·   Log in

Hypoxia-activated prodrug TH-302 could help reducing pancreatic tumour: Threshold

Wednesday, April 21, 2010, 5:46 This news item was posted in Clinical Trials category and has 0 Comments so far.

TH-302, an investigative prodrug to treat cancerous tumours, is found to be safe and effective in preclinical studies, Threshold Pharmaceuticals announced.

Threshold Pharmaceuticals, Inc will present multiple preclinical presentations on its clinical stage hypoxia-activated prodrug, TH-302, at the American Association for Cancer Research (AACR) Annual Meeting in Washington, D.C.

The clinical trial is a Phase 1/2, three arm, multicenter, dose escalation and dose expansion trial to determine the safety, efficacy and pharmacokinetics of TH-302 in combination with gemcitabine or docetaxel or pemetrexed in patients with advanced solid tumors.

About 43 patients enrolled with gastrointestinal cancer, 38 patients have been assessed for response. Of the 38 patients assessed, 12 patients (32%) had a RECIST criteria partial response, 22 patients achieved stable disease and 4 patients (10%) had progressive disease.

The majority of the patients had first-line pancreatic cancer, 18 of whom received TH-302 plus gemcitabine, 3 of whom received TH-302 plus pemetrexed and one who received TH-302 plus docetaxel.

Across the 22 patients with pancreatic cancer, 20 patients were assessed for response and 19 (95%) achieved stable disease or better. For these 20 patients, the mean time on study was over 3.5 months and 9 patients continue to receive therapy on study.

The TH-302 maximum tolerated dose (MTD) continues under investigation with the dose cohort currently being expanded at 340 mg/m2.

“While limited in number, the results we have seen in first-line pancreatic cancer are notable as compared to historical standards,” state dJohn Curd, M.D., Threshold’s president and chief medical officer.

Historically, the response rates in first-line pancreatic cancer with gemcitabine have been less than ten percent. The current safety and activity data supports an additional study of TH-302 in combination with full dose gemcitabine to determine if TH-302 adds clinical benefit to patients fighting pancreatic cancer, he added.

Hematologic toxicity was more frequent and more severe in the combinations than might be expected if chemotherapy was administered by itself, but the combinations were generally well tolerated.

The trial was initiated in August 2008 and is expected to enroll 120 patients in total across various solid tumors but primarily focused on pancreatic cancer and non-small cell lung cancer.

In the TH-302 plus gemcitabine arm, TH-302 is administered intravenously for 30 to 60 minutes on days 1, 8 and 15 of a 28 day cycle.

Gemcitabine is dosed according to its package insert. TH-302 is currently being investigated at a dose of 340 mg/m2 in combination with full dose gemcitabine in patients with first-line pancreatic cancer.

In the TH-302 plus docetaxel arm, TH-302 is administered intravenously on days 1 and 8 of a 21 day cycle.

Docetaxel is dosed according to its package insert. TH-302 is currently being investigated at a dose of 340 mg/m2 in combination with full dose docetaxel in patients with second-line NSCLC and in patients with first-line castrate-resistant prostate cancer.

In the TH-302 plus pemetrexed arm, TH-302 is administered intravenously on days 1 and 8 of a 21 day cycle.

The results support the hypothesis that TH-302 can eliminate at the radical anion stage and release its cytotoxic warhead in a hypoxia-dependent manner.

What are hypoxia-activated prodrugs or HAPs?
Tumor hypoxia is a region of very low oxygen concentration in solid tumors. Abnormal or poor blood vessel growth, a fundamental hallmark of tumors, was later shown to be the cause of tumor hypoxia.

Many solid tumors have significant hypoxic regions, and because these regions have limited access to the blood supply and oxygen, the cells in them divide slowly, making them resistant to traditional chemotherapy and radiation treatment, which target rapidly dividing cells.

Moreover, many scientists now believe that hypoxia can accelerate tumor invasiveness and metastatic potential.

Thus, therapeutics that specifically target resistant hypoxic zones could provide significant additional anti-tumor activity and clinical benefit over current chemotherapeutic and radiation therapies.

A prodrug is an inactive compound that is converted in the human body by enzymatic processes to form an active drug.

The prodrug concept is well established in chemotherapy, but initially employed only to modify the pharmacokinetic properties of compounds. More recently, the prodrug concept been applied to the design of agents that are selectively activated in tumor tissues by specific activation processes.

TH-302 is a hypoxia-activated prodrugs or HAPs. It consists of two distinct parts, a toxic portion and an attached molecular trigger. To prevent general toxicity, the molecular trigger keeps the toxin inactive until the prodrug is in the hypoxic region of the tumor, where it is then activated by low oxygen concentration. Once activated, the toxin kills cells in its vicinity.

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. This approach offers broad potential to treat most solid tumors.

By selectively targeting tumor cells, these drugs could be more effective and less toxic to healthy tissues than conventional anticancer drugs.

Scroll down to comment on this story
You can leave a response, or trackback from your own site.

Leave a Reply