Phase I study of procaspase activating compound-1 (PAC-1) for treatment of advanced malignancies.

Abstract

TPS2621 Background: Dysregulation in apoptotic pathways is a hallmark feature of cancer, offering opportunities for pharmacologic intervention in its treatment. Caspases, a family of proteases, play several roles in apoptosis. Caspase-3 catalyzes the intra-cellular proteolysis that characterizes part of the apoptotic process. Caspase-3 levels are low in many tumors including: glioblastoma; breast, colon, lung, and liver cancers: lymphoma: neuroblastoma; and melanoma. In contrast, procaspase-3, the precursor of caspase-3 is elevated in these tumors. We describe a phase I study of PAC-1, a drug that catalyzes the conversion of procaspase -3 to caspase-3. It induces apoptosis in tumor cell lines in vitro. In vivo activity has also been shown, when combined with alkylating chemotherapy, in rodent glioma models and in canines diagnosed with malignant glioma. Methods: This Phase I dose escalation study has two components: the first (C1) to determine the maximum tolerated dose (MTD) of PAC-1 in advanced malignancies; the second (C2) to determine the MTD of PAC-1 when combined with temozolomide (TMZ) in patients with recurrent anaplastic astrocytoma (AA) or glioblastoma (GBM). A modified Fibonacci 3 + 3 design is used, expanding to nine subjects at the MTD level in each component. PAC-1 pharmacokinetics is assessed in all subjects during the first cycle. Secondary objectives include pharmacodynamics and correlations of PAC-1 activity with procaspase-3 expression in tumor tissue. Neurologic toxicity is closely monitored throughout the study. Inclusion criteria: diagnoses of advanced malignancies (C1) and recurrent AA or GBM (C2), ECOG PS 0-2, adequate organ function. Exclusion criteria: prior cytotoxic therapy in the last 3-6 weeks (varying with drug class) or uncontrolled chronic illness. Administration and design: For C1, PAC-1 (orally administered) is dosed at 75-1,000 mg daily on days 1-21 of each 28 day cycle. For C 2, the first PAC-1 dose is 375 mg daily with potential for escalation to 1,000 mg daily. TMZ, PO, is dosed at 150 mg/m2 daily, days 8-12, of each cycle. Enrollment to date for C1 is 27, (dose level 6); and for C2 is 4 (dose level 1). The study is open to accrual. Clinical trial information: NCT02355535.