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Cancer. 2019 Feb 1;125(3):463-472. doi: 10.1002/cncr.31812. Epub 2018 Nov 1.

Phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF-mutated melanoma and other advanced malignancies.

Author information

1
Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, California.
3
Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California.
4
Thomas Jefferson University, Philadelphia, Pennsylvania.
5
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Developmental Therapeutics, Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
10
Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
11
California Pacific Medical Center Research Institute, San Francisco, California.
12
Sarah Cannon Research Institute at Health ONE, Denver, Colorado.

Abstract

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.

KEYWORDS:

BRAF mutation; carboplatin; paclitaxel; vemurafenib

PMID:
30383888
PMCID:
PMC6340722
[Available on 2020-02-01]
DOI:
10.1002/cncr.31812

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