Phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF-mutated melanoma and other advanced malignancies. Cancer 2019 Feb 01;125(3):463-472
Date
11/02/2018Pubmed ID
30383888Pubmed Central ID
PMC6340722DOI
10.1002/cncr.31812Scopus ID
2-s2.0-85055952073 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
BACKGROUND: BRAF inhibitors are effective against selected BRAFV600 -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity.
METHODS: Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs).
RESULTS: Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m2 intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m2 were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non-dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P = .045).
CONCLUSIONS: The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAFV600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors.
Author List
Bhatty M, Kato S, Piha-Paul SA, Naing A, Subbiah V, Huang HJ, Karp DD, Tsimberidou AM, Zinner RG, Hwu WJ, Javle M, Patel SP, Hu MI, Varadhachary GR, Conley AP, Ramzanali NM, Holley VR, Kurzrock R, Meric-Bernstam F, Kwang Chae Y, Kim KB, Falchook GS, Janku FAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Antineoplastic Combined Chemotherapy Protocols
Carboplatin
Disease Progression
Female
Humans
Male
Maximum Tolerated Dose
Melanoma
Middle Aged
Mutation
Neoplasm Metastasis
Neoplasms
Paclitaxel
Proto-Oncogene Proteins B-raf
Skin Neoplasms