A novel drug that is activated under conditions of hypoxia significantly delayed progression in locally advanced or metastatic pancreatic adenocarcinoma when combined with gemcitabine in untreated patients. The findings of the randomized phase II TH-CR-04 trial were presented at the 2012 ESMO Congress by Mitesh J. Borad, MD, Assistant Professor of Medicine at the Mayo Clinic in Scottsdale, Arizona.¹

TH-302 is a tumor-selective, hypoxia-activated cytotoxic prodrug. “Pancreatic cancer is one of the more hypoxic tumors,” he noted.

Study Details

The multicenter TH-CR-04 trial randomly assigned 214 patients with previously untreated advanced pancreatic adenocarcinoma to gemcitabine plus TH-302 (240 mg/m² or 340 mg/m²) or placebo.

Median progression-free survival was 6.0 months with gemcitabine plus TH-302 at the higher dose, 5.6 months with the lower dose of the drug, and 3.6 months with placebo, for a 41% reduction in progression with TH-302 given at 340 mg/m² (P = .008). All subgroups showed benefit, Dr. Borad reported.

Mean nadir change in CA19-9 was –523 U/mL with placebo, –3,909 U/mL with the lower dose of TH-302 and –5,385 U/mL with the higher dose, for a greater mean decrease with TH-302. Response rates were increased from 10% without the drug to 26% with TH-302.

Median overall survival was approximately 9 months with either active treatment arm and 6.9 months with placebo, which was not statistically significant (the study was not powered for this endpoint). In a post-hoc analysis, a significant difference was shown in 6-month survival between the gemcitabine arm (57%) and the high-dose TCH-302 arm (73%, P = .037), he added.

In addition, in the small group of 11 patients in the control arm who crossed over to the experimental arms, median overall survival reached 13.4 months with gemcitabine plus TH-302 given at 340 mg/m². While this open-label phase was not designed to estimate an overall survival treatment effect, and the number of patients is small, “this seems to be a wide disparity,” he noted.

Safety Considerations

The addition of the drug to gemcitabine primarily increased rash, fatigue, and stomatitis but these were mild. Grade 3/4 hematologic toxicities were significantly increased with the addition of the drug, but overall rates of serious adverse events were similar (54% with gemcitabine alone, 49% with gemcitabine plus the low-dose drug, and 58% with gemcitabine plus high-dose TH-302).

“There was no increase in creatinine, which is important as it distinguishes the safety profile of this drug vs ifosfamide, which has renal toxicity in high doses,” Dr. Borad noted. There was also no excess in study discontinuations among patients receiving TH-302.

A phase III study has been initiated to evaluate TH-302 at 340 mg/m². ■

Disclosure: Dr. Borad received research funding pertaining to conduct of the clinical study from Threshold Pharmaceuticals.

Reference

1. Borad MJ, Reddy S, Bahary N, et al: TH-302 plus gemcitabine vs gemcitabine in patients with untreated advanced pancreatic adenocarcinoma. Abstract 6660. Presented September 29, 2012.