Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675.
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/m/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.
Roxana S
RS
Dronca
Jacob B
JB
Allred
Domingo G
DG
Perez
Wendy K
WK
Nevala
Elizabeth A T
EA
Lieser
Michael
M
Thompson
William J
WJ
Maples
Edward T
ET
Creagan
Barbara A
BA
Pockaj
Judith S
JS
Kaur
Timothy D
TD
Moore
Benjamin T
BT
Marchello
Svetomir N
SN
Markovic
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D000068338:Everolimus; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077204:Temozolomide; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003606:Dacarbazine; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000077204:Temozolomide