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Phase II Study of Temozolomide (TMZ) and Everolimus (RAD001) Therapy for Metastatic Melanoma: A North Central Cancer Treatment Group Study, N0675

Dronca, Roxana S. MD*; Allred, Jacob B. MS*; Perez, Domingo G. MD; Nevala, Wendy K. MS*; Lieser, Elizabeth A.T. BS*; Thompson, Michael*; Maples, William J. MD*; Creagan, Edward T. MD*; Pockaj, Barbara A. MD; Kaur, Judith S. MD*; Moore, Timothy D. MD§; Marchello, Benjamin T. MD; Markovic, Svetomir N. MD, PhD*

American Journal of Clinical Oncology: August 2014 - Volume 37 - Issue 4 - p 369–376
doi: 10.1097/COC.0b013e31827b45d4
Original Articles: Cutaneous

Objective: Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents (temozolomide [TMZ]) and inhibition of tumor angiogenesis.

Methods: We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/wk) and 200 mg/m2/d of TMZ for 5 days each cycle.

Results: Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%-59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia).

Conclusions: The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma.

*Mayo Clinic Rochester, Rochester

Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, MN

Mayo Clinic Arizona, Scottsdale, AZ

§Columbus CCOP, Columbus, OH

Montana Cancer Consortium, Billings, MT

Additional participants: Carle Cancer Center CCOP, Urbana, IL (Kendrith M. Rowland, Jr, MD); Meritcare Hospital CCOP, Fargo, ND 58122 (Preston D. Steen, MD); Rapid City Regional Oncology Group, Rapid City, SD (Richard C. Tenglin, MD); CentraCare Clinic, St Cloud, MN (Donald Jurgens, MD); Missouri Valley Cancer Consortium, Omaha, NE (Gamini S. Soori, MD); Cancer Care Associates, Tulsa, OK (Allan Keller, MD); Lehigh Valley Hospital, Allentown, PA (Suresh Nair, MD); Sioux Community Cancer Consortium, Sioux Falls, SD (Miroslaw Mazurczak, MD); Wichita Community Clinical Oncology Program, Wichita, KS (Shaker R. Dakhil, MD); Colorado Cancer Research Program, Denver, CO (Eduardo R. Pajon, Jr, MD); Essentia Duluth CCOP, Duluth, MN (Daniel A. Nikcevich, MD); Iowa Oncology Research Association CCOP, Des Moines, IA (Robert J. Behrens, MD); St. Vincent Regional Cancer Center CCOP, Green Bay, WI (Anthony J. Jaslowksi, MD); Northern Indiana Cancer Research Consortium CCOP, South Bend, IN (Robin T. Zon, MD).

Conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-35195, CA-35103, CA-35267, CA-35431, CA-35269, CA-35101, CA-37417, and CA-63849.

The content is solely the responsibility of the authors and does not necessarily represent the views of the National Cancer Institute or the National Institute of Health.

The authors declare no conflicts of interest.

Reprints: Svetomir N. Markovic, MD, PhD, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. E-mail:

© 2014 by Lippincott Williams & Wilkins, Inc