[491] Phase I/II Trial of Bortezomib + CHOP-Rituximab in Diffuse Large B Cell (DLBCL) and Mantle Cell Lymphoma (MCL): Phase I Results. Session Type: Oral Session
John P. Leonard, Richard R. Furman, Ying-Kuen K. Cheung, Eric J. Feldman, Hearn J. Cho, Julie M. Vose, Gwen Nichols, Patricia W. Glynn, Maureen A. Joyce, Jamie Ketas, Jia Ruan, John Carew, Ruben Niesvizky, Ann LaCasce, Amy Chadburn, Ethel Cesarman, Morton Coleman Center for Lymphoma and Myeloma, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; University of Nebraska Medical Center, Omaha, NE, USA; Dana Farber Cancer Institute, Boston, MA, USA
BACKGROUND: Bortezomib (PS-341, VelcadeR) is a proteasome inhibitor with anti-tumor activity in B cell malignancies including MCL. These effects, which in part may be mediated via NF-kappaB pathways, could sensitize tumor cells to standard chemotherapy-based treatment regimens and enhance efficacy. We report phase I findings from a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab in DLBCL and MCL patients.
METHODS: Thirty-five patients have been enrolled and initiated treatment, with the first 20 subjects comprising the phase I group. Patients received CHOP-21 + rituximab (375 mg/m2 each cycle) plus bortezomib at 0.7 mg/m2 (Arm 0, n=4), 1.0 mg/m2 (Arm 1, n= 9) or 1.3 mg/m2 (Arm 2, n=7 in phase I, then all subsequent patients in phase II) on days 1,4 of each cycle. Phase 1 dose assignments were conducted according to the continual reassessment method as patients entered the study.
RESULTS: Phase I included 16 DLBCL and 4 MCL patients. Median age was 65 years (range 29-84) and all patients were treatment-naïve except for 1 MCL subject who had received prior local radiotherapy. Fourteen subjects (70%) had stage IV disease at study entry, and 11 (55%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores of 2 in 7 subjects (35%) and 3 or 4 in 10 subjects (50%). Median followup of the phase I cohort is 9 months (range 5 - 18 months). Treatment was generally well tolerated. Peripheral neuropathy occurred in 15 subjects (75%), with 65% grade 1, 5% grade 2 and 5% grade 3. Grade 4 hematologic toxicity (platelets and/or white blood cells) was observed in 7 subjects (35%). Three subjects did not complete therapy (1 withdrawal by patient request with subsequent death, 1 due to dose-limiting pulmonary toxicity and 1 with concurrent lyme meningitis). Intent to treat overall response rate (n=20) is 95% with 80% CR/CRu and 80% of subjects currently alive without progression.
CONCLUSIONS: Bortezomib can be administered with acceptable toxicity in conjunction with CHOP-R chemotherapy. Further safety and efficacy analyses, as well as molecular correlative studies, are ongoing with both the phase I and II cohorts. Preliminary findings with the combination regimen in this adverse prognosis group of patients are encouraging.
Abstract #491 appears in Blood, Volume 106, issue 11, November 16, 2005
Keywords: Lymphoma therapy|CHOP|Bortezomib
Monday, December 12, 2005 2:30 PM
Simultaneous Session: Lymphoma: Therapy with Biologic Agents, excluding Pre-Clinical Models II (1:30 PM-3:00 PM) |
