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

• Published in: British journal of cancer Vol. 128; no. 5; pp. 783 - 792
• Main Authors: Danciu, Oana C., Holdhoff, Matthias, Peterson, Richard A., Fischer, James H., Liu, Li C., Wang, Heng, Venepalli, Neeta K., Chowdhery, Rozina, Nicholas, M. Kelly, Russell, Meredith J., Fan, Timothy M., Hergenrother, Paul J., Tarasow, Theodore M., Dudek, Arkadiusz Z.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.03.2023; Nature Publishing Group
• Subjects: 692/4028; 692/4028/67/1059/153; Antineoplastic Agents - therapeutic use; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cancer Research; Caspase 1; Caspase-3; Clinical trials; Cognition; Cognitive ability; Dosage; Drug Resistance; Epidemiology; Humans; Malignancy; Maximum Tolerated Dose; Molecular Medicine; Neoplasms - drug therapy; Neuroendocrine tumors; Oncology; Oral administration; PAC1 protein; Patients; Pharmacokinetics; Toxicity
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-022-02089-7

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 t 1/2 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 Trials.gov: NCT02355535.