Preclinical modeling of a phase 0 clinical trial protocol

Abstract

14058 Background: The Exploratory IND program initiated at NCI (“Phase 0”) is designed to evaluate the pharmacodynamic effects (PD) of candidate drugs at the molecular level in the clinic. Trials employ patient biopsies and surrogate tissues (e.g. PBMCs) to determine the quantitative effect of the agent on its putative target, after a minimum number of doses. The approach requires repeated biopsy of the tumor, an understanding of the time-effect window, and some knowledge of the dose level likely to cause a measurable drug effect. Methods: Prior to initiating a Phase 0 study of the PARP (PolyAdenosyl-Ribose Polymerase) inhibitor, ABT-888, we developed a pre-clinical model to mirror the clinical protocol. Colo 829 and A375 xenografts in athymic nude [nu/nu (NCr)] mice were examined for time and dose effect on PARP using a validated, quantitative PAR assay. Extracts of entire xenografts, quartered xenografts and 18 gauge needle biopsies were examined for variability of baseline and post-treatment PAR levels. Results were cross-checked with Western analysis for polyADP-Ribose (PAR)-labeled proteins in treated mice. Pharmacokinetics (PK) were modeled using plasma drug levels. Additional studies examined the influence of previous biopsy, contralateral biopsy, vehicle treatment, and general anesthesia on PAR in xenografts. Results: A single dose of ABT-888 produced a significant decrease in intracellular PAR levels that could be measured 2 to 6 hours post-dose. PAR levels and drug effect on PAR levels were not influenced by repeated needle biopsies. Variation across xenografts was random for single and bilateral xenograft animal models in the ABT-888 treated, vehicle- and topotecan-treated control groups. Animal handling and socialization appeared to elevate baseline PAR levels, which could confound analysis of study results. Conclusions: Pre-clinical modeling of a specific Phase 0 clinical protocol for drug effects and biological variability provided valuable insights into the development, refinement, and analysis of the currently-active NCI Phase 0 clinical trial of ABT-888. Animal studies were conducted in an AAALAC approved facility under an approved IACUC protocol. Funded by NCI Contract N01-CO-12400. No significant financial relationships to disclose.