title: A phase I trial of bortezomib and interferon-α-2b in metastatic melanoma.
abstract: The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximum tolerated dose of bortezomib when administered in combination with IFN-α-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-α subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose for bortezomib was 1.3 mg/m(2). One patient had a partial response, and 7 had stable disease. Progression-free survival was 2.5 months, and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of proangiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.
authors: Divisions of *Medical Oncology †Surgical Oncology ‡Center for Biostatistics, The Ohio State University, Columbus, OH.
authors: Joseph
authors: J
authors: Markowitz
authors: Eric A
authors: EA
authors: Luedke
authors: Valerie P
authors: VP
authors: Grignol
authors: Erinn M
authors: EM
authors: Hade
authors: Bonnie K
authors: BK
authors: Paul
authors: Bethany L
authors: BL
authors: Mundy-Bosse
authors: Taylor R
authors: TR
authors: Brooks
authors: Thao-Vi
authors: TV
authors: Dao
authors: Sri V
authors: SV
authors: Kondalasula
authors: Gregory B
authors: GB
authors: Lesinski
authors: Thomas
authors: T
authors: Olencki
authors: Kari L
authors: KL
authors: Kendra
authors: William E
authors: WE
authors: Carson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011719:Pyrazines / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011719:Pyrazines; D011994:Recombinant Proteins; D000069286:Bortezomib