Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors.
OBJECTIVE
Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities.


METHODS
Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed.


RESULTS
Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response.


CONCLUSIONS
Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.
Duran
Ignacio
I
Princess Margaret Hospital Phase II Consortium, Canada.
Hotté
Sebastien J
SJ
Hirte
Holger
H
Chen
Eric X
EX
MacLean
Martha
M
Turner
Sandra
S
Duan
Lixia
L
Pond
Gregory R
GR
Lathia
Chetan
C
Walsh
Scott
S
Wright
John J
JJ
Dancey
Janet
J
Siu
Lillian L
LL
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077157:Sorafenib
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D011799:Quinazolines; D009536:Niacinamide; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor