Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma.
OBJECTIVE
To determine the safety, maximum tolerated dose, pharmacokinetics, and efficacy, and to evaluate biomarkers, of the multikinase inhibitor sorafenib plus IFN alpha-2a in advanced renal cell carcinoma (RCC) or melanoma.


METHODS
Patients received 28-day cycles of continuous, oral sorafenib twice daily and s.c. IFN thrice weekly: sorafenib 200 mg twice daily plus IFN 6 million IU (MIU) thrice weekly (cohort 1); and sorafenib 400 mg twice daily plus IFN 6 MIU thrice weekly (cohort 2); or plus IFN 9 MIU thrice weekly (cohort 3). Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and dynamic contrast-enhanced ultrasonography.


RESULTS
Thirteen patients received at least one dose of sorafenib plus IFN (12 RCC; one melanoma). The maximum tolerated dose was not reached [only one dose-limiting toxicity (grade 3 asthenia)]. Most frequently reported drug-related adverse events were grade 2 or less in severity, including fatigue, diarrhea, nausea, alopecia, and hand-foot skin reaction. One (7.7%) RCC patient achieved partial response and eight (61.5%) had stable disease (including the melanoma patient). Good responders assessed by dynamic contrast-enhanced ultrasonography had increased progression-free survival and overall survival, relative to poor responders. IFN had no effect on the pharmacokinetics of sorafenib. There were no significant changes in absolute values of lymphocytes, levels of proangiogenic cytokines, or inhibition of phosphorylated extracellular signal-regulated kinase in T cells or natural killer cells, with combination therapy.


CONCLUSIONS
This sorafenib combination was well tolerated, with preliminary antitumor activity in advanced RCC and melanoma patients. There were no drug-drug interactions and the recommended dose for future studies is sorafenib 400 mg twice daily plus IFN 9 MIU.
Escudier
Bernard
B
Department of Medicine, Institut Gustave Roussy, Villejuif, France. escudier@igr.fr
Lassau
Nathalie
N
Angevin
Eric
E
Soria
Jean Charles
JC
Chami
Linda
L
Lamuraglia
Michele
M
Zafarana
Eric
E
Landreau
Veronique
V
Schwartz
Brian
B
Brendel
Eric
E
Armand
Jean-Pierre
JP
Robert
Caroline
C
D000328:Adult; D000368:Aged; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007107:Immune System / Q000187:drug effects; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011994:Recombinant Proteins; D000077157:Sorafenib; D016896:Treatment Outcome
D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010671:Phenylurea Compounds; D011725:Pyridines; D011994:Recombinant Proteins; D009536:Niacinamide; D000077157:Sorafenib