Tracy Murray Stewart1, Daniel Von Hoff2,3, Michael Fitzgerald4, Laurence J Marton5, Carlos H Roberto Becerra2,6, Thomas E Boyd7, Paul R Conkling2,8, Lawrence E Garbo2,9, Robert M Jotte2,10, Donald A Richards2,11, David A Smith12, Joe J Stephenson13, Nicholas J Vogelzang2,14, Hillary H Wu15, Robert A Casero16,17. 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.
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.
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.
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: Hillary A Hahm; David S Ettinger; Kathy Bowling; Beth Hoker; Tian Ling Chen; Yelena Zabelina; Robert A Casero Journal: Clin Cancer Res Date: 2002-03 Impact factor: 12.531
Authors: Natalia A Ignatenko; Hagit F Yerushalmi; Ritu Pandey; Karen L Kachel; David E Stringer; Laurence J Marton; Eugene W Gerner Journal: Cancer Genomics Proteomics Date: 2009 May-Jun Impact factor: 4.069
Authors: Elizabeth C Lewis; Jacqueline M Kraveka; William Ferguson; Don Eslin; Valerie I Brown; Genevieve Bergendahl; William Roberts; Randal K Wada; Javier Oesterheld; Deanna Mitchell; Jessica Foley; Peter Zage; Jawhar Rawwas; Maria Rich; Elizabeth Lorenzi; Kristine Broglio; Donald Berry; Giselle L Saulnier Sholler Journal: Int J Cancer Date: 2020-05-24 Impact factor: 7.396