Biotechnology company Threshold Pharmaceuticals, Inc. announced that its 214 patient randomized controlled phase 2b clinical trial evaluating the efficacy and safety of two doses of the investigational agent TH-302 in combination with gemcitabine compared to gemcitabine alone in patients with first-line advanced pancreatic cancer achieved its primary endpoint, with a 63 per cent improvement in progression free survival and a safety profile consistent with previous studies.

"With the results of this trial, we are again very encouraged that TH-302 is conferring benefit to patients with aggressive and difficult to treat cancers," said Barry Selick, CEO of Threshold. "We look forward to its ongoing development with our partner Merck KGaA in this and other indications."

Study TH-CR-404 is a multi-centre, randomized, controlled, dose-ranging, Phase 2b crossover clinical trial of TH-302 in combination with gemcitabine in patients with first line advanced pancreatic cancer. The primary endpoint of the trial is progression-free survival. The secondary endpoints are overall response rate, overall survival, change in CA19-9 as well as various other efficacy and safety parameters. Tumour 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, pooled data from the two gemcitabine plus TH-302 dose groups in comparison to gemcitabine alone.

The median progression-free survival (PFS) was 5.6 months for patients treated with gemcitabine in combination with TH-302 at 240 mg/m2 and 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 response rate in the combination arms was 22% compared to 12% in the gemcitabine alone group. Results also demonstrated greater efficacy in the higher TH-302 dose group compared to the lower dose group.

The combination was well tolerated with a safety profile that was consistent with our prior study of this combination regimen. As in that study, skin and mucosal toxicities related to TH-302 were dose dependent but not dose limiting. Further detailed information regarding the results of this trial will be presented at a future major medical conference.

"This study provides the proof of concept demonstration that TH-302 contributes to the efficacy of a known active agent and supports the rationale for combining TH-302, a hypoxia targeting agent, with other approved therapies," said Stew Kroll, senior vice president of biostatistics and clinical operations of Threshold.

TH-302 is a hypoxia-targeted drug that is thought to be activated under tumour hypoxic conditions, a hallmark of many cancer indications. Areas of low oxygen levels (hypoxia) within tissues are common in many solid tumours due to insufficient blood vessel growth. Similarly, the bone marrow of patients with haematological malignancies has also been shown, in some cases, to be extremely hypoxic. TH-302 has been investigated in over 550 patients in phase 1/2 clinical trials to date in a broad spectrum of tumour types, both as a monotherapy and in combination with chemotherapy treatments and other targeted cancer drugs.

Threshold has several ongoing clinical trials with TH-302 including, but not limited to, a phase 3 trial of TH-302 in patients with first-line advanced soft tissue sarcoma (STS). This randomized, multi-centre phase 3 trial will investigate the use of TH-302 plus doxorubicin compared with doxorubicin alone. The primary efficacy endpoint is overall survival. The study is conducted under a Special Protocol Assessment with the US Food and Drug Administration. It is being run in partnership with the Sarcoma Alliance for Research through Collaboration (SARC) and aims to enroll 450 patients with metastatic or locally advanced unresectable STS.

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 tumours as well as the bone marrows of some haematologic malignancies.