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A phase I dose-escalation study of the polyamine analog PG-11047 in patients with advanced solid tumors

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Polyamines are essential for the sustained proliferation and biomass required by tumor cells. Bis-alkylated polyamine analogs are nonfunctional competitors of natural polyamines. Of these, PG-11047, a second-generation unsaturated analog of the polyamine spermine, has demonstrated anticancer activity in cell lines and animal models of multiple cancer types. This report describes the first phase I clinical trial to investigate PG-11047 in patients with advanced refractory metastatic solid tumors.

Methods

Forty-six patients were treated with 60-min intravenous infusions of PG-11047 using a 28-day dosing cycle with treatments on days 1, 8, and 15. Doses ranged from 50 to 750 mg. The treatment period consisted of at least two cycles.

Results

The maximum tolerated dose of PG-11047 administered at this dosing schedule was 610 mg. Dose-limiting toxicities (DLT) were mainly gastrointestinal, including oral/anal mucositis and diarrhea; other DLTs included one case each of angioedema and a grade 3 alanine aminotransferase (ALT) increase. The most common adverse effects were fatigue and anorexia. Stable disease was documented in 30% of patients.

Conclusion

Results of this phase I trial suggest that PG-11047 can be safely administered to patients on the once weekly dosing schedule described. The manageable toxicity profile and high MTD determination provide a safety profile for further clinical studies, including those in combination with current chemotherapeutic agents.

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Availability of data and material

Data collected during the study are available on www.clinicaltrials.gov, #NCT00705653.

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Acknowledgements

The authors would like to acknowledge Mark J. Ratain, M.D. of the University of Chicago, for serving as principle investigator of this study.

Funding

Funding for portions of this research was provided by the National Institutes of Health National Cancer Institute (R01CA51085, R01CA204345 and R01CA235863 to RAC).

Author information

Authors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRB 1, Room 562, Baltimore, MD, 21287, USA

    Tracy Murray Stewart

  2. Illinois Cancer Specialists, Elgin, IL, 60123, USA

    Apurva A. Desai

  3. Apex, NC, 27502, USA

    Michael L. Fitzgerald

  4. Cancer Commons, Los Altos, CA, 94022, USA

    Laurence J. Marton

  5. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRB 1, Room 551, Baltimore, MD, 21287, USA

    Robert A. Casero Jr.

Authors
  1. Tracy Murray Stewart
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  2. Apurva A. Desai
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  3. Michael L. Fitzgerald
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  4. Laurence J. Marton
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  5. Robert A. Casero Jr.
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Corresponding authors

Correspondence to Tracy Murray Stewart or Robert A. Casero Jr..

Ethics declarations

Conflict of interest

During the development of PG-11047, in vitro and in vivo preclinical studies of PG-11047 and related analogs were funded in part by a gift to the laboratory of RAC by Cellgate, Inc., the previous owner of PG-11047.

Ethics approval

The trial was conducted in accordance with the IRB-approved protocol, the ethical principles of Good Clinical Practice, according to the ICH Harmonized Tripartite Guideline, and the Declaration of Helsinki.

Informed consent

All participants provided written informed consent that was approved by the Institutional Review Board (IRB) of the University of Chicago.

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Murray Stewart, T., Desai, A.A., Fitzgerald, M.L. et al. A phase I dose-escalation study of the polyamine analog PG-11047 in patients with advanced solid tumors. Cancer Chemother Pharmacol 85, 1089–1096 (2020). https://doi.org/10.1007/s00280-020-04082-4

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  • DOI: https://doi.org/10.1007/s00280-020-04082-4

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