Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.
BACKGROUND
Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin.


METHODS
Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid.


RESULTS
Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected.


CONCLUSIONS
Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.
Richly
H
H
West German Cancer Center, University of Essen, Essen, Germany.
Henning
B F
BF
Kupsch
P
P
Passarge
K
K
Grubert
M
M
Hilger
R A
RA
Christensen
O
O
Brendel
E
E
Schwartz
B
B
Ludwig
M
M
Flashar
C
C
Voigtmann
R
R
Scheulen
M E
ME
Seeber
S
S
Strumberg
D
D
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001557:Benzenesulfonates / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage; D016879:Salvage Therapy; D000077157:Sorafenib
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D004317:Doxorubicin; D000077157:Sorafenib