The study reached its pre-specified primary efficacy endpoint with a median increase in progression-free survival (PFS) from 3.6 months to 5.6 months in the pooled patients treated with TH-302 (at a dose of 240 mg/m2 or a dose 340 mg/m2) in combination with gemcitabine compared to gemcitabine alone. The combination regimen was also associated with an increase in tumor response rate from 12% to 22% and a greater decrease in serum CA19-9. In addition, a dose response was identified with the greatest efficacy in the higher 340 mg/m2 group with a median PFS of 6.0 months, response rate of 27% and larger CA19-9 decreases. TH-302-related toxicities were also dose dependent. TH-302 related toxicities including skin and mucosal toxicities and myelosuppression were dose dependent and consistent with previous trials and did not result in an increase in discontinuations due to adverse events.
"The detailed results from this first randomized study of TH-302 confirm the earlier results from our previous non-randomized 402 study for patients with pancreatic cancer. In that study, patients in a number of indications including pancreatic cancer appeared to benefit from the addition of TH-302 to standard chemotherapy based on comparisons to historical control data," said
Clinical Trial Design
TH-CR-404 (the "404 study") is a multi-center, randomized, controlled, dose-ranging, Phase 2b crossover clinical trial of TH-302 in combination with a standard gemcitabine regimen in patients with first-line advanced pancreatic cancer. The primary endpoint of the trial was PFS. The secondary endpoints were overall response rate, overall survival, and change in CA19-9 as well as various other efficacy and safety parameters. Tumor response was evaluated at baseline and every eight weeks using RECIST. Patients for whom monotherapy with gemcitabine is considered standard therapy were eligible for the trial. Patients were randomized equally into one of three cohorts: TH-302 at a dose of 240 mg/m2 plus gemcitabine, TH-302 at a dose of 340 mg/m2 plus gemcitabine, or gemcitabine alone. Patients who successfully completed six cycles of treatment without evidence of significant treatment-related toxicity or progressive disease could continue to receive treatment. If a patient experienced cancer progression on gemcitabine alone, the patient could cross over into one of the TH-302 plus gemcitabine cohorts. The primary efficacy analysis was performed based upon 149 investigator-assessed PFS events and, per protocol, the primary efficacy endpoint pooled data from the two gemcitabine plus TH-302 dose groups in the comparison to gemcitabine alone.
The median PFS was 5.6 months for pooled patients treated with gemcitabine in combination with TH-302 at either 240 mg/m2 or 340 mg/m2 compared to 3.6 months for patients treated with gemcitabine alone. The PFS hazard ratio comparing the TH-302 combination to gemcitabine alone was 0.61 (95% confidence interval: 0.43 - 0.87), which was highly statistically significant (p = 0.005). The median PFS was 6.0 months in the 340 mg/m2 group. The response rate in the pooled combination arms was 22% compared to 12% in the gemcitabine alone group with a 17% response rate in the 240 mg/m2 group and 27% response rate in the 340 mg/m2 group. A similar dose dependency was reported in serum CA19-9 levels.
There was greater drug exposure in the combination groups with a median of 4 cycles received with gemcitabine alone compared with 5 cycles in the 240 mg/m2 group and 6 cycles in the 340 mg/m2 group. The combination safety profile was consistent with the prior study of this combination regimen. As in that study, skin and mucosal toxicities and myelosuppression were TH-302 dose dependent and consistent with previous trials and did not result in an increase in discontinuations due to adverse events. The doses used in the 404 study were less than the single-agent maximum tolerated dose of TH-302, which was previously established at 575 mg/m2. The incidence of grade 3/4 thrombocytopenia and grade 3/4 neutropenia was significantly higher in the combination arms and highest in the 340 mg/m2 group. Discontinuations for adverse events were lowest in the 340 mg/m2 group.
An update of the efficacy and safety data from the study, including data on overall survival, is expected to be released later this year.
About Pancreatic Cancer
Pancreatic cancer is a malignant neoplasm of the pancreas with current treatment options including surgery, radiotherapy and chemotherapy. Gemcitabine as a single agent or in combination with other treatments is the most commonly used chemotherapeutic agent in patients with advanced pancreatic cancer. It is estimated that approximately 279,000 cases of pancreatic cancer were diagnosed worldwide in 2008. Pancreatic cancer is the fourth most common cause of cancer death both in
TH-302 is a hypoxia-targeted drug that is thought to be activated under tumor hypoxic conditions, a hallmark of many cancer indications. Areas of low oxygen levels (hypoxia) within tissues are common in many solid tumors due to insufficient blood vessel growth. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be extremely hypoxic.
TH-302 has been investigated in over 600 patients in Phase 1/2 clinical trials to date in a broad spectrum of tumor types, both as a monotherapy and in combination with chemotherapy treatments and other targeted cancer drugs. Threshold has several additional ongoing clinical trials, the most advanced of which is a Phase 3 pivotal study evaluating TH-302 in combination with doxorubicin versus doxorubicin alone in patients with soft tissue sarcoma, and recently completed a Phase 2b trial of TH-302 in combination with gemcitabine versus gemcitabine alone in pancreatic cancer. In
Threshold is a biotechnology company focused on the discovery and development of drugs targeting tumor hypoxia, the low oxygen condition found in microenvironments of most solid tumors as well as the bone marrows of some hematologic malignancies. This approach offers broad potential to treat a variety of cancers. By selectively targeting tumor cells, we are building a pipeline of drugs that hold promise to be more effective and less toxic to healthy tissues than conventional anticancer drugs. For additional information, please visit our website (www.thresholdpharm.com).
Except for statements of historical fact, the statements in this press release are forward-looking statements, including statements regarding TH-302's potential ability to treat cancers, planned clinical trials and anticipated results, and potential therapeutic uses and benefits of TH-302. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Potential risks and uncertainties include, but are not limited to, Threshold's ability to enroll or complete its anticipated clinical trials, the time and expense required to conduct such clinical trials and analyze data, whether such trials confirm results from earlier trials and preclinical studies, potential side effects associated with TH-302, issues arising in the regulatory or manufacturing process and the results of such clinical trials (including product safety issues and efficacy results. Further information regarding these and other risks is included under the heading "Risk Factors" in Threshold's Annual Report on Form 10-K, which has been filed with the
Joel A. Fernandes Threshold Pharmaceuticals, Inc.650.474.8273 Email Contact
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