Abstract LB-330: Phase I study of procaspase activating compound-1 (PAC-1) for treatment of advanced malignancies
Authors: Danciu Oana C. , Holdhoff Matthias , Peterson Richard A. , Hergenrother Paul J. , Tarasow Theodore M. , Dudek Arkadiusz Z. 
Published: September 2020

Abstract
Background: PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. This first-in-human, phase I, multicenter study for treatment of solid tumors or lymphoma evaluated safety, pharmacokinetics (PK), and preliminary clinical activity of single agent PAC-1 (NCT02355535).
Methods: A modified- Fibonacci dose-escalation 3+3 design was used in both components. The primary objective was to assess maximum tolerated dose (MTD). PAC-1 was dosed from 75 to 750 mg daily orally (7 dose levels (DL)) on days 1-21 on 28 days cycle. Dose limiting toxicity (DLT) was assessed during first two cycles of therapy. For all dose cohorts, PK of PAC-1 was assessed following doses administered on days 1 and 21 of the first cycle. Disease response evaluation was done every two cycles. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study due to concerns for potential neurotoxicity.
Results: Forty-eight patients were enrolled with thirty-three completing two cycles of therapy and evaluable for DLT and response. DL 1-5 no DLTs were observed. DL 6 was expanded to 6 patients due to one episode of intracranial bleed that occurred during cycle 4 of treatment, assessed initially as possibly related to study drug, but later attributed to new brain metastasis and unrelated to PAC-1. Grade 1 and 2 neurological adverse events such as ataxia and hallucinations were noted in DL 7 and that DL was established as MTD and expanded to 9 patients to assure safety. This cohort was later expanded by additional 3 patients with diagnosis of gastrointestinal or pancreatic neuroendocrine tumors (NET), because of partial response was seen in one patient in first 9 patients at this DL. Review of NNCF testing showed a consistent pattern of stable neurologic and cognitive evaluations. Twenty patients had progressive disease, eleven stable disease (SD), and two patients had partial response (PR) (both with diagnosis of NET). The longest progression free survival was seen in patient with leiomyosarcoma (12 months). Three patients with NET had SD for 4, 6, and 8 months, two had PR with disease control for 4, and 6 months. The PK data demonstrated satisfactory systemic delivery of PAC-1 following oral administration and acceptable absorption and elimination profiles. The dose proportionality was shown for PAC-1 systemic exposure. The PAC-1 half-life was established at 31.1 hours.
Conclusions: Single agent PAC-1 is well tolerated and 750 mg was determined to be safe and recommended for phase 2 studies. Intriguing activity of PAC-1 was seen in all patients with NET refractory to standard therapies that warrants further investigation in phase 2 clinical setting.
Citation Format: Oana C. Danciu, Matthias Holdhoff, Richard A. Peterson, Paul J. Hergenrother, Theodore M. Tarasow, Arkadiusz Z. Dudek. Phase I study of procaspase activating compound-1 (PAC-1) for treatment of advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-330.