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

Summary

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.

Introduction

Systemic treatment options for refractory advanced sarcoma are limited and the prognosis for these patients is poor.¹ A substantial proportion of sarcomas seem to be driven by chromosomal translocations or specific pathways, with characteristic molecular events² that could be new targets for therapy. The insulin-like growth factor (IGF) signalling pathway is involved in sarcomagenesis and regulates cellular growth, proliferation, survival, and transformation.³ The insulin-like growth-factor-1 receptor (IGF-1R) is the key positive regulator for this IGF system.⁴ IGF-1R is a plasma-membrane-bound heterotetrameric receptor composed of two α-subunits and two β-subunits, linked by disulphide bonds. Binding of IGF-I and IGF-II to the α-subunits activates tyrosine kinases within the β-subunits, leading to autophosphorylation and activation of downstream processes.⁵ IGF-1R has a crucial role in tumour-cell growth, by mediating mitogenesis and maintaining a transformed phenotype, protecting tumour cells from apoptosis, and reducing growth-factor requirements.³ Impairment of IGF-1R function in vitro results in large-scale apoptosis of tumour cells, and abrogation of tumour growth and metastasis.⁶ The expression of IGF-1R and its ligands are disregulated in many tumour types.7, 8, 9 Inhibiting IGF-1R in different xenograft cancer models results in tumour growth inhibition and increased sensitivity to different cancer therapies.¹⁰

These data support the assessment of IGF-1R-targeting drugs in human malignant disease and have led to the development of molecularly targeted anticancer drugs comprising both monoclonal antibodies and small molecules. Studies support the investigation of IGF-1R blockade in several sarcoma subtypes, where this receptor seems to have a central role in disease initiation and maintenance.¹¹ Specifically, IGF-1R has been implicated in growth, metastasis, and angiogenesis in Ewing's sarcoma¹² and rhabdomyosarcoma.¹³ These data, combined with case reports describing antitumour activity of IGF-1R-targeting agents in Ewing's sarcoma, led us to pursue single-stage expansions of a phase 1 study of figitumumab (Pfizer Inc, New London, CT, USA) for the treatment of patients with Ewing's sarcoma and other sarcomas.

Figitumumab (previously CP-751,871) is a highly specific, fully human IgG2 monoclonal antibody that inhibits IGF-1R autophosphorylation induced by IGF-I and IGF-II, resulting in receptor internalisation and degradation.¹⁰ Phase 1 trials found that figitumumab has a favourable pharmacodynamic profile and is well tolerated as a single agent in patients with solid tumours,¹⁴ and in patients with myeloma.¹⁵ No dose-limiting toxicities were reported, and dose escalation was terminated at 20 mg/kg because it was not feasible to give higher doses. Figitumumab is also tolerable in combination with paclitaxel and carboplatin¹⁶ or docetaxel¹⁷ in different solid tumours, at the maximum feasible dose (MFD) of 20 mg/kg once every 3 weeks. However, to our knowledge there have been no specific reports of safety, tolerability, pharmacokinetics, and preclinical activity of IGF-IR monoclonal antibodies in a large series of patients with sarcoma, including young and paediatric patients. Here, we report data from two consecutive expansion cohorts from a phase 1 dose-escalation study of figitumumab in solid tumours.¹⁴