Phase II trial of tanespimycin (KOS-953), a heat shock protein-90 (Hsp90) inhibitor in patients with metastatic melanoma

Abstract

8558 Background: Tanespimycin binds to and inhibits the activity of Heat Shock Protein 90 (Hsp90). Hsp90 inhibition results in the degradation of a variety of RAF family proteins, including mutant BRAF. As the majority of melanomas have activation of the BRAF-MAPK pathway, we postulate that tanespimycin will interrupt the MAPK pathway and may lead to clinically significant anti-melanoma effects. Methods: This is a multi-center two-stage Simon design study; continuation to the second stage required at least 1 pt with progression free survival (PFS) of at least 24 weeks (the primary endpoint of this trial). Eligibility: pts with stage M1 melanoma, measurable/unresectable disease, up to 1 prior chemotherapy treatment for metastatic disease and ECOG PS 0 or 1. Tanespimycin (275 mg/m 2 IV) was given D1,4,8,11 q 3/52 until disease progression or toxicity. Where available, assessment of BRAF mutation (V600E) was performed on historical tissue. Results: 14 pts have been enrolled, 3 were non-evaluable. Data are available for the first 11 pts (9 evaluable) completing accrual to the 1 st stage of the Simon design. Demographics: 8 M/6 F; median age 55 years (range 30, 83). A total of 30 treatment cycles were administered (n=11); with relative dose intensity of 89%; 1 pt required a dose reduction. Grade 1–2 toxicity included nausea, vomiting, diarrhoea, anorexia, fatigue, headache, raised alkaline phosphatase/ALT/AST, and back pain. Four pts (29%) experienced Grade 3–4 toxicities: 1) reversible metabolic acidosis with LFT and electrolyte abnormalities; 2) anorexia, dehydration and fatigue; 3) raised gamma-GT; 4) abdominal pain. Two pts withdrew due to toxicity. Of the 4 pts with available tissue: 2 had V600E BRAF positive mutations. One pt achieved a ≥ 24 week PFS, meeting the conditions for accrual of Stage 2. This pt (with V600E mutation) was assessed as having a best response of stable disease as per RECIST, in addition to reduction in size and number of extensive subcutaneous nodules. Conclusions: There is evidence of clinical activity of single-agent tanespimycin in metastatic melanoma. Further accrual with determination of BRAF status to a total of 30 pts will better define the activity of tanespimycin in this population. No significant financial relationships to disclose.