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7507 Background: BAY 43-9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. BAY inhibits CRAF and BRAF (wild type/V599E mutant) and inhibits growth of melanoma xenografts. This phase I/II study was initiated to define safety, pharmacokinetics (PK), and efficacy of oral BAY administered in combination with C and P. Methods: BAY was given from day 2 to 19 of a 21 day cycle at 3 dose levels (DL): DL 1, 100 mg bid; DL 2, 200 mg bid; and DL 3, 400 mg bid. C (AUC 6) and P (225 mg/m2) were each administered on day 1. PK data were collected on days 1, 2, 22, and 23. Tumor samples were obtained pretreatment for BRAF mutation analysis. Based on responses during the dose escalation phase, melanoma pts were accrued in the expansion phase. Results: 35 melanoma patients (pts) (median age 47, PS 0–1) have been treated for at least 6 weeks and 32 are evaluable for response. Twenty-one (60%) pts received ≥ 1 prior therapy, and 68% had AJCC M1c disease. Early data shows this combination is well tolerated with no unexpected adverse events. Responses using RECIST criteria demonstrated 11 partial responses; 10 are ongoing at 3–16 months (response rate 31%). Median time to response is 3 months. Nineteen pts have stable disease as best response, and 12 remain on study for ≥3 months since entry. Median time to progression has not been reached at a median follow-up of 5 months. Preliminary PK shows lack of interaction between BAY, P, and C. There was no change in the preliminary PK values of P, the 6-OH metabolite, total platinum, or free platinum from Cycle 1 to Cycle 2. Conclusions: The combination of BAY with C and P has demonstrated activity in melanoma with a favorable safety profile and no apparent PK interaction. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Health Care; Bayer Pharmaceuticals Bayer AG; Bayer Pharmaceuticals
Flaherty et al. (Thu,) studied this question.