Threshold Pharmaceuticals (THLD) on Friday announced early data from the Phase 1 portion of an investigator-sponsored Phase 1/2 trial of its investigational hypoxia-targeted drug TH-302 in combination with Avastin (bevacizumab) (Genentech/Roche (ROG.VX)).
Glioblastoma is the most common and most aggressive of the primary malignant brain tumors in adults. Median survival is approximately 15 months; the five-year survival rate is approximately 3%. There are an estimated 30,000 new cases each year in the U.S. and E.U. Standard care for glioblastoma is chemotherapy with radiation.
First line therapy is usually Temodar (Merck (MRK)), an oral chemotherapy agent. Avastin is approved for patients with recurrent glioblastoma; however, some patients find their cancer returns after several cycles of Avastin. Threshold designed TH-302 to be given in combination with Avastin after failure on Avastin alone.
The drug targets the low-oxygen (hypoxic) characteristic of many solid tumors. The hope is that by targeting specific cells, the drugs will be more effective and less toxic to healthy tissues than non-targeted treatments.
The ongoing phase 1/2 trial (Study 4003) is a single-center, dose-escalation trial in patients with recurrent glioblastoma who have failed on Avastin alone. The low progression free survival rate (15% at three months) for patients with recurrent glioblastoma limits the number of evaluable patients in the study. The study covers 14 evaluable patients who received combination therapy of Avastin and TH-302 (every two weeks. Best response was assessed by Response Assessment in Neuro-Oncology (RANO) criteria. Preliminary data in 14 patients showed TH-302 in combination with Avastin was associated with a median time to progression of 2.8 months. One patient achieved a complete response and two patients achieved partial responses. So far, no dose-limiting toxicity has been reported. Enrollment continues at 670 mg/m2 of TH-302.
We remain skeptical about the long-term potential for hypoxic-targeted tumor therapy. In addition to this study, TH-302 is currently under evaluation in two Phase 3 trials: one in combination with doxorubicin in patients with soft tissue sarcoma, and the other in combination with gemcitabine in patients with advanced pancreatic cancer (MAESTRO).