Adding an investigational hypoxia-activated cytotoxic agent, TH-302, to standard gemcitabine chemotherapy significantly improved progression-free survival and the tumor response rate in a phase II clinical trial of adults with advanced or metastatic pancreatic cancer, according to a report published online Dec. 15 in the Journal of Clinical Oncology.

The encouraging results of this industry-sponsored open-label trial (NCT01144455) spurred the initiation of an international phase III study of TH-302 (NCT01746979), which “has the potential to provide an alternative regimen to the current standard-of-care regimens,” as well as a phase I/II study combining TH-302 with gemcitabine plus nab-paclitaxel (NCT02047500) for pancreatic cancer, said Dr. Mitesh J. Borad of the Mayo Clinic, Scottsdale, Ariz., and his associates.

In this trial, 214 patients who hadn’t received any systemic therapy for pancreatic cancer were enrolled during a 1-year period and treated at 45 U.S. medical centers. The study participants were randomly assigned to receive gemcitabine alone, which was the standard of care at the time (69 patients); a lower dose of TH-302 (240 mg/m2) plus gemcitabine (71 patients); or a higher dose of TH-302 (340 mg/m2) plus gemcitabine (74 patients). Any patients in the gemcitabine-only group whose disease progressed were allowed to cross over and be randomly assigned to one of the other study groups, and 26 patients did so.

The primary efficacy endpoint, progression-free survival, was significantly prolonged with the addition of TH-302 (median, 5.6 months), compared with gemcitabine alone (median, 3.6 months). The rate of complete or partial tumor response also was significantly higher with the addition of lower-dose TH-302 (17%) or higher-dose TH-302 (26%) than with gemcitabine alone (12%).

The median overall survival was longer with lower-dose TH-302 (8.7 months) or higher-dose TH-302 (9.2 months) than with gemcitabine alone (6.9 months), but this difference did not attain statistical significance. However, the study wasn’t sufficiently powered to compare overall survival, which would have required a larger sample size. And permitting crossover from the control to the TH-302 groups also disallowed valid comparisons in overall survival, Dr. Borad and his associates said (J. Clin. Oncol. 2014 Dec. 15 [doi:10.1200/JCO.2014.55.7504]).

As expected, skin toxicity, mucosal toxicity, and enhanced myelosuppression were the most frequent adverse events related to TH-302. However, these effects were “manageable,” given that the rate of treatment discontinuation was no higher among patients who received the drug than among those who did not, the investigators added.


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