O-0008 Phase II Study of Gemcitabine + TH-302 vs Gemcitabine Alone in Patients with Locally Advanced and Metastatic Pancreatic Cancer

ABSTRACT Introduction TH-302 is a cytotoxic prodrug designed to specifically target the hypoxic microenvironment of tumours. Combining TH-302 with gemcitabine may enable the targeting of both the normoxic and hypoxic regions of PAC. Methods Results from a Phase II open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with gemcitabine versus gemcitabine alone (randomized 1:1:1) are presented. 214 patients participated, 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age was 65 (range 29-86); M/F 59%/41% 40% ECOG 0 and 60% ECOG 1; 58% involved head of pancreas; 36% biliary stent. Median PFS was 3.6 months (mo) in gemcitabine vs 5.6 mo in combination with a HR of 0.61 (95% CI: 0.43 – 0.87), p-value 0.005. In patients with distant metastases the median PFS was 3.5 mo in gemcitabine and 5.1 mo in each of the combination arms with a HR of 0.62 (95% CI: 0.42 – 0.90). Results In patients with unresectable locally advanced disease the median PFS was 5.3 mo in gemcitabine, 8.5 mo in the 240 dose group and 9.5 mo in the 340 dose group with a HR for the two combination arms of 0.59 (95% CI: 0.25 – 1.38). RECIST best response was 12% in gemcitabine, 17% in 240 dose group and 27% in 340 dose group. The response rate in the 340 group was 24% in pts with distant metastases and 35% in pts with locally advanced disease. The most common adverse events were fatigue (49%), nausea (43%), constipation (34%) and peripheral edema (34%), similar across groups. Rash (45% in 340 group) and stomatitis (36% in 340 group) were greater in combination groups with no CTC G4 (4 pts with G3). G3/4 thrombocytopenia (11% gemcitabine, 39% 240 and 59% 340) and G3/4 neutropenia (28% gemcitabine, 56% 240 and 59% 340) were higher with the combination. Conclusion Data warrant further investigation of the compound in Phase III in advanced PAC regardless of disease stage.