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Clinical Studies

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

British Journal of Cancer volume 128, pages 783–792 (2023)Cite this article

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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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Fig. 1: Pharmacokinetics of PAC-1.
Fig. 2: Duration of therapy and response to treatment at different dose levels.
Fig. 3: Procaspase-3 (PC-3) expressions in diverse tumour histologies categorised as moderate-to-strong immunostaining intensities.

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Data availability

The data generated in this study are available upon request from the corresponding author.

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Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Oana C. Danciu, Neeta K. Venepalli, Rozina Chowdhery & M. Kelly Nicholas

  2. Clinical Trials Office, University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA

    Oana C. Danciu & Meredith J. Russell

  3. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    Matthias Holdhoff

  4. HealthPartners Institute, Regions Cancer Care Center, St. Paul, MN, USA

    Richard A. Peterson & Arkadiusz Z. Dudek

  5. Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA

    James H. Fischer

  6. Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA

    Li C. Liu & Heng Wang

  7. Vanquish Oncology, Inc., Champaign, IL, USA

    Timothy M. Fan, Paul J. Hergenrother, Theodore M. Tarasow & Arkadiusz Z. Dudek

  8. Department of Veterinary Clinical Medicine, University of Illinois, Urbana-Champaign, IL, USA

    Timothy M. Fan

  9. Cancer Center at Illinois, Urbana-Champaign, IL, USA

    Timothy M. Fan & Paul J. Hergenrother

  10. Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL, USA

    Timothy M. Fan & Paul J. Hergenrother

  11. Department of Chemistry, University of Illinois, Urbana-Champaign, IL, USA

    Paul J. Hergenrother

Authors
  1. Oana C. Danciu
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  2. Matthias Holdhoff
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Contributions

AZD and OCD designed the study. OCD, MH, RAP, NKV, and MJR acquired the data. OCD, MH, RAP, and NKV provided RECIST assessments. JHF did the pharmacokinetic testing. LCL did the statistical analysis. AZD, PJH, TMF, TMT, and OCD provided data analysis. AZD and OCD prepared the initial draft of the manuscript. Revisions were prepared by AZD, PJH, TMF, TMT, and OCD. All authors contributed to subsequent manuscript drafts and agreed with the submission of the manuscript for publication.

Corresponding author

Correspondence to Oana C. Danciu.

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Competing interests

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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Not applicable.

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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 128, 783–792 (2023). https://doi.org/10.1038/s41416-022-02089-7

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