A phase I dose-escalation study of weekly IMC-1121B, a fully human anti-vascular endothelial growth factor receptor 2 (VEGFR2) IgG1 monoclonal antibody (Mab), in patients (pts) with advanced cancer

Abstract

3032 Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and solid tumor models. IMC-1121B is a fully human anti-VEGFR2 IgG1 Mab. Methods: Cohorts of 3–6 pts (ECOG PS ≤ 2) with advanced cancer and no significant cardiovascular, thrombotic or bleeding disorders received escalating doses of IMC-1121B. A single initial dose with extended PK sampling was followed by 4 x weekly infusions per treatment cycle starting at 2mg/kg. 7 dose levels up to a maximum of 16 mg/kg are planned. Human anti-human antibodies (HAHA) directed against IMC-1121B were assessed at baseline and before each Week 4 dose. Tumor response was assessed every 2 cycles. PD analyses include DCE-MRI, serum VEGF and sVEGFR1/2 levels, and peripheral blood mononucleocyte gene expression profiling at baseline and post-dosing. Results: 12 pts (8 M; 4 F), median age 58 years (range: 36–76), have entered the study: cohort 1 (2mg/kg) n=6, cohort 2 (4mg/kg) n=4 and cohort 3 (6mg/kg) n=2. No toxicities ≥ grade 2, considered definitely or probably related to study drug, have occurred. Toxicities ≥ grade 2 possibly drug-related include anorexia, vomiting, anemia, depression, fatigue, and insomnia. To date, there has been one unconfirmed partial response (melanoma) and 5 pts with stable disease for >3 months (colon: 2, breast, gastric, thyroid). Preliminary non-compartmental PK analysis reveals dose-dependent elimination and non-linear exposure, consistent with saturable clearance mechanism(s): mean t1/2 = 63.62, 93.46, 99.63 hrs, mean Cmax = 43.67, 80.25, 264 ug/mL, and AUC0-Inf = 3860, 9242, 27437 hr*ug/mL, at the 2, 4, and 6 mg/kg dose levels, respectively. Conclusions: Weekly administration of IMC-1121B is well tolerated at doses up to 6mg/kg/week. There is early evidence of a non-linear dose-PK relationship. Dose escalation continues. Updated safety, PK, PD, HAHA, and efficacy data will be presented. [Table: see text]