title: A phase I study of high-dose interleukin-2 with sorafenib in patients with metastatic renal cell carcinoma and melanoma.
abstract: This study was designed to evaluate the safety and feasibility of high-dose interleukin-2 (HD IL-2) followed by sorafenib in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Biomarkers relevant to the antitumor effects of IL-2 that may be altered by sorafenib including the percentages of natural T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and STAT5 phosphorylation (pSTAT5) in T cells were evaluated. We hypothesized that the proposed treatment schedule is feasible and safe and may lead to enhanced tumor response. A phase I dose escalation trial was conducted in patients with either metastatic RCC or MM. HD IL-2 (600,000 IU/kg IV q8h × 8-12 doses) was administered on days 1-5 and 15-19, followed by sorafenib on days 29-82. The sorafenib dose was escalated. The percentage of Tregs, MDSC, and pSTAT5 in T cells were evaluated in peripheral blood by flow cytometry. Twelve of the 18 patients were evaluable for dose-limiting toxicity. No dose-limiting toxicity was observed. The treatment-related toxicity was predictable and did not seem to be additive with this schedule of administration. Partial responses were seen in 3 patients. No significant changes in the percentage of circulating Treg and MDSC were observed, whereas sorafenib did not adversely affect the ability of IL-2 to induce pSTAT5 in T cells. HD IL-2 followed by sorafenib was safe and feasible in patients with MM and RCC and did not adversely affect T-cell signaling through STAT5 in response to IL-2.
authors.affiliation: *Division of Medical Oncology, Comprehensive Cancer Center, The Ohio State University, and Arthur G. James Cancer Hospital and Solove Research Institute, Columbus, OH †Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Paul
authors.initials: P
authors.lastname: Monk
authors.forename: Elaine
authors.initials: E
authors.lastname: Lam
authors.forename: Amir
authors.initials: A
authors.lastname: Mortazavi
authors.forename: Kari
authors.initials: K
authors.lastname: Kendra
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mace
authors.forename: Susan
authors.initials: S
authors.lastname: Geyer
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.forename: Sanaa
authors.initials: S
authors.lastname: Tahiri
authors.forename: Arvinder
authors.initials: A
authors.lastname: Bhinder
authors.forename: Steven K
authors.initials: SK
authors.lastname: Clinton
authors.forename: Thomas
authors.initials: T
authors.lastname: Olencki
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D050799:STAT5 Transcription Factor / Q000378:metabolism; D000077157:Sorafenib; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D007376:Interleukin-2; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D009536:Niacinamide; D000077157:Sorafenib