Results from an ongoing Phase II study of Carfilzomib, a selective, next generation proteasome inhibitor, showed encouraging results in a broad clinical trial program in multiple myeloma. Overall, the new drug candidate demonstrated promising overall response rates when carfilzomib was administered as a single agent in patients with relapsed and/or refractory multiple myeloma. These data were presented at the 51st annual meeting of the American Society of Hematology (ASH) held from december 5 – 8, 2009 in New Orleans.Multiple myeloma (MM) is the second most common hematologic cancer and results from an abnormality of plasma cells, usually in the bone marrow. Based on data from the National Cancer Institute, Surveillance Epidemiology and End Results (2007 Facts and Figures, there are, more than 50,000 people in the United States living with MM and approximately 20,000 new cases are diagnosed annually. The International Agency for Research on Cancer (Globoscan) estimates that worldwide, more than 180,000 people are living with MM and approximately 86,000 new cases are diagnosed annually.004 TrialIn an open label, single agent trial, ongoing Phase II study (004) conducted in collaboration with the Multiple Myeloma Research Consortium, patients were divided into two populations: 73 evaluable patients with relapsed and/or refractory multiple myeloma who had not received prior bortezomib (Velcade?, Millennium Pharmaceuticals, Inc) treatment, classified as bortezomib-naive patients, and 33 evaluable patients with relapsed and/or refractory disease following bortezomib treatment, classified as bortezomib-treated patients.Prior therapies include alkylating agents, stem cell transplant, thalidomide (Thalomid? , Celgene Corporation), lenalidomide (Revlimid? , Celgene Corporation),and anthracyclines, and bortezomib in the bortezomib-treated patients.Michael Wang, M.D., assistant professor, department of lymphoma and myeloma at the University of Texas M. D. Anderson Cancer Center and co-investigator of the study, reported that the bortezomib-naive patients when treated with carfilzomib achieved an overall response rate (ORR) of 46% in 54 evaluable patients at 20 mg/m2 and 53% in 19 evaluable patients with dose escalation to 27 mg/m2. Additionally, Dr. Wang reported interim results for secondary endpoints at the 20 mg/m2 dose, including time-to-progression (TTP) of 7.6 months and duration of response (DoR) of 8.4 months.David Siegel, M.D., Ph.D., division chief of myeloma at the John Theurer Cancer Center and co-investigator of the study, reported that 33 evaluable patients who were previously treated with bortezomib achieved an ORR of 18% when administered carfilzomib. Dr. Siegel reported interim results for a secondary endpoint of TTP at 5.3 months and DoR of more than 9 months. More than 20% of patients were able to complete the full 12 cycles (48 weeks) of therapy in both studies without cumulative side effects.”These interim results suggest that carfilzomib could benefit patients with multiple myeloma who are no longer responding to current therapies,” said Dr. Siegel. “Additionally, given the low incidence of neuropathy and generally mild and manageable adverse events in this trial, these results suggest that increasing the dosage of carfilzomib up to 27 mg/m2 is well tolerated despite a high degree of coexisting medical conditions, such as renal insufficiency and diabetes.”Overall, treatment with carfilzomib was well tolerated and no unexpected side effects occurred. The most common grade 3 treatment-related adverse events occurred in less than 5 percent of the patients and included fatigue, pneumonia, neutropenia, lymphopenia and anemia. Peripheral neuropathy of any grade was rare and there were no grade 4 adverse events observed.Other findings from the two populations include:– Carfilzomib has substantial single-agent activity despite several prior treatments with different combination regimens.- Carfilzomib was well-tolerated with chronic administration, even in patients with renal insufficiency- Patients were able to remain on full-dose therapy for more than 12 cycles.”These data support our ongoing carfilzomib program in multiple myeloma, a disease that has poor long-term survival, and for which there are no alternative courses of therapy for patients who relapse following treatment or become resistant to currently approved therapies,” said Michael Kauffman, M.D., Ph.D., interim chief medical officer at Onyx Pharmaceuticals, the compay developing the new drug candidate.. “There is a clear need to provide new treatment options to patients with multiple myeloma, and we are working to potentially file a New Drug Application for carfilzomib by the end of 2010.”Ongoing researchCarfilzomib is currently undergoing evaluation as a single agent in multiple Phase II and Phase I clinical trials in relapsed or refractory multiple myeloma. These trials include a Phase IIb monotherapy study, known as the 003 study, in patients with relapsed, refractory multiple myeloma, the pivotal trial that could support a new drug application (NDA) filing by the end of 2010. Carfilzomib is also being evaluated in advanced solid tumors.Carfilzomib is being developed by Onyx Pharmaceuticals, Inc.For more information:O’Connor OA, Stewart AK, Vallone M, Molineaux CJ, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009 Nov 15;15(22):7085-91. Epub 2009 Nov 10.Shah JJ, Orlowski RZ. Proteasome inhibitors in the treatment of multiple myeloma. Leukemia. 2009 Nov;23(11):1964-79. Epub 2009 Sep 10.Parlati F, Lee SJ, Aujay M, Suzuki E, Levitsky K, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood. 2009 Oct 15;114(16):3439-47. Epub 2009 Aug 11Kuhn DJ, Chen Q, Voorhees PM, Strader JS, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 2007 Nov 1;110(9):3281-90. Epub 2007 Jun 25.