Threshold Pharmaceuticals, Inc. has initiated a phase I clinical trial evaluating the safety of TH-302, the company's first hypoxia-activated prodrug (HAP), in patients with advanced solid tumours.
"TH-302 is a novel cancer therapeutic specifically activated under the low oxygen or "hypoxic" conditions typical of solid tumour cancer cells," said Barry Selick, PhD., Threshold's chief executive officer. "Hypoxic tumour cells typically evade traditional anti-cancer drugs that target rapidly dividing cells, ultimately leading to drug resistance, relapse, and metastasis. If TH- 302 can reduce the metastatic potential of tumours or prevent the growth of drug-resistant cancer cells, it could be a significant clinical breakthrough for the treatment of a variety of cancers." TH-302 is the first compound from Threshold's Hypoxia-Activated Prodrug (HAP) programme to enter human clinical trials, and Threshold is developing other novel HAPs that specifically target tumour hypoxia.
Approximately 50 patients with advanced solid tumours are planned to enrol in the phase I, open-label, dose-escalation clinical trial to be conducted in the United States. Up to six patients per dose level will participate in the dose escalation phase of the trial. Once a maximum tolerated dose (MTD) has been established, six additional patients will be enrolled at the MTD level.
TH-302 is administered as a 30-minute intravenous infusion weekly for three weeks followed by one week off therapy. Patients who have received one or more regimens of chemotherapy, or for whom no effective therapy is available, are eligible for the trial. Patients will not receive any additional chemotherapy while receiving TH-302. Patients who successfully complete a four week treatment cycle without evidence of significant treatment-related toxicity or progressive disease will continue to receive treatment for up to six cycles. Tumour response will be measured at the end of cycles 2, 4 and 6.
The primary objectives of the study are to determine the MTD and dose- limiting toxicities of TH-302 in patients with advanced solid tumours and to establish the appropriate dose for testing in potential phase II clinical trials.
The secondary objectives of the trial include establishing the pharmacokinetics and assessing the anti-tumour activity of TH-302, as measured by objective response rate, duration of response, progression-free survival, overall survival, and various safety parameters. Tumours will be evaluated at baseline and every eight weeks using the Response Evaluation Criteria In Solid Tumours (RECIST).
Threshold's HAP programmes focus on highly active anti-cancer compounds with safety profiles that should be improved by targeting them to the hypoxic regions of solid tumours. TH-302 is a nitroimidazole-linked prodrug of a brominated derivative of an isophosphoramide mustard previously used in cancer drugs such as ifosfamide, cyclophosphamide, and glufosfamide.
TH-302 has been shown, in preclinical studies, to be both efficacious and well tolerated. Mark Matteucci, PhD., Threshold's senior vice president of discovery research and leader of its HAP programs said, "TH-302 has shown remarkable activity in animal models of human pancreatic and prostate cancers and is active against a wide variety of other tumour types in both cell-based as well as animal models. We are hopeful that TH-302, alone or in combination with other anti-tumour therapies, will provide a significant improvement in the treatment of cancer patients." Threshold is actively pursuing additional HAP product candidates, based on already approved as well as novel anti-tumour drugs.