Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma.
OBJECTIVE
This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma.


METHODS
Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins.


RESULTS
A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK.


CONCLUSIONS
Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK.
Departments of Melanoma Medical Oncology, Systems Biology, Biostatistics, Pathology, Experimental Therapeutics, and Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Michael A
MA
Davies
Patricia S
PS
Fox
Nicholas E
NE
Papadopoulos
Agop Y
AY
Bedikian
Wen-Jen
WJ
Hwu
Alexander J
AJ
Lazar
Victor G
VG
Prieto
Kirk S
KS
Culotta
Timothy L
TL
Madden
Quanyun
Q
Xu
Sha
S
Huang
Wanleng
W
Deng
Chaan S
CS
Ng
Sanjay
S
Gupta
Wenbin
W
Liu
Janet E
JE
Dancey
John J
JJ
Wright
Roland L
RL
Bassett
Patrick
P
Hwu
Kevin B
KB
Kim
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000077157:Sorafenib; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; C401859:temsirolimus; D000077157:Sorafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020123:Sirolimus