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Clinical Trial
. 2023 Mar;128(5):783-792.
doi: 10.1038/s41416-022-02089-7. Epub 2022 Dec 5.

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

Oana C Danciu  1   2 , Matthias Holdhoff  3 , Richard A Peterson  4 , James H Fischer  5 , Li C Liu  6 , Heng Wang  6 , Neeta K Venepalli  7 , Rozina Chowdhery  7 , M Kelly Nicholas  7 , Meredith J Russell  8 , Timothy M Fan  9   10   11   12 , Paul J Hergenrother  9   11   12   13 , Theodore M Tarasow  9 , Arkadiusz Z Dudek  4   9
Affiliations
Clinical Trial

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

Oana C Danciu et al. Br J Cancer. 2023 Mar.

Abstract

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.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1. Pharmacokinetics of PAC-1.
a PAC-1 plasma concentration-time profiles following a single oral dose of 75, 150, 250, 375, 450, 625, or 750 mg (mean ± standard deviation). b PAC-1 plasma concentration-time profiles following a multiple oral dose of 75, 150, 250, 375, 450, 625, or 750 mg administered daily for 11 or 21 days (mean ± standard deviation).
Fig. 2
Fig. 2. Duration of therapy and response to treatment at different dose levels.
Responses were assessed in accordance with RECIST v1.1. PD progressive disease, SD stable disease, PR partial response, NET neuroendocrine tumour.
Fig. 3
Fig. 3. Procaspase-3 (PC-3) expressions in diverse tumour histologies categorised as moderate-to-strong immunostaining intensities.
Paired H&E and PC-3 from a, e metastatic neuroendocrine tumour, b, f metastatic hemangioendothelioma, c, g ductal breast carcinoma, and d, h carcinosarcoma. Magnification ×400.
See this image and copyright information in PMC

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