A Multicenter Phase 1 Clinical Trial Of Tanespimycin (Kos-953) + Bortezomib (Bz): Encouraging Activity And Manageable Toxicity In Heavily Pre-Treated Patients With Relapsed Refractory Multiple Myeloma (Mm).
BLOOD(2006)
摘要
Background: Tanespimycin (KOS-953, 17-AAG) disrupts the function of Hsp90, a molecular chaperone of MM client proteins such as IL-6, IGF-1R that are key to growth, survival and drug resistance. In vitro, BZ + KOS-953 show additive cytotoxicity against MM cells. Single-agent KOS-953 produced durable MR and SD (ASH 2005 A#361) in relapsed and refractory MM pts with an MTD ≥ 420 mg/m2. Objectives: Define a 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. Explore changes in intracellular signaling proteins in PBMCs and CD138+ MM cells. Methods: Pts receive BZ as IVB followed by 1-hr infusion KOS-953 (in a Cremophor formulation) D1,4,8,11 q 21d. Dose escalation occurred in a step-wise manner (KOS-953: 100, 150, 220, 275 and 340 mg/m2; BZ: 0.7, 1.0 and 1.3 …
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