"Carfilzomib is one of the second generation of proteasome inhibitors. In the laboratory, in cases where there is resistance to Velcade, it looks like the second generation proteasome inhibitors retain their activity."
Dr. Robert Orlowski
To view the video full screen, click on the small button next to the volume control in the lower right hand corner. Safety and Antitumor Efficacy of the Proteasome Inhibitor Carfilzomib (PR-171) Dosed for Five Consecutive Days in Hematologic Malignancies: Phase 1 Results. Session Type: Oral Session
Robert Z. Orlowski, Keith Stewart, Marcy Vallone, Chris Molineaux, Lori Kunkel, John Gericitano, Owen A. O'Connor Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Mayo Clinic, Scottsdale, AZ, USA; Proteolix, Inc., South San Francisco, CA, USA; Memorial Sloan Kettering, New York, NY, USA; Comprehensive Cancer Center, Columbia University, New York, NY, USA
Introduction: Carfilzomib (CFZ) is a structurally- and mechanistically-novel proteasome inhibitor (PI) of the peptide epoxyketone class that exhibits a high level of selectivity for the unique N-terminal threonine active sites within the proteasome. CFZ is similar to bortezomib (BTZ; VELCADE), in that it is a potent inhibitor of the chymotrypsin-like activity, but unlike BTZ, CFZ has shown minimal cross-reactivity with the other catalytic sites within the proteasome or across other protease classes. Preclinical human tumor xenograft models indicate that consecutive day (D1, D2) dosing resulting in 48 hours of proteasome suppression was superior to split dosing (D1, D4). Methods: This phase 1 sequential dose escalation trial tested an intensive proteasome inhibition schedule with CFZ administered as an intravenous push (IVP) daily (QD) for 5 consecutive days on a 14 day cycle. The doses administered ranged from 1.2 mg/m2 to 20 mg/m2. Multiple myeloma (MM), non-Hodgkins lymphoma (NHL) that included mantle cell lymphoma (MCL), Hodgkins disease (HD), or Waldenstrms macroglobulinemia (WM) were eligible if they had relapsed after 2 or more prior therapies. Results: A total of 29 subjects have been treated. The minimal effective dose (MED) was 11 mg/m2. A maximum of 80% proteasome inhibition was achieved in peripheral blood and mononuclear cells at 15 mg/m2. Five responses have occurred in 14 patients (6 MM, 3 MCL, 1 WM, 4 NHL) enrolled at the MED: 1 MM partial response (PR), 2 MM minimal responses (MR), 1 WM MR and one macroscopic CR in a patient with gastrointestinal MCL. Responses occurred in patients whose disease had failed therapy with BTZ, immunomodulatory agents, and stem cell transplant. Four NHL patients have had stable disease and remained on treatment for up to 7 months. Dose limiting toxicity reported at 20 mg/m2 included febrile neutropenia (reversible) and grade 4 thrombocytopenia. Grade 3 (25%) or grade 4 events (8%) were primarily hematologic events. Most withdrawals occurred due to the inconvenience of frequent visits, or progressive disease. Conclusions: This study demonstrates that intensive CFZ dosing leading to sustained proteasome inhibition is well tolerated. The selectivity of the epoxyketone class of PI may promote a favorable safety profile. Furthermore, antitumor responses in heavily pretreated patients suggest non-cross resistant activity. Phase 2 trials in MM and solid tumors are proceeding with an alternate IV schedule. An oral agent suitable for frequent dosing schedules is under development.
Abstract #409 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: Myeloma|Non-Hodgkin Lymphoma|Chemotherapy
Disclosure: Employment: Authors Vallone, Molineaux, and Kunkel are employees of Proteolix, Inc. Consultancy: Authors Orlowski, Stewart, and OConnor have served as consultants for Proteolix, Inc. Ownership Interests: Authors Molineaux, Vallone, and Kunkel are stock holders in Proteolix, Inc. Membership Information: Authors OConnor, Orlowski and Stewart are on advisory committees for Proteolix, Inc.
Monday, December 10, 2007 11:00 AM
Session Info: Simultaneous Session: Myeloma: Novel Therapies in Relapsed Multiple Myeloma (11:00 a.m.-12:30 p.m.)