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

Olmos, David; Postel-Vinay, Sophie; Molife, L Rhoda; Okuno, Scott H.; Schuetze, Scott M.; Paccagnella, M. Luisa; Batzel, Gretchen N.; Yin, Dong; Pritchard‐Jones, Kathy; Judson, Ian; Worden, Francis P.; Gualberto, Antonio; Scurr, Michelle; Bono, Johann S. de; Haluska, Paul

doi:10.1016/s1470-2045(09)70354-7

Cited by 302 publications

(208 citation statements)

References 32 publications

Supporting

Mentioning

190

Contrasting

Unclassified

Order By: Relevance

“…Humanized monoclonal antibodies that bind and inactivate the type-I IGF receptor (IGFRI), the primary IGF-II signaling receptor, are currently undergoing clinical trials to prevent IGF-II signaling in cancers [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

IGF2 expression and β-catenin levels are increased in Frozen Shoulder Syndrome

Raykha¹,

Crawford²,

Burry³

et al. 2014

CIM

View full text Add to dashboard Cite

IGF2 expression and β-catenin levels are increased in Frozen Shoulder Syndrome Abstract Purpose: Frozen Shoulder Syndrome is a brosis of the shoulder joint capsule that is clinically associated with Dupuytren's disease, a brosis of the palmar fascia. Little is known about any commonalities in the pathophysiology of these connective tissue broses. β-catenin, a protein that transactivates gene expression, and levels of IGF2 mRNA, encoding insulin-like growth factor-II, are elevated in Dupuytren's disease. e aim of this study was to determine if correlating changes in β-catenin levels and IGF2 expression are evident in Frozen Shoulder Syndrome.Methods: Tissue from patients with Frozen Shoulder Syndrome and rotator cu tear were obtained during shoulder arthroscopies. Total protein extracts were prepared from tissue aliquots and β-catenin immunoreactivity was assessed by Western immunoblotting. In parallel, primary broblasts were derived from these tissues and assessed for IGF2 expression by quantitative PCR.Results: β-catenin levels were signi cantly increased in Frozen Shoulder Syndrome relative to rotator cu tear when assessed by Western immunoblotting analyses. IGF2 mRNA levels were signi cantly increased in primary broblasts derived from frozen shoulder syndrome tissues relative to broblasts derived from rotator cu tissues. Conclusions:As in Dupuytren's disease, β-catenin levels and IGF2 expression are elevated in Frozen Shoulder Syndrome. ese ndings support the hypothesis that these connective tissue broses share a common pathophysiology. Materials and Methods Tissue collectionTissue sections were collected with approval of the Human Subjects Research Ethics Board (HSREB) at Western University from surgical specimens of patients undergoing shoulder arthroscopy for the treatment of either FSS or subacromial decompression for RCT. An arthroscopic punch was used to obtain tissue specimens from the rotator cu interval immediately adjacent to the antero-superior arthroscopic portal from patients with FSS and RCT. Representative samples of these tissues were removed at the time of surgery and immediately transported to the laboratory. e tissues were either snap frozen in liquid nitrogen for total protein extraction or processed for primary broblast derivation. Western immunoblottingTotal protein extracts were prepared from snap frozen tissue using modi ed RIPA bu er. Tissue lysate (25 μg) was subjected to Western blot analysis and β-catenin levels were assessed using an anti-β-catenin monoclonal antibody (clone 14, Transduction Laboratories, Lexington, KY). β-actin levels were assessed in parallel using an anti-β-actin antibody (Sigma, St Louis, MO) to normalize for variability in total protein loading. Antibody speci c bands were visualized using enhanced chemiluminescence (ECL) and Kodak XLS lm. Densitometry analysis was carried out using Scion Image so ware (Scion Corporation, Beta 4.0.2, Frederick, MD). Normalized measurements of β-catenin were plotted as the sample mean (β-catenin /actin) ratio ± standard error...

show abstract

Section: Discussionmentioning

confidence: 99%

IGF2 expression and β-catenin levels are increased in Frozen Shoulder Syndrome

Raykha¹,

Crawford²,

Burry³

et al. 2014

CIM

View full text Add to dashboard Cite

show abstract

“…[22][23][24]. However, efficacy of anti-IGF-IR antibodies has been disappointing in clinical trials to date (25)(26)(27)(28)(29)(30).…”

Section: Igf-i Signals By Binding To the Igf-i Receptor (Igf-ir) Or Tmentioning

confidence: 99%

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

Friedbichler

Hofmann

Kroez

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Insulin-like growth factor (IGF) signaling is thought to play a role in the development and progression of multiple cancer types. To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR). Here, we describe the pharmacologic profile of BI 836845, a fully human monoclonal antibody that utilizes an alternative approach to IGF signaling inhibition by selectively neutralizing the bioactivity of IGF ligands. Biochemical analyses of BI 836845 demonstrated high affinity to human IGF-I and IGF-II, resulting in effective inhibition of IGF-induced activation of both IGF-IR and IR-A in vitro. Cross-reactivity to rodent IGFs has enabled rigorous assessment of the pharmacologic activity of BI 836845 in preclinical models. Pharmacodynamic studies in rats showed potent reduction of serum IGF bioactivity in the absence of metabolic adverse effects, leading to growth inhibition as evidenced by reduced body weight gain and tail length. Moreover, BI 836845 reduced the proliferation of human cell lines derived from different cancer types and enhanced the antitumor efficacy of rapamycin by blocking a rapamycininduced increase in upstream signaling in vitro as well as in human tumor xenograft models in nude mice. Our data suggest that BI 836845 represents a potentially more effective and tolerable approach to the inhibition of IGF signaling compared with agents that target the IGF-I receptor directly, with potential for rational combinations with other targeted agents in clinical studies. Mol Cancer Ther; 13(2); 399-409. Ó2013 AACR.

show abstract

“…Responses to IGF-1R antibody were seen on phase I studies of AMG 479 (Amgen, Thousand Oaks, CA), 10 figitumumab (Pfizer, New London, CT), 11 and R1507. 10,12 The initial clinical benefit coupled with the preclinical promise of this signaling pathway led to the joint collaborative program between the Sarcoma Alliance for Research through Collaboration (SARC) and Roche (Nutley, NJ) for the development of R1507 in patients with recurrent sarcoma including ESFT.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 99%

R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor 1 Receptor, in Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors: Results of a Phase II Sarcoma Alliance for Research Through Collaboration Study

Pappo

Patel

Crowley

et al. 2011

JCO

279

209

View full text Add to dashboard Cite

A B S T R A C T PurposeThe type 1 insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the pathogenesis of the Ewing sarcoma family of tumors (ESFT). We conducted a multicenter phase II study of the fully human IGF-1R monoclonal antibody R1507 in patients with recurrent or refractory ESFT. Patients and MethodsPatients Ն 2 years of age with refractory or recurrent ESFT received R1507 at doses of 9 mg/kg intravenously one a week or 27 mg/kg intravenously every three weeks. Response was measured by using WHO criteria. Tumor imaging was performed every 6 weeks for 24 weeks and then every 12 weeks. ResultsFrom December 2007 through April 2010, 115 eligible patients from 31 different institutions were enrolled. The median age was 25 years (range, 8 to 78 years). The location of the primary tumor was bone in 57% of patients and extraskeletal in 43% of patients. A total of 109 patients were treated with R1507 9 mg/kg/wk, and six patients were treated with 27 mg/kg/3 wk. The overall complete response/partial response rate was 10% (95% CI, 4.9% to 16.5%). The median duration of response was 29 weeks (range, 12 to 94 weeks), and the median overall survival was 7.6 months (95% CI, 6 to 9.7 months). Ten of 11 responses were observed in patients who presented with primary bone tumors (P ϭ .016). The most common adverse events of grades 3 to 4 were pain (15%), anemia (8%), thrombocytopenia (7%), and asthenia (5%). ConclusionR1507 was a well-tolerated agent that had meaningful and durable benefit in a subgroup of patients with ESFT. The identification of markers that are predictive of a benefit is necessary to fully capitalize on this approach.

show abstract

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

Cited by 302 publications

References 32 publications

IGF2 expression and β-catenin levels are increased in Frozen Shoulder Syndrome

IGF2 expression and β-catenin levels are increased in Frozen Shoulder Syndrome

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor 1 Receptor, in Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors: Results of a Phase II Sarcoma Alliance for Research Through Collaboration Study

Contact Info

Product

Resources

About