Abstract B123: A phase I study of R1507, a human monoclonal antibody IGF-1R (insulin-like growth factor receptor) antagonist in patients with advanced solid tumors
Authors: Gore Lia , Aisner Joseph , Kurzrock Razelle , McCarthy Cinara D. , Winter Erica , Grippo Joseph , Frankel Stanley , Mita Alain 
Published: June 2012

Abstract
Background: R1507 is a fully human monoclonal antibody (IgG1) which selectively inhibits insulin-like growth factor receptor (IGF-1R). This phase I dose-escalation study in patients with advanced malignant solid tumors explored the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of R1507 manufactured using a Chinese hamster ovarian (CHO) cell line.
Materials and Methods: R1507 was administered as a weekly (qW) or every 3 weeks (q3W) infusion until dose-limiting toxicity (DLT) or progressive disease were observed. Standard phase 1 inclusion criteria were used including adequate organ function, lack of uncontrolled intercurrent illnesses, and CD4 count &gt;200/µl. Clinical assessments for safety and DLT, tumor assessments (every 6 weeks), PK and PD blood sampling were performed.
Results: 36 pts were sequentially enrolled in dose levels 3 mg/kg (n= 3), 6 mg/kg (n= 13), 9 mg/kg (n= 7) qW or 16 mg/kg q3W (n= 13). Median pt age 52 yrs (range 18–80), M:F 21:15.
Efficacy: 12 (33%) pts showed stable disease (mean duration 25 weeks, range 11–50 weeks) [prostate 4, sarcoma 4; adrenal, appendix, soft tissue, stomach 1 each], including 1 pt with prostate cancer on study for 72+ weeks. Safety: No DLT was observed and a maximum-tolerated dose (MTD) was not reached. Drug-related adverse events (AEs) by CTCAE were mostly grade 1 or 2: fatigue (11 pts), myalgia and nausea (5 each), hyperglycemia and muscle spasms (4 each), and anorexia (3). Fourteen pts had 20 SAEs, of which 2 were related to R1507: dyspnea and pyrexia. Six pts (17%) had 9 drug-related AEs grade ≥3: hyperglycemia and fatigue (2 each), diabetes mellitus, performance status decreased, weight decreased, thrombocytopenia, and dyspnea.
PK: R1507 pharmacokinetics were nonlinear. After a single IV infusion, mean clearance (CL) decreased from ∼1000 mL/Day (CV=17.4%) at 3 mg/kg qW to 580 mL/Day (CV=25.7%) in the 16 mg/kg q3W dose group, suggesting saturable elimination. Volume of distribution (Vd) was relatively small, ranging from 5.8 – 7.8 L (CV=7.8–77%), and the mean half life was 10.5 days (CV=28.2%). At week 10, mean trough concentration at steady state (Css,min) was 40.5, 97.3, 127.5, and 90.3 ug/mL for the 3, 6, 9 qW and 16 mg/kg q3W groups respectively. Mean CL and Vd values calculated after multiple administrations were comparable to those calculated after single administration.
PD: Dose proportional increase in total IGF-1 levels was observed after treatment with R1507. This increase was sustained until redosing at the 9 mg/kg qW dose level but not sustained in the 16 mg/kg q3W dose level.
Conclusions: Treatment with R1507 is tolerable at the doses tested without DLT and has resulted in stable disease. The 9 mg/kg qW dose achieves sustained PK and PD effects and is currently being evaluated in phase II trials. Doses higher than 16 mg/kg q3W are being explored.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B123.