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

Cancer Chemother Pharmacol. 2020 Jun;85(6):1089-1096. doi: 10.1007/s00280-020-04082-4. Epub 2020 May 23.

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.

Trial registration: ClinicalTrials.gov NCT00705653.

Keywords: Bis-alkyl polyamine analog; Cancer; Chemotherapy; Clinical trial.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Prognosis
  • Spermine / administration & dosage
  • Spermine / analogs & derivatives*
  • Spermine / pharmacokinetics
  • Tissue Distribution

Substances

  • (N(1),N(12))bis(ethyl)-6,7-dehydrospermine
  • Spermine

Associated data

  • ClinicalTrials.gov/NCT00705653