A SARC global collaborative phase II trial of R1507, a recombinant human monoclonal antibody to the insulin-like growth factor-1 receptor (IGF1R) in patients with recurrent or refractory sarcomas

Abstract

10503 Background: The IGF1 system has been implicated in sarcoma development and inhibition of IGF1R function has been shown to induce clinical responses in select sarcomas. Methods: Objectives included response rate (RR) and progression-free survival (PFS) to R1507 in patients with recurrent or refractory Ewing's (ES, 2 cohorts- primary refractory vs. others) osteo (OS), synovial (SS), rhabdomyosarcoma (RMS), and other sarcomas. Eligibility included recurrent/refractory measurable disease, age ≥ 12 yrs, life expectancy ≥ 6 weeks, Karnofsky PS ≥ 70, adequate renal, hepatic and bone marrow function. R1507 was administered i.v. at 9 mg/kg over one hour weekly. Response was assessed by WHO criteria every 6 wks X 4 and every 12 wks thereafter. A two-stage design (Green and Dahlberg) was used. The endpoint for the primary refractory ES cohort was PFS at week 18 (planned n=65). RR was the primary endpoint for the remaining cohorts (planned n=240). Results: From 12/07–12/08, 203 eligible patients from 29 centers across the US, Europe and Australia were enrolled. Age ranged from 12–85 yrs (median=27 yrs) and 126 were male. Verified histologic subtypes were ES (n=71), OS (n=43), RMS (n=28), SS (n=25), and others (n=25). 15 severe adverse events were reported in 9 patients, the most common being fatigue (n=2), thrombocytopenia (n=2), dehydration (n=2), and hyperglycemia (n=2). Clinically significant activity has been observed in ES, RMS and OS with several dramatic responses seen in ES and RMS. Independent radiologic review is currently ongoing and updated data will be presented. Conclusions: The rapid accrual amongst many centers in diverse geographical locations demonstrates the feasibility of collaborative research in sarcomas. R1507 is well tolerated and a promising new agent for the treatment of various sarcomas. SARC and Roche are collaborating in additional clinical trials to better define the role of R1507 in the treatment of selected sarcomas. [Table: see text]

IGF-1R as an anti-cancer target--trials and tribulations

“…The most notable activity of anti–IGF-1R mAbs was demonstrated in EWS, with reports of complete responses (CRs) or partial responses (PRs) and prolonged stable disease (SD) in phase 1 trials [33] , [39] – [41] . These promising results led to a series of phase 2 evaluations in the indication ( Table 4 ).…”

Targeting the Insulin-Like Growth Factor Pathway in Rhabdomyosarcomas: Rationale and Future Perspectives

“…The activity of IGF1R monoclonal antibodies has been confirmed by the early reports of clinical activity in Ewing sarcoma [ 89 – 91 , 94 ]. However, in RMS patients, despite some responses observed with R1507 [ 92 ], targeting IGF1R alone does not seem the optimal strategy due to the complexity of this pathway and the key role of IGF2 in this pathology. To extend the benefits of these therapeutic approaches there is an urgent need to identify predictive biomarkers to improve patient selection and facilitate the development of rational combination regimens.…”

“…Both cases were heavily pretreated metastatic ARMS and both progressed within 6 weeks of starting treatment on figitumumab (a monoclonal antibody against IGF1R) [ 89 ]. More recently, in a preliminary report of the SARC011, a phase II trial in multiple sarcoma types, described 3 objective radiological responses in patients with RMS treated with the anti-IGF1R antibody R1507 [ 92 ]. However, more mature data in Ewing's sarcoma has shown that many responses only lasted for a finite period of time [ 93 , 94 ].…”

In Search of Targeted Therapies for Childhood Cancer

“…A second, and more challenging, model occurs when targeted agents show insufficient promise in adult cancers to merit further commercial development, yet preclinical or early clinical studies suggest potential activity in pediatric cancer (Figure 1 , Pathway #2). For example, the IGF1 signaling pathway seems to be a significant axis for targeting Ewing's sarcoma, with an overall 10–15% objective response rate as a single agent in patients with refractory disease (Patel et al, 2009 ). While it is unclear if this response rate as a single agent is sufficient for FDA approval, multiagent therapies could be effective.…”