The data were analyzed using nonlinear mixed‐effects modeling with the NONMEM software system. Age, weight, and gender were examined as covariates for the ability to explain interindividual variability in actinomycin‐D pharmacokinetics. The final model was qualified via predictive check and nonparametric bootstrap procedures. A 3‐compartment model with first‐order elimination was chosen as the structural model. Allometric expressions incorporating weight were used to describe the effects of body size on actinomycin‐D pharmacokinetics. Age and gender had no discernible effects on actinomycin‐D pharmacokinetics in the population studied. The predictive check showed that the developed model was able to simulate data in close agreement with the actual study observations. The availability of an initial population pharmacokinetic model to describe actinomycin‐D pharmacokinetics will facilitate the development of a large‐scale clinical trial to study the actinomycin‐D dose/exposure relationship in pediatric patients with rhabdomyosarcoma and Wilms tumor. The covariate analysis described by the current data set suggests that indices of body size captured via allometric expressions improve the partition of variation in actinomycin‐D pharmacokinetics from this pilot data set. Relationships between pharmacokinetics and toxicity will be examined in future prospective studies in which children less than 1 year old will be enrolled.

Discrete Event Simulation Applied to Pediatric Phase I Oncology Designs

Little attention has been paid to the study of trial efficiency despite increasing pressures to conduct clinical research in an expedient manner and the ever‐present “time is money” mantra that governs the pharmaceutical research concerned with drug development. Still less appreciated is the impact that trial inefficiency can have when studies compete for a finite study population desperate to test potentially lifesaving new medicines. We have used discrete event simulation techniques to examine such sensitivities in pediatric oncology.

Approaches to clear residual chemotherapeutics from indwelling catheters in children with cancer

Objectives: To develop a method for drug dosing and pharmacokinetic (PK) sampling in children with cancer from a single indwelling central venous catheter that minimized drug contamination. Methods: A benchtop system was designed to simulate dosing and clearing actinomycin-D (AMD) and vincristine (VCR) from central venous catheters. The authors evaluated the effects of flush volume, composition and pH, timed drug instillation, and number of blood-draw return cycles on residual drug concentrations. A proof-of-principle study was conducted in three pediatric patients with cancer with paired PK samples obtained by both central and peripheral catheters. Results: Nearly complete removal of drug from the catheter was obtained after five blood-draw return cycles consisting of 5 mL of whole blood. Residual concentration of AMD was 0.18 ± 0.02 ng/mL or 0.16% of the initial infusion concentration. VCR exhibited lower propensity for catheter adsorption than AMD with residual concentrations undetectable after three blood-draw return cycles. In patients in which the clearance procedure was used, higher drug concentrations were generally observed from centrally cleared samples at most time points, but differences relative to peripherally obtained samples were not statistically significant for either AMD or VCR. Two of three patients had higher exposure for AMD based on PK samples obtained from central catheters, whereas exposure for VCR was similar for both sampling catheters in all patients. Conclusions: A reliable procedure to efficiently reduce AMD and VCR contamination during PK sampling has been established and is currently being used in a PK study being conducted by the Childrens Oncology Group.

Tyrosine Kinase Inhibitors in Pediatric Malignancies

Tyrosine kinase inhibitors have been used to treat adult cancers for over a decade. Since the discovery of imatinib mesylate (STI–571, Gleevec; Novartis), tyrosine kinase inhibitors have ushered in a new age of targeted therapy. Although the United States Food and Drug Administration has approved several kinase inhibitors for use in adult cancers, currently only imatinib mesylate is approved for use in children with cancer. This review highlights the mechanisms of tyrosine kinase inhibition, the potential role of tyrosine kinase pathways in the treatment of pediatric cancers, and the current status of pediatric clinical investigation of a spectrum of tyrosine kinase inhibitors for the treatment of childhood cancer.

A Reliable and Safe Method of Collecting Blood Samples from Implantable Central Venous Catheters for Determination of Plasma Gentamicin Concentrations

Study Objective. To evaluate the extent of agreement between plasma gentamicin concentrations determined from samples collected by using implantable subcutaneous central venous catheters (ports) with the push‐pull method and those collected by finger lancet punctures in children with febrile neutropenia.

PII-74A model-based approach for evaluating potential contamination of blood samples from a common indwelling catheter and its effects on estimated Actinomycin-D pharmacokinetics

A structural model derived from Actinomycin‐D (Act‐D) exposure following dosing through a central venous line (CVL) and sampling from a peripheral vein was modified to approximate contamination when dosing and sampling from the same CVL.

Refining the Phase I pediatric trial

Jeffrey M Skolnik1,2† & Jeffrey S Barrett2 †Author for correspondence 1AstraZeneca, LP, Mail Stop C2B-112, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA Tel.: +1 302 885 7686; Fax: +1 302 886 2622; E-mail: jeffrey.skolnik@ astrazeneca.com 2The Children’s Hospital of Philadelphia, Clinical Pharmacology & Therapeutics, Abramson Research Center, Room 916H, 3615 Civic Center Boulevard, PA 19104-4318, USA Tel.: +1 215 590 6359; Fax: +1 215 590 7544; E-mail: barrettj@ email.chop.edu ‘...despite these minor advances, pediatrics continues to use trial methodology first suggested over 60 years ago.’

PI-75An improved liquid chromatography/tandem mass spectrometry method for detecting actinomycin-D and vincristine in plasma

Actinomycin‐D (Act‐D) and vincristine (VCR) are used in treating pediatric cancer. Empiric dosing continues due a lack of information on drug disposition. We report a major modification to our published Act‐D and VCR LC/MS/MS assay that has reduced our lower limit of quantification (LLOQ), and decreased run time.