title: Phase II trial of the antiangiogenic agent IM862 in metastatic renal cell carcinoma.
abstract: IM862 is a naturally occurring dipeptide (L-glu-L-trp) with immunomodulatory and antiangiogenic properties. A significant anticancer activity has been reported recently in AIDS-related Kaposi's sarcoma, a tumour of endothelial cell origin. The high vascularity and responsiveness to immunotherapy of renal cell carcinoma (RCC) makes such a tumour a potential target for IM862. In all, 25 patients were accrued in a prospective phase II trial using a standard two-step design. The main inclusion criteria were WHO performance status </=2, age over 18 years, expected survival >3 months, normal marrow, kidney and liver functions. IM862 was given intranasally at a dose of 20 mg three times daily. Each cycle consisted of 8 consecutive weeks of treatment. All 25 patients were fully evaluable for response and 24 for toxicities. Median age was 62 years (range 42-76), median WHO PS was 1 (0-2). No grade 2 or 3 toxicities related to the study drug have been recorded. Eight patients had stable disease (SD) and 17 progressed while on treatment. Median survival was 7.9 months (range 2.7-20). Median time to progression was 1.9 months (range 1.2-12.6). Median duration of SD was 6 months (range 5.2-12.6+). Analysis of blood angiogenic markers showed a significant decrease of plasma vascular endothelial growth factor (VEGF) levels after 4 and 8 weeks of therapy. Treatment with IM862 has no toxicity, but does not lead to any significant objective responses in metastatic RCC. IM862 should not be further evaluated as a single agent at these doses and schedule for this population of patients. The decrease in VEGF levels warrants further investigation of IM862 as an antiangiogenic therapy.
authors.affiliation: University of Oxford, Cancer Research UK Medical Oncology Unit, The Churchill, Old Road, Oxford OX3 7LJ, England.
authors.forename: G
authors.initials: G
authors.lastname: Deplanque
authors.forename: S
authors.initials: S
authors.lastname: Madhusudan
authors.forename: P H
authors.initials: PH
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Wellmann
authors.forename: K
authors.initials: K
authors.lastname: Christodoulos
authors.forename: D C
authors.initials: DC
authors.lastname: Talbot
authors.forename: T S
authors.initials: TS
authors.lastname: Ganesan
authors.forename: A
authors.initials: A
authors.lastname: Blann
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004151:Dipeptides / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D011446:Prospective Studies; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; D004151:Dipeptides; C060736:thymogen