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Addition of Hypoxia-Activated Prodrug TH-302 to Gemcitabine Improves Progression-Free Survival in Advanced Pancreas Cancer

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Key Points

  • The addition of TH-302 to gemcitabine significantly increased progression-free survival.
  • Combination treatment was associated with higher tumor response rate and greater CA 19-9 response.

TH-302 is a hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. In a phase II trial reported in the Journal of Clinical Oncology, Borad et al found that the addition of TH-302 to gemcitabine improved progression-free survival in patients with previously untreated advanced pancreatic cancer. A phase III trial of TH-302/gemcitabine is underway.

Study Details

In this open-label study, 214 U.S. patients with locally advanced or metastatic pancreas cancer were randomly assigned 1:1:1 between June 2010 and July 2011 to receive gemcitabine at 1,000 mg/m2 without (n = 69) or with intravenous TH-302 at 240 mg/m2 (n = 71) or 340 mg/m2 (n = 74) on days 1, 8, and 15 of 28-day cycles. Overall, 77% of patients had metastatic disease.

Randomized crossover after progression on gemcitabine was permitted. The primary endpoint was progression-free survival for the pooled TH-302 groups vs gemcitabine alone.

Progression-Free Survival

Median progression-free survival was 5.6 months in the pooled TH-302 groups vs 3.6 months in the gemcitabine group (hazard ratio [HR] = 0.61, P = .005), including 5.1 vs 3.4 months (HR = 0.59, 95% confidence interval [CI] = 0.41–0.86) among patients with metastatic disease and 9.0 vs 6.2 months (HR = 0.82, 95% CI = 0.36–1.89) among those with locally advanced disease. In multivariate analysis adjusting for age, Eastern Cooperative Oncology Group performance status, metastatic disease and sites, and sex, the hazard ratio remained significant (0.61, 95% CI = 0.43–0.85). Median progression-free survival was also significantly prolonged in both the lower-dose TH-302/gemcitabine group (5.6 months, HR = 0.66, P = .040) and the higher-dose combination group (6.0 months, HR = 0.59,  P = .008) compared with gemcitabine alone.

After progression, 26 patients in the gemcitabine group (38%) crossed over to randomized TH-302 at 240 mg/m2 (n = 14) or 340 mg/m2 (n = 12).

Other Outcomes

Median overall survival was 8.7 months in the lower-dose TH-302 group (P = .77 vs gemcitabine alone), 9.2 months in the higher-dose TH-302 group (P  = .39), and 6.9 months with gemcitabine alone. Objective response rates were 17% and 26% (P = .04 vs gemcitabine alone) vs 12%. Reduction in CA 19-9 in the higher-dose TH-302/gemcitabine group was significantly greater than that with gemcitabine alone (decrease of 5,398 vs 549 U/mL, P = .008). CA 19-9 decreases > 90% of baseline values occurred in 32% of the higher-dose combination group, 25% of the lower-dose combination group, and 16% of the gemcitabine group.

Adverse Events

The most common nonhematologic adverse events of any grade in the lower-dose and higher-dose TH-302 combination groups vs gemcitabine alone were fatigue (61% and 55% vs 42%), nausea (39% and 46% vs 39%), and peripheral edema (37% and 42% vs 39%); rash (42% and 50% vs 17%) and stomatitis (18% and 36% vs 7%) were more common in the combination groups. Grade 3 or 4 hematologic adverse events were 30% and 55% vs 12% for thrombocytopenia, 34% and 43% vs 17% for neutropenia, 2.8% and 5.4% vs 0% for febrile neutropenia, and 34% and 43% vs 29% for anemia.

Adverse events led to discontinuation of treatment in 15% and 14% vs 19% of patients. Gemcitabine dose reductions during the first six cycles occurred in 51% and 72% vs 42% of patients.

The investigators concluded: “[Progression-free survival], tumor response, and CA 19-9 response were significantly improved with [gemcitabine plus] TH-302…. On the basis of the findings in this phase II study, a global phase III clinical trial (MAESTRO; NCT01746979) comparing gemcitabine plus TH-302 at 340 mg/m2 versus gemcitabine plus placebo was initiated.”

Mitesh J. Borad, MD, of Mayo Clinic, Scottsdale, Arizona, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by Threshold Pharmaceuticals and Merck KGaA. For full disclosures of the study authors, visit jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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