Publication Date:
2011-11-18
Description:
Abstract 1877 Introduction: Carfilzomib (CFZ) is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. Phase (ph) 1 and 2 studies with CFZ have demonstrated durable single-agent activity and acceptable safety in patients (pts) with relapsed and/or refractory multiple myeloma (MM). Preliminary side-by-side comparison of efficacy results from PX-171-003-A0 and PX-171-003-A1, 2 studies performed with nearly identical entry criteria and schedules but using different doses of CFZ (20 mg/m2 vs 20/27 mg/m2), suggested a dose–response relationship. The rates of pts achieving either a partial response (PR) or better or a minimal response or better appeared to be greater in 003-A1 than in 003-A0. An analogous comparison of efficacy results from the 2 bortezomib (BTZ)-naïve dosing cohorts (20/27 mg/m2 vs 20 mg/m2) in PX-171-004 revealed similar trends. The present analysis was undertaken to rigorously evaluate the evidence of a potential dose–response relationship for CFZ by employing dose– response modelling. Methods: A pooled multivariate dose–response model was derived using data from the following ph 2 studies of CFZ: 003-A1, 004 (BTZ-naïve), and 004 (BTZ-treated). A multivariate logistic regression analysis for the primary outcome of overall response rate (ORR) was fitted that adjusted for study, CFZ dose, and a broad range of prognostic covariates (eg, cytogenetic status and International Staging System (ISS) stage). In addition, a repeated measures model used generalized estimating equations (GEE) to analyze the association between cycle-specific response status and cycle-specific CFZ dose. Multivariate Cox regression models with the same covariates, stratified by study, were fitted for the time-to-event endpoints (duration of response [DOR], progression-free survival [PFS], and overall survival [OS]). Time-dependent Cox regression models were also fitted for these endpoints using cycle-specific cumulative dose. Results: Evaluation of the effect of actual CFZ dose on the primary efficacy outcome of overall response rate (ORR) demonstrated that the odds of achieving a PR or better for a given pt treated with 27 mg/m2 were 4.08-fold higher (95% CI: 2.30–7.24, P
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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