title: Phase IB trial for malignant melanoma using R24 monoclonal antibody, interleukin-2/alpha-interferon.
abstract: The inflammatory tumor lymphocytic infiltrates and spontaneous tumor regressions seen in patients with metastatic malignant melanomas suggest a cellular immune involvement. Enhancement of such responses has been the goal of R24 (GD3 ganglioside-specific) monoclonal antibody trials, alone and in combination with other agents. This study reports the results of 21 patients treated in a phase IB trial employing R24 (0, 5, 25, 50 mg/m2) administered by continuous i.v. infusion on days 1-5 followed by 3 MU each of interleukin-2 (IL-2) and alpha interferon (alpha-IFN) given subcutaneously on days 8-12, 15-19 and 22-26. R24-related toxicities occurred pre-dominantly at the 25 and 50 mg/m2 doses. One patient (50 mg/m2 R24) exhibited a dose-limiting Grade 4 anaphylaxis. Cytokine-related toxicities required IL-2/alpha-IFN dose reduction in two patients and early termination of treatment in five additional patients. Nine of 20 baseline biopsies showed chronic inflammation; six with lymphocytic tumor infiltration and three where inflammation was confined to the perivascular/peritumoral spaces. No day 8 or 29 biopsies in the R24-treated groups demonstrated treatment-induced tumor lymphocytic infiltrates. However, one patient randomized to no R24 treatment, showed a significant inflammatory tumor lymphocytic infiltration at days 8 and 29. Eighteen of 21 treated patients were evaluable for response. One (5%) patient receiving IL-2/alpha-IFN alone had stable disease lasting 1.5 years. Five (28%) R24, IL-2/alpha-IFN-treated patients had stable disease ranging from 6 to 32 weeks, with one patient remaining alive 2.5 years post-treatment. Although this combined treatment program was generally well tolerated, no objective responses were seen and significant R24-induced tumor lymphocytic infiltrates were not demonstrated.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Alpaugh
authors.forename: M
authors.initials: M
authors.lastname: von Mehren
authors.forename: I
authors.initials: I
authors.lastname: Palazzo
authors.forename: M B
authors.initials: MB
authors.lastname: Atkins
authors.forename: J A
authors.initials: JA
authors.lastname: Sparano
authors.forename: L
authors.initials: L
authors.lastname: Schuchter
authors.forename: L M
authors.initials: LM
authors.lastname: Weiner
authors.forename: J P
authors.initials: JP
authors.lastname: Dutcher
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D013601:T-Lymphocytes
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D005732:Gangliosides; D016898:Interferon-alpha; D007376:Interleukin-2; C026226:ganglioside, GD3