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.
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.
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.
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.
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The data generated in this study are available upon request from the corresponding author.
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We thank James P. Zacny, PhD for his editorial support with the clinical protocol and manuscript. LC-MS/MS was performed at the Toxicology Research Laboratory, College of Medicine at the University of Illinois at Chicago. We thank the patients who participated and the Clinical Trials Office of the University of Illinois Cancer Center for providing the necessary clinical research infrastructure to execute this study.
Financial support was provided by Vanquish Oncology. Inc., the University of Illinois Cancer Center, the University of Illinois, the NIH (R01CA120439), and Engdahl Family Foundation.
PJH serves as Chief Scientific Officer and has equity in Vanquish Oncology, Inc. TMT serves as Chief Executive Officer and has equity in Vanquish Oncology, Inc. TMF serves as VP Preclinical Development and has equity in Vanquish Oncology, Inc. AZD reports research funding from Eli Lilly. AZD served as Chief Medical Officer for Vanquish Oncology, Inc. AZD serves as Chief Executive Officer for TTC Oncology, LLC, and Chief Medical Officer for IGF Oncology. All other authors declare no competing interests.
Ethics approval and consent to participate
The study was conducted according to International Conference on Harmonisation of Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The protocol was approved by the Institutional Review Board/Ethics Committee at each study location. All patients provided written informed consent before enrolment.
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Danciu, O.C., Holdhoff, M., Peterson, R.A. et al. Phase I study of procaspase-activating compound-1 (PAC-1) in the treatment of advanced malignancies. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-02089-7