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A Phase Ib multicenter, dose-escalation study of the polyamine analogue PG-11047 in combination with gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil, or sunitinib in patients with advanced solid tumors or lymphoma

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Abstract

Purpose

Polyamines are absolutely essential for maintaining tumor cell proliferation. PG-11047, a polyamine analogue, is a nonfunctional competitor of the natural polyamine spermine that has demonstrated anticancer activity in cells and animal models of multiple cancer types. Preclinical investigations into the effects of common chemotherapeutic agents have revealed overlap with components of the polyamine metabolic pathway also affected by PG-11047. This report describes a Phase Ib clinical trial investigating PG-11047 in combination with cytotoxic and anti-angiogenic chemotherapeutic agents in patients with advanced refractory metastatic solid tumors or lymphoma.

Methods

A total of 172 patients were assigned to treatment arms based on cancer type to receive the appropriate standard-of-care therapy (gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil (5-FU), or sunitinib as directed) along with once weekly intravenous infusions of PG-11047. PG-11047 dose escalation ranged from 50 to 590 mg.

Results

The maximum tolerated dose (MTD) of PG-11047 in combination with bevacizumab, erlotinib, cisplatin, and 5-FU was 590 mg. Dose-limiting toxicities (DLTs) in these groups were rare (5 of 148 patients). Overall partial responses (PR) were observed in 12% of patients treated with PG-11047 and bevacizumab, with stable disease documented in an additional 40%. Stable disease occurred in 71.4% of patients in the 5-FU arm, 54.1% in the cisplatin arm, and 33.3% in the erlotinib arm. Four of the patients receiving cisplatin + PG-11047 (20%) had unconfirmed PRs. MTDs for gemcitabine, docetaxel, and sunitinib could not be determined due to DLTs at low doses of PG-11047 and small sample size.

Conclusions

Results of this Phase Ib trial indicate that PG-11047 can be safely administered to patients in combination with bevacizumab, erlotinib, cisplatin, and 5-FU on the once weekly dosing schedule described and may provide therapeutic benefit. The manageable toxicity profile and high MTD determination provide a safety profile for further clinical studies.

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Data availability

Data collected during the study are available on www.clinicaltrials.gov, #NCT00705874.

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Funding

Funding for portions of this research was provided by the National Institutes of Health National Cancer Institute (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 & Robert A. Casero Jr.

  2. US Oncology Research, The Woodlands, TX, USA

    Daniel Von Hoff, Carlos H. Roberto Becerra, Paul R. Conkling, Lawrence E. Garbo, Robert M. Jotte, Donald A. Richards & Nicholas J. Vogelzang

  3. Translational Genomics Research Institute, Phoenix, AZ, USA

    Daniel Von Hoff

  4. Apex, NC, USA

    Michael Fitzgerald

  5. Cancer Commons, Mountain View, CA, USA

    Laurence J. Marton

  6. Texas Oncology, Dallas, TX, USA

    Carlos H. Roberto Becerra

  7. Yakima Valley Memorial Hospital North Star Lodge, Yakima, WA, USA

    Thomas E. Boyd

  8. Virginia Oncology Associates, Norfolk, VA, USA

    Paul R. Conkling

  9. New York Oncology Hematology, Albany, NY, USA

    Lawrence E. Garbo

  10. Rocky Mountain Cancer Centers, Lone Tree, CO, USA

    Robert M. Jotte

  11. Texas Oncology, Tyler, TX, USA

    Donald A. Richards

  12. Compass Oncology, Vancouver, WA, USA

    David A. Smith

  13. Prisma Health Cancer Institute (ITOR), Greenville, SC, USA

    Joe J. Stephenson Jr.

  14. Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA

    Nicholas J. Vogelzang

  15. Indiana University Health, Fishers, IN, USA

    Hillary H. Wu

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

    Robert A. Casero Jr.

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  1. Tracy Murray Stewart
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  2. Daniel Von Hoff
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  3. Michael Fitzgerald
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  15. Robert A. Casero Jr.
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Corresponding authors

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

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Conflict of interest

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

Ethics approval and consent to participate

All participants provided written informed consent that was approved by the Institutional Review Boards (IRBs) associated with the study site prior to study initiation. The trial was conducted in accordance with the IRB-approved protocol and amendments, Good Clinical Practice guidelines, and the Declaration of Helsinki.

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Murray Stewart, T., Von Hoff, D., Fitzgerald, M. et al. A Phase Ib multicenter, dose-escalation study of the polyamine analogue PG-11047 in combination with gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil, or sunitinib in patients with advanced solid tumors or lymphoma. Cancer Chemother Pharmacol 87, 135–144 (2021). https://doi.org/10.1007/s00280-020-04201-1

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