Dose escalating trial of 17-AAG with bortezomib (BZ) in patients with relapsed refractory multiple myeloma (MM)

Abstract

6682 Background: In vitro, 17AAG (a benzaquinoid ansamycin) inhibits HSP90, reducing cellular levels of oncoproteins such as Raf-1, HER2, mutant p53, IL-6 and IGF-R1. Disruption of these heteroprotein complexes results in their decreased stability and impaired cellular trafficking. Single-agent 17AAG shows in vitro activity against MM cells from patients resistant to BZ. BZ induces apoptosis of p53 wild-type and p53 mutant MM cells, reverses resistance to apoptosis in MM cells conferred by IL-6; BZ also decreases adherence of MM cells to bone marrow stromal cells (BMSCs) and NFkB-dependent induction of IL-6 secretion in BMSCs. Non-clinical in vivo safety studies of the combination of 17-AAG and BZ showed possible additive hepatotoxicity. Treatment of MM cells with BZ triggered significant Hsp90 up-regulation as a stress response in MM cells; 17AAG blocks this stress response, thereby markedly enhancing MM cell sensitivity to BZ. Methods: Study objectives define the recommended dose of each agent when given in combination, to determine the pharmacokinetics (PK) of 17AAG and its active metabolite, to evaluate biological activity of 17AAG + BZ (proteasome 20S in PBLs; apoptosis, changes in HSP70/90, pAKT and expression of IL-6R and IGF-R1 in MM cells). Pts receive IV therapy twice weekly for 2 out of 3 weeks; 17AAG (denoted KOS-953 in a Cremophor-based formulation) is administered at 100 mg/m2 over 1 hour; BZ follows as IVB at doses of 0.7 and 1.0 mg/m2. Escalation of both agents is planned. Results: 4 pts (2F; median age 56 yrs; KPS 80; prior regimens 3, range 3–4) were enrolled in 2 dose levels. Dose limiting toxicity has not been observed to date. Drug-related toxicity (Grade 1–2): diarrhea, nausea, fatigue and infusional reactions. Bone marrow aspirates showed evidence of increased apoptosis on day 11 as measured by Annexin V, with reduced expression of IL-6R on the surface of CD138+ plasma cells. PK and proteasome data will be presented. One pt treated at the 1st dose level showed decreased size of palpable plasmacytoma. Conclusions: Dose escalation continues to define the dose of 17AAG when administered with BZ. Combination of two targeted therapies may hold promise in the treatment of refractory myeloma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Kosan Biosciences Kosan Biosciences Kosan Biosciences