A secondary analysis of a combination of an investigational hypoxia-targeted agent called TH-302 with the chemotherapy drug gemcitabine slightly improved overall survival (OS) compared with patients who received gemcitabine alone, but the results were not statistically significant.
However, the positive results are consistent with previous data that showed a statistically significant improvement in progression-free survival (PFS) among the same group of pancreatic cancer patients.
TH-302 targets areas of low oxygen, or hypoxia, in solid tumors. Research has found that subregional hypoxia in tumors often leads to the failure of other cancer treatment options like chemotherapy and radiotherapy. Hence, TH-302 is being investigated in several different solid tumor types, including pancreatic cancer, soft tissue sarcoma, renal cell carcinoma, and gastrointestinal stromal tumors, as well as some hematologic malignancies like multiple myeloma in which hypoxia is implicated.
The results of the phase IIB study were released by the manufacturer, Threshold Pharmaceuticals, in advance of the 2012 meeting of the European Society for Medical Oncology (ESMO), held from September 28 to October 2, 2012, where they will also be presented. Threshold has a global license and co-development agreement with Merck KGaA of Germany for TH-302.
The randomized, controlled trial enrolled 214 previously untreated patients with locally advanced unresectable or metastatic pancreatic cancer. These patients were randomized to receive either 240 mg/m2 TH-302 plus gemcitabine (n=71), 340 mg/m2 TH-302 plus gemcitabine (n=74), or gemcitabine alone (n=69). Patients in the gemcitabine alone arm whose disease progressed were allowed to be randomized to either of the other two arms of the study. Threshold reported that the trial was 80% powered to detect a 50% improvement in PFS with a P
-value of .20, with overall survival as a secondary endpoint.
The study found that patients who received 340 mg/m2 TH-302 plus gemcitabine experienced a median overall survival of 9.2 months compared with 6.9 months in patients who received gemcitabine alone (hazard ratio [HR] = 0.955; 95% confidence interval [CI], 0.67-1.37, P
= .800). Patients who received 240 mg/m2 TH-302 plus gemcitabine experienced a median overall survival period of 8.7 months compared with the gemcitabine alone arm (HR = 0.960; 95% CI, 0.67-1.38, P
= .827). Threshold said that patients who crossed over from the gemcitabine arm to either of the other two study arms did contribute to an increase in survival of the control arm.
At the American Association for Cancer Research meeting held earlier this year, phase II data showed a statistically significant improvement in PFS among pancreatic cancer patients who received the TH-302 and gemcitabine combination. The median PFS was 3.6 months in patients who received gemcitabine alone compared with 5.6 months in patients who received TH-302 plus gemcitabine (HR = 0.61; 95% CI, 0.43 - 0.87; P
Threshold reported that the most common adverse events observed in the phase IIB study were fatigue, nausea, constipation and peripheral edema, with similar results across groups. Grade 1 and 2 skin and mucosal toxicities and myelosuppression were the most common adverse events related to TH-302, but they did not result in an increase in patients who discontinued treatment during the study, according to Threshold.
“We are pleased with the overall consistency of results from this study demonstrating activity of TH-302 and, as a consequence, a randomized phase III trial of TH-302 in patients with advanced first-line pancreatic cancer is planned to be initiated together with our partner Merck KGaA,” said Barry Selick, PhD, Chief Executive Officer of Threshold.
An estimated 37,390 people in the United States will die from pancreatic cancer in 2012, according to the National Cancer Institute. The government agency recommends clinical trials for patients with any stage of the disease because these patients tend to have poor responses to conventional treatments such as chemotherapy, radiation therapy, and surgery. Gemcitabine-based regimens are recommended across all stages of disease, according to guidelines issued by the National Comprehensive Cancer Network.
Borad MJ, Reddy S, Uronis H, et al. Randomized phase II study of the efficacy and safety of gemcitabine plus TH-302 versus gemcitabine alone in previously untreated patients with advanced pancreatic cancer. Presented at the American Association for Cancer Research; March 31-April 4, 2012; Chicago, IL. Abstract LB-121.