Phase 1 Clinical Trial of KOS-953 + Bortezomib (BZ) in Relapsed Refractory Multiple Myeloma (MM). (2005)

Abstract Background: KOS-953 is a novel formulation of 17-AAG, an inhibitor of HSP90 chaperone function. Disruption of specific heteroprotein complexes results in their decreased stability, impaired cellular trafficking and proteasomal degradation. KOS-953 shows in vitro activity against MM cells from patients (pts) resistant to BZ and extends survival of MM mice models. Treatment of MM cells with BZ triggers significant HSP90 up-regulation as a stress response; KOS-953 blocks this stress response, thereby enhancing MM cell sensitivity to BZ. Objectives: To define the recommended dose of KOS 953 and BZ in pts with relapsed and relapsed/refractory MM; to evaluate the PK of KOS-953 and its active metabolite in combination with BZ, and to evaluate biological activity of the combination. Methods: Pts receive IV therapy (BZ followed by 1-hr infusion KOS-953) twice weekly for 2 out of 3 weeks. Dose escalation of both agents in a step-wise manner occurs (BZ: 0.7, 1.0 and 1.3 mg/m2; KOS-953 100, 150 and 220 mg/m2). PK and PD are performed following the 1st and 4th infusion. KOS-953 and its metabolite are quantified in plasma. Bone marrow aspirates (BM) are examined for apoptosis, proliferation, pAKT, and change in HSP, IL-6 and IGF-R1 expression; peripheral blood leucocytes are examined for change in HSP70/90 levels and proteasome 20S function. EMBT criteria are used to assess response. Results: 15 pts (8F; median age 61 yrs; median prior regimens 4; 11 BZ-refractory and 9 with prior SCT)) enrolled in 4 dose levels (DLs 1–4). Dose limiting toxicity (G4 hepatotoxicity) was observed in 1 pt at DL#3 with hepatic involvement with MM and congestive heart failure (secondary to cardiac amyloidosis) who subsequently died of heart disease. No further toxicity was seen in the 5 other pts at this dose level. Enrollment to DL#4 is underway (BZ 1.3 mg/m2; KOS-953 150 mg/m2); no other G≥3 drug-related toxicity has been seen. G1-2 drug-related toxicity: diarrhea (n=5), fatigue (n=5), thrombocytopenia (n=3), infusional reactions (n=4), increased AST (n=3), anemia (n=3) and rash (n=3). Comparison of PK data for parent and metabolite to the single agent data showed similar kinetics (clearance remained unchanged at 48.9 ± 16.6 L/hr). Ratio of exposure comparing metabolite to parent was 96.5% ± 90.5. Evaluation of 20S proteasome function showed a 40% decrease at BZ (0.7 and 1.0 mg/m2) at the end of infusion on Day 11 (similar to predicted). Signs of antitumor activity: 1 BZ-refractory pt with SD x 6 cycles at DL#1; at DL#2, 2 BZ-refractory pts with MR after 9 cycles and one BZ-naive pt with MR (100% reduction of urine M-protein; 41% reduction in serum IgA x 9 cycles); and DL#3 1 BZ-refractory pt with MR x 6+ cycles. PBLs showed increased apoptosis by Annexin V (P=0.02). Conclusions: Dose escalation continues to define the optimal doses of the combination. No additive toxicity has been observed; no adverse PK interactions are observed at doses tested to date. Similar inhibition of the 20S proteasome is observed compared to historical BZ data. Encouraging activity has been seen in both BZ-naive and heavily treated, BZ-refractory MM pts.