The addition of the investigational agent TH-302 to gemcitabine significantly improved PFS, tumor response and CA 19-9 response in patients with treatment-naive locally advanced or metastatic pancreatic cancer, according to results of a randomized phase 2 study.
TH-302 (Threshold Pharmaceuticals) — a hypoxia-activated, cytotoxic prodrug designed to release the DNA alkylator bromoisophosphoramide mustard in hypoxic settings — has demonstrated clinical activity in several types of solid tumors, including pancreatic cancer.
Mitesh J. Borad, MD, assistant professor of medicine and director of phase 1 drug development at Mayo Clinic in Scottsdale, Ariz., and colleagues conducted an open-label, multicenter trial to evaluate the combination of TH-302 and gemcitabine in previously untreated pancreatic cancer.
The analysis included 214 patients treated at 45 sites in the United States between June 2010 and July 2011.
Borad and colleagues randomly assigned patients to one of three treatment arms: 69 patients received single-agent gemcitabine 1,000 mg/m2; 71 patients received gemcitabine plus TH-302 administered at a dose of 240 mg/m2; and 74 patients received gemcitabine plus TH-302 administered at a dose of 340 mg/m2.
Treatment was administered on days 1, 8 and 15 of each 28-day cycle. Patients assigned single-agent gemcitabine received it via IV infusion over 30 minutes. Patients assigned one of the combination regimens received TH-302 via IV infusion over 30 to 60 minutes, followed 2 hours later by a 30-minute IV infusion of gemcitabine.
Patient demographics and disease characteristics at baseline were balanced between groups. Study protocols allowed patients who progressed on single-agent gemcitabine to cross over to combination treatment.
PFS served as the primary endpoint. Secondary endpoints included OS, tumor response, CA 19-9 response and safety.
Median PFS was 6 months among patients assigned the higher dose of TH-302, 5.6 months among patients assigned the lower dose of TH-302, and 3.6 months among patients assigned gemcitabine alone.
Pooled results of the two combination regimens showed patients assigned gemcitabine plus TH-302 demonstrated longer median PFS than those assigned gemcitabine alone (5.6 months vs. 3.6 months; HR=0.61; 95% CI, 0.43-0.87). Researchers also observed a PFS benefit with TH-302 among patients with metastatic disease (5.1 months vs. 3.4 months).
Response rates were 26% among patients assigned the higher TH-302 dose, 17% among those assigned the lower TH-302 dose and 12% among those assigned gemcitabine alone (P=.04).
The difference in CA 19-9 levels was greater among those assigned gemcitabine plus the higher dose of TH-302 vs. those assigned gemcitabine alone (5,398 U/mL vs. 549 U/mL; P=.008).
Researchers observed improved OS among patients assigned the combination regimens, but the differences were not statistically significant. Median OS was 9.2 months among patients assigned the higher TH-302 dose, 8.7 months among those assigned the lower TH-302 dose and 6.9 months among those assigned gemcitabine alone.
The combination of TH-302 and gemcitabine appeared well tolerated, according to researchers. Fifty-five percent of patients reported grade 3 or grade 4 myelosuppression, and 2% of patients developed grade 3 skin and mucosal toxicities.
A global phase 3 trial designed to compare gemcitabine plus TH-302 at a dose of 340 mg/m2 vs. gemcitabine plus placebo is underway.
“If successful, the combination of gemcitabine plus TH-302 has the potential to provide an alternative regimen to the current standard-of-care regimens, gemcitabine plus nap-paclitaxel and FOLFIRINOX, particularly given the limited neuropathy of gemcitabine plus TH-302,” Borad and colleagues wrote.