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J Clin Oncol. 2015 May 1;33(13):1475-81. doi: 10.1200/JCO.2014.55.7504. Epub 2014 Dec 15.

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

Author information

1
Mitesh J. Borad, Mayo Clinic, Scottsdale; Tomislav Dragovich, Arizona Cancer Center, Tucson, AZ; Shantan G. Reddy, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA; Nathan Bahary, University of Pittsburgh Medical Center, Pittsburgh, PA; Hope E. Uronis, Duke University Medical Center, Durham, NC; Darren Sigal, Scripps Clinic, La Jolla; Peter J. Rosen, Disney Family Cancer Center, Burbank; Clarence Eng and Stew Kroll, Threshold Pharmaceuticals, South San Francisco, CA; Allen L. Cohn, Rocky Mountain Cancer Center, Denver, CO; William R. Schelman, University of Wisconsin Carbone Cancer Center, Madison, WI; Joe Stephenson Jr, Institute for Translational Oncology Research, Greenville, SC; E. Gabriela Chiorean, Indiana University Simon Cancer Center, Indianapolis, IN; Brian Ulrich, Texas Oncology, Wichita Falls, TX; Salvatore A. Del Prete, Hematology Oncology PC, Stamford, CT; Mark Rarick, Kaiser Permanente Northwest Region Oncology Hematology, Portland, OR; and David P. Ryan, Massachusetts General Hospital Cancer Center, Boston, MA. Borad.mitesh@mayo.edu.
2
Mitesh J. Borad, Mayo Clinic, Scottsdale; Tomislav Dragovich, Arizona Cancer Center, Tucson, AZ; Shantan G. Reddy, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA; Nathan Bahary, University of Pittsburgh Medical Center, Pittsburgh, PA; Hope E. Uronis, Duke University Medical Center, Durham, NC; Darren Sigal, Scripps Clinic, La Jolla; Peter J. Rosen, Disney Family Cancer Center, Burbank; Clarence Eng and Stew Kroll, Threshold Pharmaceuticals, South San Francisco, CA; Allen L. Cohn, Rocky Mountain Cancer Center, Denver, CO; William R. Schelman, University of Wisconsin Carbone Cancer Center, Madison, WI; Joe Stephenson Jr, Institute for Translational Oncology Research, Greenville, SC; E. Gabriela Chiorean, Indiana University Simon Cancer Center, Indianapolis, IN; Brian Ulrich, Texas Oncology, Wichita Falls, TX; Salvatore A. Del Prete, Hematology Oncology PC, Stamford, CT; Mark Rarick, Kaiser Permanente Northwest Region Oncology Hematology, Portland, OR; and David P. Ryan, Massachusetts General Hospital Cancer Center, Boston, MA.

Abstract

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).

PMID:
25512461
PMCID:
PMC4881365
DOI:
10.1200/JCO.2014.55.7504
[Indexed for MEDLINE]
Free PMC Article

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