Validation of the phase 0 concept.

Abstract

TPS143 Background: Over 90% of drugs entering Phase I trials eventually fail, however, it is not currently possible to predict failure prior to undergoing costly and lengthy clinical trials. In response, the FDA proposed an “exploratory IND” (investigational new drug), a novel clinical trial design commonly referred to as “Phase 0”, aimed at accelerating the critical path of drug development. Phase 0 trials expose a small number of patients to a single “microdose” (starting at 1/50th of the no observed adverse effect level, NOAEL, from the most sensitive animal species) of an experimental drug with the goal of validating pre-clinical models to aid in the ‘go/no-go’ decision of drug development. The ultimate goal is to allow Phase 0 effective drugs to enter combination studies earlier, and Phase 0 ineffective drugs to avoid further costly development (Kummar S, Nat Rev Cancer 7:131-139, 2007). We are concerned that potentially effective drugs or classes of drugs may be discarded based on a microdosing concept which has not been effectively validated in human subjects. To our knowledge, the Phase 0 dosing concept has not been evaluated using a known effective agent. Our hypothesis is that a microdose may not be an accurate surrogate for standard doses, and thus, a Phase 0 trial may yield false negative results. We are now conducting a Phase 0 trial evaluating the effects of microdoses of an FDA-approved drug, temsirolimus, on its known pharmacodynamic (PD) targets. The primary endpoint is PD target modulation. Methods: Patients with advanced cancer, preferably with tumor available for biopsy, >5 half lives removed from previous therapy, and being screened for Phase I trials involving temsirolimus will be eligible (n = maximum 15). The exclusion criteria are pregnancy or lactation, <18 years of age, bleeding diathesis, or hypersensitivity to temsirolimus. Temsirolimus will be administered once, with a starting dose level of 0.02 mg (~1/50th NOAEL). PD markers will be assessed in PBMCs before and after dosing. Phase 0 patients who subsequently enroll on a temsirolimus-containing Phase I trial will have the same PD markers assessed to compare drug effect of Phase 0 and Phase I doses. The trial was activated in November 2010, currently has enrolled 4 patients, and is supported in part by 2K12CA088084-11.