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Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer.

Publication ,  Journal Article
Borad, MJ; Reddy, SG; Bahary, N; Uronis, HE; Sigal, D; Cohn, AL; Schelman, WR; Stephenson, J; Chiorean, EG; Rosen, PJ; Ulrich, B; Dragovich, T ...
Published in: J Clin Oncol
May 1, 2015

PURPOSE: TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide 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/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (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).

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Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

May 1, 2015

Volume

33

Issue

13

Start / End Page

1475 / 1481

Location

United States

Related Subject Headings

  • United States
  • Treatment Outcome
  • Time Factors
  • Proportional Hazards Models
  • Phosphoramide Mustards
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Nitroimidazoles
  • Neoplasm Staging
  • Middle Aged
 

Citation

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Borad, M. J., Reddy, S. G., Bahary, N., Uronis, H. E., Sigal, D., Cohn, A. L., … Ryan, D. P. (2015). Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer. J Clin Oncol, 33(13), 1475–1481. https://doi.org/10.1200/JCO.2014.55.7504
Borad, Mitesh J., Shantan G. Reddy, Nathan Bahary, Hope E. Uronis, Darren Sigal, Allen L. Cohn, William R. Schelman, et al. “Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer.J Clin Oncol 33, no. 13 (May 1, 2015): 1475–81. https://doi.org/10.1200/JCO.2014.55.7504.
Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, et al. Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer. J Clin Oncol. 2015 May 1;33(13):1475–81.
Borad, Mitesh J., et al. “Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer.J Clin Oncol, vol. 33, no. 13, May 2015, pp. 1475–81. Pubmed, doi:10.1200/JCO.2014.55.7504.
Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, Schelman WR, Stephenson J, Chiorean EG, Rosen PJ, Ulrich B, Dragovich T, Del Prete SA, Rarick M, Eng C, Kroll S, Ryan DP. Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer. J Clin Oncol. 2015 May 1;33(13):1475–1481.

Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

May 1, 2015

Volume

33

Issue

13

Start / End Page

1475 / 1481

Location

United States

Related Subject Headings

  • United States
  • Treatment Outcome
  • Time Factors
  • Proportional Hazards Models
  • Phosphoramide Mustards
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Nitroimidazoles
  • Neoplasm Staging
  • Middle Aged