A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients.
BACKGROUND
Sorafenib has demonstrated single agent activity in non-small cell (NSCLC) and small cell lung cancer (SCLC). Carboplatin/pemetrexed (CbP) and cisplatin/etoposide (PE) are commonly used in the treatment of these diseases.


METHODS
A phase I trial escalating doses of sorafenib in combination with fixed doses of PE (Arm A) or CbP (Arm B) was performed using a 3-patient cohort design to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT); DLT were assessed in the first cycle. The trial was subsequently amended with closure of Arm B and to include Arm C with a reduced dose of carboplatin.


RESULTS
Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 42-73), male/female ratio 12/8, PS 0/1 ratio 6/14, and median number of prior therapies 2 (range 1-4). The most common tumor types were NSCLC and SCLC. On Arm A at dose level 0 (sorafenib 200 mg BID), 2 of 4 patients experienced DLT; 2 patients were enrolled at dose level -1 (sorafenib 200 mg QD) without DLT, but this arm was closed due to slow accrual. On Arm B, 2 of 3 patients experienced DLT at dose level 0 (sorafenib 200 mg BID). On Arm C at dose level 0 (sorafenib 200 mg BID), 1 of 6 patients experienced DLT, and at dose level +1 (sorafenib 400 mg BID) 2 of 5 patients experienced a DLT.


CONCLUSIONS
The MTD of sorafenib was 200 mg BID continuously in combination with carboplatin (AUC of 5) and pemetrexed 500 mg/m² every 3 weeks. However, only 6 patients were treated at this dose level, and the results should be interpreted cautiously.
Davies
Janine M
JM
Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hil, USA.
Dhruva
Nirav S
NS
Walko
Christine M
CM
Socinski
Mark A
MA
Bernard
Stephen
S
Hayes
D Neil
DN
Kim
William Y
WY
Ivanova
Anastasia
A
Keller
Kimberly
K
Hilbun
Layla R
LR
Chiu
Michael
M
Dees
E Claire
EC
Stinchcombe
Thomas E
TE
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D005047:Etoposide / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000627:therapeutic use; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D000068437:Pemetrexed; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D005971:Glutamates; D010671:Phenylurea Compounds; D011725:Pyridines; D000068437:Pemetrexed; D009536:Niacinamide; D006147:Guanine; D005047:Etoposide; D000077157:Sorafenib; D016190:Carboplatin; D002945:Cisplatin