Phase 1 clinical trial of KOS-953 + bortezomib (BZ) in relapsed refractory multiple myeloma (MM)

3066 Background: KOS-953 (17-AAG in Cremophor) inhibits HSP90 chaperone function, resulting in disruption of protein complexes and proteasomal degradation. Single-agent 17-AAG is active in relapsed/refractory MM patients (pts) (ASH 2005 A#361), with a recommended dose ≥ 275 mg/m2. In vitro, BZ + KOS-953 show additive cytotoxicity of myeloma cells. Objectives: Define phase 2 dose of BZ+KOS-953 in pts with relapsed refractory MM. Determine PK of KOS-953 and its active metabolite. Evaluate proteasome inhibition in whole blood lysates and explore changes in intracellular signaling proteins in pt PBMCs and MM cells. Methods: Pts received BZ as IV bolus followed by 1-hour infusion KOS-953 twice weekly for 2 out of 3 weeks. Dose escalation occurred in a step-wise manner. PK and collection of surrogates are performed following the 1st and 4th infusion. Pts assessed for response by EBMT criteria. Results: 20 pts were enrolled in 4 cohorts: BZ+KOS-953 (mg/m2): 0.7+100 (n=3); 1.0+100 (n=3); 1.0+150 (n=8); and 1.3+15...