Aeterna Zentaris Inc. announced the completion of patient recruitment for the ongoing phase III trial with perifosine in refractory advanced colorectal cancer. The trial, involving over 430 patients, is being conducted pursuant to a Special Protocol Assessment (SPA) with the Food and Drug Administration (FDA) and with Fast Track Designation. It is sponsored by Keryx Biopharmaceuticals, Inc., (Keryx), Aeterna Zentaris' licensee for perifosine in North America. Perifosine is a novel, potentially first-in-class, oral anticancer drug candidate that inhibits Akt activation in the phosphoinositide 3-kinase (PI3K) pathway.

Juergen Engel, PhD, Aeterna Zentaris president and chief executive officer, commented, “We wish to congratulate our partner Keryx and thank all those involved in reaching this key patient recruitment milestone within a 16-month timeframe. We now look forward to the completion of this pivotal phase III trial in order to potentially provide an additional treatment to refractory advanced colorectal cancer patients.”

The phase III trial, entitled the “X-PECT” (Xeloda + Perifosine Evaluation in Colorectal cancer Treatment) trial, is a randomized (1:1), double-blind trial comparing the efficacy and safety of perifosine + capecitabine vs. placebo + capecitabine in over 430 patients with refractory advanced colorectal cancer. Patients must have failed available therapy including 5-fluorouracil (5-FU), oxaliplatin (Eloxatin), irinotecan, bevacizumab (Avastin) and, if KRAS wild-type, failed prior therapy with cetuximab (Erbitux) and/or panitumumab (Vectibix). The primary endpoint is overall survival, with secondary endpoints including overall response rate (complete + partial responses), progression-free survival and safety. Approximately 360 events of death will trigger the un-blinding of the study.

Dr Johanna Bendell, director of GI Oncology Research for the Sarah Cannon Research Institute, Nashville, Tennessee, is Study Chair for the phase III investigational team. Dr Cathy Eng, associate medical director for the Colorectal Centre at MD Anderson Cancer Centre in Houston, Texas, is the Lab Correlative Study Chair leading the biomarker analyses. Sixty-five US sites are participating in the study.

According to the American Cancer Society, colorectal cancer is the third most common form of cancer diagnosed in the United States. It is estimated that over 141,000 people will be diagnosed with some form of colorectal cancer with over 49,000 patients dying from colorectal cancer in 2011. Surgery is often the main treatment for early stage colorectal cancer. When colorectal cancer metastasizes (spreads to other parts of the body such as the liver) chemotherapy is commonly used.

Treatment of patients with recurrent or advanced colorectal cancer depends on the location of the disease. Chemotherapy regimens (i.e. FOLFOX or FOLFIRI either with or without bevacizumab) have been shown to increase survival rates in patients with advanced colorectal cancer. Currently, there are seven approved drugs for patients with advanced colorectal cancer: 5-fluorouracil (5-FU), capecitabine (Xeloda), irinotecan, oxaliplatin (Eloxatin), bevacizumab (Avastin), cetuximab (Erbitux), and panitumumab (Vectibix).

Depending on the stage of the cancer, two or more of these types of treatment may be combined at the same time or used after one another. For example, FOLFOX combines 5-FU, leucovorin and oxaliplatin and FOLFIRI combines 5-FU, leucovorin and irinotecan. Bevacizumab, a VEGF monoclonal antibody, is commonly administered with chemotherapy. Typically, patients who fail 5-FU, oxaliplatin, irinotecan, and bevacizumab-containing therapies, and who have wild-type KRAS status receive EGFR monoclonal antibody therapy with either cetuximab or panitumumab. Once patients progress on these agents, there are no further standard treatment options.

Perifosine is a novel, oral anticancer treatment that inhibits Akt activation in the phosphoinositide 3-kinase (PI3K) pathway. The product works by interfering with membranes of cancer cells thereby inhibiting Akt signalling which then affects cell death, growth, differentiation and survival. Perifosine, in combination with chemotherapeutic agents, is currently being studied for the treatment of multiple myeloma, colorectal cancer and other cancers, and is the most advanced anticancer agent of its class. Perifosine, as monotherapy, is being explored in other indications.

The FDA has granted perifosine orphan drug designation in multiple myeloma and neuroblastoma, and Fast Track designations in both multiple myeloma and refractory advanced colorectal cancer. Additionally, an agreement was reached with the FDA to conduct the phase III trials in both of these indications under a SPA. Perifosine has also been granted orphan medicinal product designation from the European Medicines Agency (EMA) in multiple myeloma.

Furthermore, perifosine has received positive Scientific Advice from the EMA for both the multiple myeloma and advanced colorectal cancer programs, with ongoing Phase 3 trials for these indications expected to be sufficient for registration in Europe. Perifosine rights have been licensed to Keryx for North America, to Yakult Honsha for Japan and to Handok for Korea.

Aeterna Zentaris is a late-stage oncology drug development company currently investigating potential treatments for various cancers including colorectal, multiple myeloma, endometrial, ovarian, prostate and bladder cancer.