Phase I study of procaspase-activating compound-1 (PAC-1) in the treatment of advanced malignancies

Oana C. Danciu, Matthias Holdhoff, Richard A. Peterson, James H. Fischer, Li C. Liu, Heng Wang, Neeta K. Venepalli, Rozina Chowdhery, M. Kelly Nicholas, Meredith J. Russell, Timothy M. Fan, Paul J. Hergenrother, Theodore M. Tarasow, Arkadiusz Z. Dudek

Research output: Contribution to journalArticlepeer-review


Background: Procaspase-3 (PC-3) is overexpressed in multiple tumour types and procaspase-activating compound 1 (PAC-1) directly activates PC-3 and induces apoptosis in cancer cells. This report describes the first-in-human, phase I study of PAC-1 assessing maximum tolerated dose, safety, and pharmacokinetics. Methods: Modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered orally at 7 dose levels (DL) on days 1–21 of a 28-day cycle. Dose-limiting toxicity (DLT) was assessed during the first two cycles of therapy, and pharmacokinetics analysis was conducted on days 1 and 21 of the first cycle. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study. Results: Forty-eight patients were enrolled with 33 completing ≥2 cycles of therapy and evaluable for DLT. DL 7 (750 mg/day) was established as the recommended phase 2 dose, with grade 1 and 2 neurological adverse events noted, while NNCF testing showed stable neurologic and cognitive evaluations. PAC-1’s t1/2 was 28.5 h after multi-dosing, and systemic drug exposures achieved predicted therapeutic concentrations. PAC-1 clinical activity was observed in patients with neuroendocrine tumour (NET) with 2/5 patients achieving durable partial response. Conclusions: PAC-1 dose at 750 mg/day was recommended for phase 2 studies. Activity of PAC-1 in treatment-refractory NET warrants further investigation. Clinical trial registration: Clinical NCT02355535.

Original languageEnglish (US)
Pages (from-to)783-792
Number of pages10
JournalBritish Journal of Cancer
Issue number5
StatePublished - Mar 23 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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