Enrollment has started for the ENDEAVOR trial , a Phase III clinical trial evaluating carfilzomib (proposed brand name Kyprolis?, Onyx Pharmaceuticals, Inc) in combination with dexamethasone, versus bortezomib (originally codenamed PS-341 and marketed as Velcade? by Millennium Pharmaceuticals) with dexamethasone in patients with relapsed multiple myeloma.

Carfilzomib is an investigational, late-stage, next-generation proteasome inhibitor that is being developed as a potential treatment for patients with multiple myeloma and solid tumors. Although the agent has generated a positive efficacy signal in multiple clinical studies with an encouraging safety profile, including low rates of neuropathy, it is not approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) or other health authorities.

In this trial, the drug will be tested against therapeutic proteasome inhibitor bortezomib which is approved in by the U.S. FDA for treating patients with relapsed multiple myeloma and mantle cell lymphoma.

Hematologic cancer
Multiple myeloma is the second most common hematologic cancer and results from an abnormality of plasma cells, usually in the bone marrow. In the United States, more than 50,000 people are living with multiple myeloma and approximately 20,000 new cases are diagnosed annually.[1] Worldwide, more than 200,000 people are living with multiple myeloma and approximately 100,000 new cases are diagnosed annually. [2] Despite treatment advances in the last several years, multiple myeloma remains a disease with poor long-term survival as a result of patients relapsing and/or becoming resistant to treatment, underlining the need for new therapies.

Head-to-head trial
“The ENDEAVOR trial is the first head-to-head trial conducted with Kyprolis, and is an important step in the development program,” said Ted W. Love, M.D., Executive Vice President, Research and Development and Technical Operations at Onyx Pharmaceuticals. “The initiation of this trial underscores our commitment to patients with multiple myeloma who are in need of new treatment options beyond the currently available therapies.”

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Phase III Trial Design
The ENDEAVOR (RandomizEd, OpeN?Label, Phase III Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial will enrol 888 patients evaluating carfilzomib in combination with dexamethasone, versus bortezomib with dexamethasone in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens.

The primary endpoint of the trial is progression-free survival. Secondary endpoints include overall survival, overall response rate, duration of response, and safety. Patients will be randomized to receive carfilzomib intravenously (20mg/m(2) on days 1 and 2 of cycle 1 only, then 56 mg/m(2) subsequently) with low-dose dexamethasone (20mg), versus bortezomib (1.3 mg/m(2)) with low-dose dexamethasone. Bortezomib can be administered subcutaneously or intravenously at the discretion of the investigator and in accordance with regulatory approval of bortezomib. The study will be conducted at approximately 200 sites worldwide.

Accelerated approval
The FDA is currently reviewing a New Drug Application (NDA) for potential accelerated approval of carfilzomib in the U.S. for the treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent (IMiD). The Prescription Drug User Fee Act (PDUFA) date for completion of the NDA review by the FDA is July 27, 2012.

The NDA submission currently under review by the FDA is based on the carfilzomib 003-A1 study, an open-label, single-arm Phase IIb trial of carfilzomib (20mg/m(2) in cycle 1 and 27mg/m(2) in subsequent cycles), as well as supportive data from additional studies.

In addition to the ENDEAVOR trial, carfilzomib is being studied in several clinical trials either as a single-agent or in combination with other therapies, including:
– A Phase III clinical trial, known as the ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma)trial, has completed enrollment and is evaluating the combination of lenalidomide and low-dose dexamethasone with or without carfilzomib in patients with relapsed multiple myeloma who have received one to three prior therapies. Onyx Pharmaceuticals, Inchas an agreement with the FDA on a Special Protocol Assessment (SPA) and has received Scientific Advice from the European Medicines Agency (EMA) on the design and planned analysis of the trial.
– A Phase 3 clinical trial, called the FOCUS trial, is evaluating single-agent carfilzomib in patients with relapsed and refractory myeloma who have received three or more prior therapies. The trial is designed to facilitate regulatory approvals around the world.
– A Phase 1/2 study, being conducted by Onyx’s partner Ono Pharmaceutical Co., Ltd, is evaluating carfilzomib in Japanese patients with relapsed/refractory multiple myeloma.

[1] National Cancer Institute, Surveillance Epidemiology and End Results, 2007 Facts and Figures
[2] International Agency for Research on Cancer, GLOBOCAN 2002 database

For more information:
NCT01568866 – Phase III Study With Carfilzomib and Dexamethasone Versus Velcade and Dexamethasone for Relapsed Multiple Myeloma Patients.

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