Randomized phase II trial of gemcitabine plus TH-302 versus gemcitabine in patients with advanced pancreatic cancer

Mitesh J. Borad, Shantan G. Reddy, Nathan Bahary, Hope E. Uronis, Darren Sigal, Allen L. Cohn, William R. Schelman, Joe Stephenson, E. Gabriela Chiorean, Peter J. Rosen, Brian Ulrich, Tomislav Dragovich, Salvatore A. Del Prete, Mark Rarick, Clarence Eng, Stew Kroll, David P. Ryan

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Purpose: TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromoisophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. Patients and Methods: Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m2), gemcitabine plus TH-302 240 mg/m2 (G+T240), or gemcitabine plus TH-302 340 mg/m2 (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. Results: Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation. Conclusion: PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

Original languageEnglish (US)
Pages (from-to)1475-1481
Number of pages7
JournalJournal of Clinical Oncology
Volume33
Issue number13
DOIs
StatePublished - May 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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