A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study

Abstract

Background: Insulin-like growth factor-1 receptor (IGF-1R) is implicated in the pathogenesis of rhabdomyosarcoma (RMS), osteosarcoma (OS), and synovial sarcoma (SS). The authors conducted a multi-institutional phase 2 trial of the monoclonal antibody R1507 in patients with various subtypes of recurrent or refractory sarcomas.

Methods: Eligibility criteria included age ≥ 2 years and a diagnosis of recurrent or refractory RMS, OS, SS, and other soft tissue sarcomas. Patients received a weekly dose of 9 mg/kg R1507 intravenously. The primary endpoint was the best objective response rate using World Health Organization criteria. Tumor imaging was performed every 6 weeks × 4 and every 12 weeks thereafter.

Results: From December 2007 through August 2009, 163 eligible patients from 33 institutions were enrolled. The median patient age was 31 years (range, 7-85 years). Histologic diagnoses included OS (n = 38), RMS (n = 36), SS (n = 23), and other sarcomas (n = 66). The overall objective response rate was 2.5% (95% confidence interval, 0.7%-6.2%). Partial responses were observed in 4 patients, including 2 patients with OS, 1 patient with RMS, and 1 patient with alveolar soft part sarcoma. Four additional patients (3 with RMS and 1 with myxoid liposarcoma) had a ≥ 50% decrease in tumor size that lasted for <4 weeks. The median progression-free survival was 5.7 weeks, and the median overall survival was 11 months. The most common grade 3/4 toxicities were metabolic (12%), hematologic (6%), gastrointestinal (4%), and general constitutional symptoms (8%).

Conclusions: R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas. Additional studies to help identify the predictive factors associated with clinical benefit in selected histologies such as RMS appear to be warranted.

Keywords: IGF-1R; SARC; insulin-like growth factor; sarcoma.

Figure 1.

This is a Consolidated Standards of Reporting Trials (CONSORT) diagram of patients registered on this study.

Figure 2.

The best individual changes in total lesion size from baseline are illustrated for all sarcoma types. WHO indicates World Health Organization classification; PR, partial response; SD, stable disease; PD, progressive disease.

Figure 3.

The best individual changes from baseline are illustrated according to sarcoma type. OSTEO indicates osteosarcoma; RHABDO, rhabdomyosarcoma.

Figure 4.

Progression-free survival for all eligible patients. Values in parentheses are the 95% confidence interval for median progression-free survival in weeks. OSTEO indicates osteosarcoma; RHABDO, rhabdomyosarcoma.

Figure 5.

Changes in R1507 concentrations are illustrated. (A) The mean concentration time profile observed after the first weekly dose is shown. (B) Peak values (C_max) (top horizontal line) and trough values (C_min) (bottom horizontal line) increased over the course of 12 weeks with some evidence for a pharmacokinetic plateau after 6 weeks of treatment. Vertical lines indicate the standard deviations.

Figure 6.

The total percentage change in insulin-like growth factor-1 (IGF-1) from baseline (BL) is illustrated in weeks.