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

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. We con...

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Bibliographic Details
Published in:	American journal of clinical oncology Vol. 37; no. 4; pp. 369 - 376
Main Authors:	DRONCA, Roxana S, ALLRED, Jacob B, MOORE, Timothy D, MARCHELLO, Benjamin T, MARKOVIC, Svetomir N, PEREZ, Domingo G, NEVALA, Wendy K, LIESER, Elizabeth A. T, THOMPSON, Michael, MAPLES, William J, CREAGAN, Edward T, POCKAJ, Barbara A, KAUR, Judith S
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 01-08-2014
Subjects:	Adult Aged Aged, 80 and over Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Dacarbazine - administration & dosage Dacarbazine - analogs & derivatives Dermatology Disease-Free Survival Everolimus Female Humans Induction Chemotherapy Male Medical sciences Melanoma - drug therapy Melanoma - mortality Melanoma - pathology Middle Aged Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Pharmacology. Drug treatments Sirolimus - administration & dosage Sirolimus - analogs & derivatives Sirolimus - pharmacology Skin Neoplasms - drug therapy Skin Neoplasms - mortality Skin Neoplasms - pathology TOR Serine-Threonine Kinases - antagonists & inhibitors Treatment Outcome Tumors Tumors of the skin and soft tissue. Premalignant lesions Vascular Endothelial Growth Factor A - blood Antineoplastic agent Sirolimus Toxicity Metastasis Macrocycle Angiogenesis Phase II trial Malignant melanoma Advanced stage Protein synthesis inhibitor Neovascularization Everolimus Human mammalian target of rapamycin (mTOR) Lactone melanoma vascular endothelial growth factor (VEGF) Malignant tumor Macrolide Alkylating agent Vascular endothelium growth factor Treatment Mammalian target of rapamycin Temozolomide Cancer
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Summary:	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. 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/m/d of TMZ for 5 days each cycle. 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). 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.
ISSN:	0277-3732 1537-453X
DOI:	10.1097/COC.0b013e31827b45d4