A phase II trial of BAY 43–9006 in metastatic melanoma with molecularly characterized B-Raf status

Abstract

8046 Background: BAY 43–9006 is a multikinase inhibitor. The RAS/BRAF/MEK/MAPK pathway (pw) is a major pw for transmitting extracellular growth factor signals to the nucleus. Activating mutations in any of the pw kinases would be expected to result in uncontrolled cell proliferation. Approximately 60% of melanomas carry B-Raf mutations. The primary trial goals are: 1) determine if treatment (tx) with BAY 43–9006 can disrupt the RAS/BRAF/MEK/MAPK pw by depleting intra-tumor stores of B-Raf and/or CDK4; and 2) determine if tx with BAY 43–9006 results in differential anti-tumor responses in pts whose tumors have been molecularly characterized. Methods: Eligibility criteria: Biopsy (bx)-accessible, untreated metastatic melanoma. Measurable disease (RECIST). Adequate hematologic and serologic parameters. Signed ICF. All pts had tumor bx for B-Raf status determined by PCR sequencing prior to tx. Exon 3 of N-Ras and exon 15 of B-Raf were sequenced. Pts stratified by B-Raf. Tx: BAY 43–9006 was administered at 400 mg po BID. D1–28 q4w. Repeat bx was done on Day 28. Re-imaging was done every 2 cycles and pts treated until POD. Stats: Stratification by B-Raf mutation status. 2 stage study design with accrual of 13 pts/arm in first stage and total of 29 pts/arm if ≥ 1 objective response (OR) in initial cohort. Results: 8 pts (2-M1a, 1-M1b, 5-M1c) enrolled. 7 wild type (WT) and 1 mutant (M) B-Raf. Median age: 54 (range 22–91). No pts with LDH ≥ 1.5 × nl. 2 withdrew prior to tx. Responses: M B-Raf (1 evaluable)-PR (lymph nodes and large SQ arm masses); WT B-Raf-1 POD during cycle 1 (NE), 1PD, 3 too early. Toxicity: Grade I diarrhea, Grade II hypertension, fatigue and oral mucositis. Correlative immunoassays of tumor B-Raf, CDK4, phospho-MAPK and cyclin-D1 and correlation of DNA extracted from peripheral blood cells assayed by fluorescent, mutant-specific PCR and tumor B-RAF are being evaluated. Conclusions: This Phase II trial will molecularly characterize tumors for B-Raf status prior to tx with BAY 43–9006 and assess the effects on Ras-Raf signaling and correlate clinical responses. This trial will address potential differences in sensitivity to BAY 43–9006 based on B-Raf. While premature, 1 pt with M B-Raf has had an OR with a significant decrease in tumor volume. Supported by NCI N01-CM17103 and TRI. No significant financial relationships to disclose.