Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer
Open accessAbstract
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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Results from recently published phase II clinical trials for TH-302 in combination with gemcitabine in pancreatic cancer or in combination with doxorubicin in soft tissue sarcoma are encouraging.
“Results from recently published phase II clinical trials for TH-302 in combination with gemcitabine in pancreatic cancer (Borad et al., 2015) or in combination with doxorubicin in soft tissue sarcoma (Chawla et al., 2014) are encouraging, and phase III studies have been initiated.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Borad et al., 2015
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- Authors
- Borad, M. J., Reddy, S. G., Bahary, N., Uronis, H. E., Sigal, D., Cohn, A. L., Schelman, W. R., Stephenson, J., Chiorean, E. G., Rosen, P. J., Ulrich, B., Dragovich, T., Del Prete, S. A., Rarick, M., Eng, C., Kroll, S., & Ryan, D. P.
- Affiliations
- Mayo Clinic in Arizona (US)
- 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....
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2015-05-01
- Volume
- 33
- Issue
- 13
- Pages
- 1475-1481
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC4881365
- OpenAlex
- W2167270217
- Cited by
- 197
- References
- 22
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 10 · 2023: 10 · 2022: 12 · 2021: 20 · 2020: 17 · 2019: 18 · 2018: 19 · 2017: 20 · 2016: 30 · 2015: 25
- FWCI
- 12.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000427)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- TH-302, gemcitabine, advanced pancreatic cancer, hypoxia-activated prodrug, combination chemotherapy, progression-free survival, overall survival, CA19-9, metastatic pancreatic cancer, locally advanced pancreatic cancer, drug safety, tolerability, predictive biomarkers, prognostic factors, tumor hypoxia, metastatic breast cancer
- MeSH terms
- Gemcitabine, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Deoxycytidine, Humans, Male, Middle Aged, Neoplasm Staging, Nitroimidazoles, Pancreatic Neoplasms, Phosphoramide Mustards, Time Factors, United States, Proportional Hazards Models, Treatment Outcome, Disease Progression, Disease-Free Survival, Kaplan-Meier Estimate
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