Promising New Drug for Pancreatic Cancer

The addition of an investigational hypoxia-targeted agent, TH-302, to gemcitabine improved overall survival (OS) versus gemcitabine alone in patients with advanced pancreatic cancer in an open-label phase 2b trial (Abstract 6660).⁵

The lead author of this trial, Mitesh Borad, MD, of the Mayo Clinic in Scottsdale, Arizona, said that the difference in OS was not significant, but that the trend was toward improved OS with the addition of TH-302. The drug will enter phase 3 trials shortly.

Hypoxia is due to the disordered vasculature that is a hallmark of pancreatic cancers and other solid tumors. TH-302 selectively targets levels of hypoxia common in tumors but rare in normal tissues. When the drug enters cancer cells, it is converted to an active form, dibromo isophoramide mustard, a potent DNA alkylator. The active form of the drug diffuses into the surrounding oxygenated regions of the tumor, exerting a bystander effect and killing more of the tumor than can be accounted for by the hypoxic fraction alone. Theoretically, this drug will produce less systemic toxicity than that caused by most cytotoxic agents.

The study randomized 214 previously untreated patients with locally advanced, unresectable or metastatic pancreatic cancer in a 1:1:1 ratio to receive either TH-302 240 mg/m2 plus gemcitabine; TH-302 340 mg/m² plus gemcitabine; or gemcitabine alone. Treatment was given on days 1, 8, and 15 of a 28-day cycle.

Median OS was 9.2 months with TH-302 340 mg/m² plus gemcitabine; 8.7 months with TH-302 240 mg/m2 plus gemcitabine; and 6.9 months with gemcitabine alone.

Borad said that these results were consistent with an overall improvement in progression-free survival reported earlier this year. The trial was not designed to detect a statistically significant improvement in OS, and survival was confounded by crossover allowing patients in the gemcitabine-alone arm to receive TH-302 plus gemcitabine at progression.

The most common adverse events related to TH-302 included skin and mucosal toxicity, and myelosuppression. At the higher dose of TH-302, the rate of rash was 47% and stomatitis was 42%, but these events were mainly mild and moderate. Hematologic toxicity on the higher dose of TH-302 was much greater than that seen with gemcitabine alone: thrombocytopenia was 63% versus 11%, respectively, and neutropenia was 60% versus 30%, respectively.
The dose of 340 mg/m2 will be taken forward in the phase 3 trial.