Phase I Study of Procaspase Activating Compound-1 (PAC-1) in the Treatment of Advanced Malignancies

The primary objective of this study was to determine the maximum tolerated dose (MTD) of first procaspase-activating compound (PAC-1) in patients with advanced malignancy by evaluation of toxicity and tolerability. The MTD of PAC-1 was determined using a modified-Fibonacci dose-escalation 3+3 design, with a total of five dose levels. PAC-1 was given at the assigned dose orally on days 1-21 of a 28 day cycle. Disease reassessment was done every 2 cycles (8 weeks). Treatment for patients in the trial continued until disease progression, unacceptable toxicity, or patient refusal. For all dose cohorts, pharmacokinetics of PAC-1 were assessed following doses administered on days 1 and 21 of the first cycle. Twenty one patients were enrolled. All 21 patients received at least 1 dose of study drug and 15 were evaluable for at least 2 cycles; 6 patients were not evaluable, including 1 who dropped out after beginning therapy for reasons other than adverse events (AEs), and 5 who had rapidly progressive disease that precluded completion of 2 full cycles of therapy. Dose was escalated from dose level 1 (75 mg daily) to dose level 5 (450 mg daily). Three patients at each dose level 1-5 received at least 2 dosing cycles and no dose-limiting toxicities (DLTs) were observed. The majority of serious adverse events were grade 2 and 3 with the most common being constipation, electrolytes abnormalities, and infections. All serious adverse events (SAEs) were determined to be unrelated or unlikely related to the study drug. One patient expired while on study due to progression of disease. Review of the neurologic exams and Mini-Mental State Examination (MMSE) test scores from time points yoked with the neurocognitive (NCF) testing showed a consistent pattern of stable neurologic exams and MMSE scores. The pharmacokinetic data supports the satisfactory systemic delivery of PAC-1 following oral administration and acceptable absorption and elimination profiles.