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Updated: Aug 18, 2025
Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Phase I study of procaspase-activating compound-1 (PAC-1) in the treatment of advanced malignancies
Oana C Danciu1,2, Matthias Holdhoff3, Richard A Peterson4
1Division of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. ocdanciu@uic.edu.
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 Trials.gov: NCT02355535.
Insights
The first human study of procaspase-activating compound 1 (PAC-1) established a recommended 750 mg/day dose for phase 2 trials. PAC-1 showed promising activity in neuroendocrine tumors, with manageable neurological side effects.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Procaspase-3 (PC-3) is overexpressed in various cancers.
- Procaspase-activating compound 1 (PAC-1) directly activates PC-3, inducing cancer cell apoptosis.
- This study reports the first-in-human Phase I trial of PAC-1.
Purpose of the Study:
- To assess the maximum tolerated dose (MTD) of PAC-1.
- To evaluate the safety and pharmacokinetics of PAC-1 in cancer patients.
- To explore preliminary clinical activity of PAC-1.
Main Methods:
- A modified Fibonacci dose-escalation 3+3 design was employed.
- PAC-1 was administered orally at 7 dose levels (DL) for 21 days in 28-day cycles.
- Dose-limiting toxicity (DLT), pharmacokinetics, and neurologic/neurocognitive function (NNCF) were assessed.
Main Results:
- The recommended Phase 2 dose was established at 750 mg/day (DL 7).
- Grade 1-2 neurological adverse events were observed, with stable NNCF.
- PAC-1 demonstrated clinical activity in neuroendocrine tumors (NET), with 2/5 patients achieving partial response.
Conclusions:
- A 750 mg/day dose of PAC-1 is recommended for Phase 2 studies.
- PAC-1 shows potential activity in treatment-refractory NET, warranting further investigation.
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