Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study

Abstract

Background: Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing's sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases.

Methods: Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing's sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760.

Findings: 29 patients, 16 of whom had Ewing's sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6.1, range 1-24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing's sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing's sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer.

Interpretation: Figitumumab is well tolerated and has antitumour activity in Ewing's sarcoma, warranting further investigation in this disease.

Funding: Pfizer Global Research and Development.

Copyright 2010 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Cycle 1 and cycle 4 mean (SD) plasma concentration–time profiles of figitumumab in patients with sarcoma after dosing every 3 or 4 weeks

Figure 2. Waterfall plot of best responses, as percentage decrease in tumour size by RECIST criteria, of the target lesions in 22 evaluable patients

Green bars are patients with disease progression (increase in target-lesion size); blue bars are patients with a decrease in size of the target lesions. The numbers above/below the bars represent the number of treatment cycles patients received before withdrawal due to disease progression. RECIST=Response Evaluation Criteria in Solid Tumours. DSRC=desmoplastic small round cell tumour. *Remains on study.†Partial response in soft-tissue disease but progressive disease with a new bone lesion. ‡Patient with a partial response after treatment and complete response after surgery. §Reduction in target lesions after two cycles of treatment and radiotherapy to the mediastinum.

Figure 3. CT scan of a 12-year-old patient with Ewing’s sarcoma, at baseline and after six cycles of treatment (A), and a 24-year-old patient with Ewing’s sarcoma with ongoing partial response (B)

In A, target lesion decreased by about 60% after six cycles, with a remaining central calcification. The residual mass was resected and confirmed as a pathological complete response. Non-target lesions also disappeared. In B, several target lung nodules disappeared after four cycles of treatment, qualifying for partial response. The non-target lesion in the mediastinum decreased by 60% (this also followed 45 Gy of radiation therapy in 15 fractions).