Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma

A North Central Cancer Treatment Group study, N047A
Domingo G. Perez, MD 1, Vera J. Suman, PhD 2, Tom R. Fitch, MD 3, Thomas Amatruda III, MD 1, Roscoe F. Morton, MD 4, Shamim Z. Jilani, MD 5, Costas L. Constantinou, MD 6, James R. Egner, MD 7, Lisa A. Kottschade, RN, MSN, CNP 2, Svetomir N. Markovic, MD, PhD 2 *§
1Metro-Minnesota Community Clinical Oncology Program, St Louis Park, Minnesota
2Mayo Clinic and Mayo Foundation, Rochester, Minnesota
3Mayo Clinic and Mayo Foundation, Scottsdale, Arizona
4Iowa Oncology Research Association CCOP, Des Moines, Iowa
5Hematology and Oncology of Dayton, Inc. Dayton, Ohio
6Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa
7Carle Cancer Center CCOP, Urbana, Illinois
email: Svetomir N. Markovic (markovic.svetomir@mayo.edu)


*Correspondence to Svetomir N. Markovic, Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905
Additional participating institutions included: Wichita Community Clinical Oncology Program, Wichita, Kansas; Sioux Community Cancer Consortium, Sioux Falls, South Dakota; Missouri Valley Cancer Consortium, Omaha, Nebraska; Mayo Clinic Jacksonville, Jacksonville, Florida.
Roscoe F. Morton owns shares of stock in Genentech.
§Fax: (507) 284-5045

Funded by:
 Public Health Service; Grant Number: CA-25224, CA-35267, CA-60276, CA-35101, CA-35090, CA-52352, CA-35195, CA-35269, CA-35431, CA-35103, CA-63849
Keywords
metastatic melanoma • angiogenesis • chemotherapy • phase 2 trials

Abstract
BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in the growth and metastatic progression of melanoma. Exposure of melanoma cells to chemotherapy induces VEGF overproduction, which in turn may allow melanoma cells to evade cell death and become chemotherapy resistant. Therefore, in patients with metastatic melanoma, the combination of chemotherapy with an agent that specifically targets VEGF might be able to control tumor growth and progression more effectively than chemotherapy alone. METHODS: A 2-stage phase 2 clinical trial was conducted in patients with unresectable stage IV (metastatic) melanoma to assess antitumor activity and the toxicity profile of the combination of carboplatin (area under the curve 6 iv on Day 1 of a 28-day cycle), paclitaxel (80 mg/m2 iv on Days 1, 8, and 15), and bevacizumab (10 mg/kg iv on Days 1 and 15). Treatment was continued until progression or intolerable toxicity. RESULTS: Fifty-three patients (62.3% male) were enrolled. Nine (17%) patients achieved partial remission, and another 30 (57%) achieved stable disease for at least 8 weeks. Median progression-free survival and median overall survival were 6 months and 12 months, respectively. One patient died after 8 treatment cycles from intracranial hemorrhage into undiagnosed brain metastases. The most common severe (grade 3) toxicities were neutropenia (53%), thrombocytopenia (11%), hypertension (9%), and anemia (8%). CONCLUSIONS: This combination of carboplatin, paclitaxel, and bevacizumab appears to be moderately well tolerated and clinically beneficial in patients with metastatic melanoma. Further study of this combination is warranted. Cancer 2009. © 2008 American Cancer Society.

Received: 3 April 2008; Revised: 29 July 2008; Accepted: 4 August 2008