Celldex Therapeutics, Inc. has completed enrollment in an initial cohort (n=25) of Avastin (bevacizumab) refractory patients in the company's ongoing ReACT study of rindopepimut in EGFRvIII (v3)-positive glioblastoma (GBM). Based on early evidence of anti-tumour activity, including stable disease, tumour shrinkage and investigator-reported response, the company has decided to add an expansion cohort of approximately 75 patients to better characterize the potential activity of rindopepimut in this refractory patient population.

Enrollment in the expansion cohort has begun and, like the initial cohort, will evaluate rindopepimut plus Avastin.

"Patients with GBM who have become refractory to Avastin tend to have very rapid disease progression," said Thomas Davis, MD, senior vice president and chief medical officer of Celldex Therapeutics. "Based upon preliminary evidence that rindopepimut may have activity in Avastin refractory GBM, we have decided to expand the refractory group with the hope of better defining possible therapeutic effect. We expect to share a formal review of the results from the initial 25 patients at the Society for Neuro-Oncology Annual Meeting in November."

ReACT is a phase II study designed to determine if adding rindopepimut to the standard of care for recurrent glioblastoma, Avastin, improves the outcomes for patients with recurrent EGFRvIII-positive glioblastoma. As amended, the ReACT study will now enroll approximately 170 patients across three groups:

Group 1 - Avastin naïve, n= apx. 70, enrollment ongoing—patients randomized to receive either rindopepimut or KLH (administered as a control), each along with Avastin.

Group 2 - Avastin refractory, n= apx. 25, enrollment completed—patients receive rindopepimut plus Avastin in a single treatment arm.

Group 2C (C = Confirmatory) - Avastin refractory expansion, n = apx. 75, enrollment initiated—patients receive rindopepimut plus Avastin in a single treatment arm.

Study endpoints include six month progression free survival rate, objective response rate, overall survival and safety and tolerability.

Avastin is a registered trademark of Genentech, a member of the Roche Group.

Rindopepimut is an investigational immunotherapy that targets the tumor specific oncogene EGFRvIII (v3), a functional and permanently activated mutation of the epidermal growth factor receptor (EGFR), a protein that has been well validated as a target for cancer therapy. Expression of EGFRvIII correlates with increased tumorigenicity in mouse models and poor long term survival in clinical studies of patients with glioblastoma (GBM). In addition, EGFRvIII-positive cells are believed to stimulate proliferation of non-EGFRvIII cells through IL-6 cell-to-cell signaling and to release microvesicles containing EGFRvIII, which can merge with neighbouring cells, transferring tumour-promoting activity. EGFRvIII expression may also be associated with tumour stem cells that have been identified in GBM. These stem cells contribute to resistance to cytotoxic therapy and tumor recurrence. EGFRvIII is expressed in tumors in about 30 per cent of patients with GBM. It has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to impact healthy tissues.

Three phase II trials of rindopepimut—ACTIVATE, ACT II, and ACT III—have been completed in newly diagnosed EGFRvIII-positive GBM and have shown consistent improvements in both overall survival and median progression-free survival. The most common adverse events for rindopepimut include injection site reactions, fatigue, rash, nausea and pruritus. Rindopepimut is currently being studied in two clinical trials in EGFRvIII-positive GBM—an international phase III study called ACT IV in newly diagnosed GBM and a phase II study called ReACT in recurrent GBM.

Celldex is developing targeted therapeutics to address devastating diseases for which available treatments are inadequate.