An independent Data Safety Monitoring Board (DSMB) for Keryx Biopharmaceuticals‘ pivotal Phase III X-PECT study of Perifosine (KRX-0401) in patients with refractory advanced colorectal cancer has completed a pre-specified interim analysis for safety and futility. The independent board has recommended that the Phase III study continue to completion, as planned.

Perifosine (KRX-0401) is a novel, potentially first-in-class, oral anti-cancer agent that inhibits Akt activation in the phosphoinositide 3-kinase (PI3K) pathway, and also affects a number of other key signal transduction pathways, including the JNK pathway, all of which are pathways associated with programmed cell death, cell growth, cell differentiation and cell survival. The effects of KRX-0401 on Akt are of particular interest because of the importance of this pathway in the development of most cancers, with evidence that it is often activated in tumors that are resistant to other forms of anticancer therapy, and the difficulty encountered thus far in the discovery of drugs that will inhibit this pathway without causing excessive toxicity. High levels of activated Akt (pAkt) are seen frequently in many types of cancer and have been correlated with poor prognosis.

Pre-clinical data
In vitro, KRX-0401 inhibits the growth of a variety of human tumor cell lines and has substantial activity in vivo against a number of murine tumor models and human xenografts. Investigators at the US National Cancer Institute, or NCI, were among the first to study the effects of KRX-0401 on Akt using a prostate cell line, PC-3, that is known to have constitutively activated Akt. Their results demonstrated that KRX-0401 blocked phosphorylation of Akt but did not decrease the total amount of Akt present in the cell. In model systems, the drug appears to be synergistic with radiotherapy and additive or synergistic with cytotoxics such as cisplatin, doxorubicin, and cyclophosphamide. In these experiments, the combination regimens were superior to chemotherapy alone and were well tolerated. Recent pre-clinical data suggest that KRX-0401 may be additive or synergistic with newer targeted agents such as the proteasome inhibitor bortezomib (Velcade?), the tyrosine kinase inhibitor sorafenib (Nexavar?), and the mTOR inhibitor temsirolimus (Torisel?).

Ongoing trial
This Phase III study has completed enrollment, with over 465 patients from 65 U.S. sites, and is being conducted pursuant to a Special Protocol Assessment (SPA) with the Food and Drug Administration (FDA) and with Fast-Track Designation.

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 465 randomized 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 therapy with prior 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.

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Commenting on the recommendation, Ron Bentsur, CEO of Keryx Biopharmaceuticals’, commented:”We believe that we are now one step closer to potentially offering a new therapy to the substantial patient population suffering from refractory advanced colorectal cancer.”

Special Protocol Assessment
Perifosine is also currently in a Phase III trial, under Special Protocol Assessment (SPA), for the treatment of relapsed/refractory multiple myeloma, with Orphan Drug Status and Fast Track Designation granted. The SPA is a procedure by which the FDA provides official evaluation and written guidance on the design and size of proposed protocols that are intended to form the basis for a new drug application.

Perifosine (KRX-0401)is in-licensed by Keryx from Aeterna Zentaris Inc. in the United States, Canada and Mexico.

For more information:
FDA: Special Protocol Assessment.

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