Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

• Authors: Bernard Escudier, Nathalie Lassau, Eric Angevin, Jean Charles Soria, Linda Chami, Michele Lamuraglia, Eric Zafarana, Veronique Landreau, Brian Schwartz, Eric Brendel, Jean-Pierre Armand, Caroline Robert
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 6 Pg. 1801-9 (Mar 15 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17363536 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Benzenesulfonates
• Biomarkers, Tumor
• Interferon alpha-2
• Interferon-alpha
• Phenylurea Compounds
• Pyridines
• Recombinant Proteins
• Niacinamide
• Sorafenib

Topics

• Adult
• Aged
• Algorithms
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Benzenesulfonates (administration & dosage, adverse effects, pharmacokinetics)
• Biomarkers, Tumor (analysis)
• Carcinoma, Renal Cell (drug therapy, pathology)
• Female
• Humans
• Immune System (drug effects)
• Interferon alpha-2
• Interferon-alpha (administration & dosage, adverse effects, pharmacokinetics)
• Kidney Neoplasms (drug therapy, pathology)
• Male
• Melanoma (drug therapy, pathology)
• Middle Aged
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Pyridines (administration & dosage, adverse effects, pharmacokinetics)
• Recombinant Proteins
• Sorafenib
• Treatment Outcome