Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors.

Abstract

PURPOSE:

Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT).

PATIENTS AND METHODS:

Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated.

RESULTS:

Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed.

CONCLUSION:

Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.

• Authors: William D Tap, George Demetri, Phillip Barnette, Jayesh Desai, Petr Kavan, Richard Tozer, Pasquale W Benedetto, Gregory Friberg, Hongjie Deng, Ian McCaffery, Ian Leitch, Sunita Badola, Sung Chang, Min Zhu, Anthony Tolcher
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 30 Issue 15 Pg. 1849-56 (May 20 2012) ISSN: 1527-7755 [Electronic] United States
• PMID: 22508822 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• EWS-FLI fusion protein
• Oncogene Proteins, Fusion
• Proto-Oncogene Protein c-fli-1
• RNA-Binding Protein EWS
• Insulin-Like Growth Factor I
• ganitumab
• Receptor, IGF Type 1

Topics

• Adult
• Aged
• Antibodies, Monoclonal (adverse effects, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Bone Neoplasms (blood, drug therapy, genetics, immunology, mortality, pathology)
• Desmoplastic Small Round Cell Tumor (blood, drug therapy, immunology, mortality, secondary)
• Female
• Humans
• In Situ Hybridization, Fluorescence
• Insulin-Like Growth Factor I (metabolism)
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Oncogene Proteins, Fusion (genetics)
• Proto-Oncogene Protein c-fli-1 (genetics)
• RNA-Binding Protein EWS (genetics)
• Receptor, IGF Type 1 (antagonists & inhibitors, immunology)
• Sarcoma, Ewing (blood, drug therapy, genetics, immunology, mortality, secondary)
• Sequence Analysis, RNA
• Time Factors
• Translocation, Genetic
• Treatment Outcome
• Young Adult