2. Academic Validation
  3. 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

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. 2021 Jan;87(1):135-144. doi: 10.1007/s00280-020-04201-1.
Tracy Murray Stewart 1,  Daniel Von Hoff 2 3,  Michael Fitzgerald 4,  Laurence J Marton 5,  Carlos H Roberto Becerra 2 6,  Thomas E Boyd 7,  Paul R Conkling 2 8,  Lawrence E Garbo 2 9,  Robert M Jotte 2 10,  Donald A Richards 2 11,  David A Smith 12,  Joe J Stephenson Jr 13,  Nicholas J Vogelzang 2 14,  Hillary H Wu 15,  Robert A Casero Jr 16 17
Affiliations

Affiliations

  • 1 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRB 1, Room 562, Baltimore, MD, 21287, USA. tmurray2@jhmi.edu.
  • 2 US Oncology Research, The Woodlands, TX, USA.
  • 3 Translational Genomics Research Institute, Phoenix, AZ, USA.
  • 4 , Apex, NC, USA.
  • 5 Cancer Commons, Mountain View, CA, USA.
  • 6 Texas Oncology, Dallas, TX, USA.
  • 7 Yakima Valley Memorial Hospital North Star Lodge, Yakima, WA, USA.
  • 8 Virginia Oncology Associates, Norfolk, VA, USA.
  • 9 New York Oncology Hematology, Albany, NY, USA.
  • 10 Rocky Mountain Cancer Centers, Lone Tree, CO, USA.
  • 11 Texas Oncology, Tyler, TX, USA.
  • 12 Compass Oncology, Vancouver, WA, USA.
  • 13 Prisma Health Cancer Institute (ITOR), Greenville, SC, USA.
  • 14 Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
  • 15 Indiana University Health, Fishers, IN, USA.
  • 16 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRB 1, Room 562, Baltimore, MD, 21287, USA. rcasero@jhmi.edu.
  • 17 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRB 1, Room 551, Baltimore, MD, 21287, USA. rcasero@jhmi.edu.
PMID: 33215270 DOI: 10.1007/s00280-020-04201-1
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.

Keywords

5-fluorouracil; Bevacizumab; Bis-alkyl polyamine analogue PG-11047; Cancer; Chemotherapy; Cisplatin; Clinical trial; Docetaxel; Erlotinib; Sunitinib.

Figures
Products