A phase I study of AVE1642, a humanized monoclonal antibody IGF-1R (insulin like growth factor1 receptor) antagonist, in patients(pts) with advanced solid tumor(ST)

Tolcher, A. W.; Patnaik, A.; Till, E.; Takimoto, Chris H.; Papadopoulos, Kyriakos P.; Massard, C.; Méry-Mignard, D.; Deslandes, Antoine; Ozoux, Marie Laure; Soria, J-C.

doi:10.1200/jco.2008.26.15_suppl.3582

Cited by 28 publications

(18 citation statements)

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“…Complete responses are rare during phase I monotherapy trials in heavily pretreated patients, but have been seen with several anti -IGF1R antibody drug candidates. 4 Such anecdotes do not represent formal evidence of efficacy, but they do provide a strong impetus for further research, as do early results of combining IGF1R antibodies with chemotherapy (57,58,64).…”

Section: Resultsmentioning

confidence: 99%

“…4 Even if IGF1R inhibition ultimately proves to have limited single-agent activity in the common cancers, there is a strong rationale for evaluating the effects of IGF1R blockade in combination with other treatment modalities. Early reports indicate that anti -IGF1R antibodies can safely be administered with chemotherapy (57,58,64). The CP-751,871 antibody appears to enhance the response to carboplatin and paclitaxel in non -small cell lung cancer, with particularly striking responses in squamous tumors (ref.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

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The Type 1 Insulin-Like Growth Factor Receptor Pathway

Chitnis

Yuen

Protheroe

et al. 2008

Clinical Cancer Research

397

349

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Research conducted over the past two decades has shown the importance of the type 1insulin-like growth factor receptor (IGF1R) in tumorigenesis, metastasis, and resistance to existing forms of cancer therapy. The IGF1R itself has only recently been accepted as a credible treatment target, however, perhaps reflecting the potential problems for drug design posed by normal tissue IGF1R expression, and close homology with the insulin receptor. Currently f12 anti-IGF1R therapeutics are undergoing clinical evaluation, including blocking antibodies and tyrosine kinase inhibitors. This review will summarize the principal signaling pathways activated by IGF1R and the preclinical data that validated this receptor as a treatment target.We will review clinical progress in the testing of IGF1R inhibitory drug candidates, the relative benefits and potential toxicities of coinhibition of the insulin receptor, and the rationale for combining IGF1R blockade with other cancer treatments. An understanding of IGF1R signaling is important because it will guide the incorporation of appropriate molecular markers into clinical trial design. This will be key to the identification of patients most likely to benefit, and so will influence the ability of IGF1R inhibition to make the transition from experimental intervention to clinical therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Clinical-translational Advancesmentioning

confidence: 99%

The Type 1 Insulin-Like Growth Factor Receptor Pathway

Chitnis

Yuen

Protheroe

et al. 2008

Clinical Cancer Research

397

349

View full text Add to dashboard Cite

show abstract

“…Due to this potential complication, the development of IGF-1R inhibitors as anticancer therapeutics has focused mainly on the identification of antibodies specific for IGF-1R. According to first reports on clinical studies, administration of IGF-1R antibodies was well tolerated and responses were observed alone (16) and in combination with chemotherapy in solid tumors (17). Interestingly, hyperglycemia was among the observed toxicities of IGF-1R antibody treatment (18).…”

Section: Introductionmentioning

confidence: 99%

BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

Carboni

Wittman

Yang

et al. 2009

Molecular Cancer Therapeutics

244

214

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BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC 50 , 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G 1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.

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“…No hypersensitivity reactions were observed. In the second one, AVE1642 was given alone (cycle 1) and then combined with docetaxel (75 mg/ m 2 ) in patients with advanced solid tumors [74]. No DLTs were encountered, and grades 1-2 drug-related adverse events included hyperglycemia, hypersensitivity reactions, asthenia, anemia, nail disorders, paresthesias, and pruritus.…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

The insulin-like growth factor pathway as a target for cancer therapy

2010

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The insulin-like growth factor (IGF) system is emerging as a promising new target in cancer therapy. Experimental models and epidemiological studies have demonstrated that the IGF system plays a key role in malignant transformation and cancer progression. Different strategies are being pursued to target this pathway. Several monoclonal antibodies and tyrosine kinase inhibitors targeting the IGF-1 receptor are in clinical development. Early clinical trials indicate these drugs have acceptable safety profiles, and there is pharmacodynamic evidence that actual target inhibition is achievable in patients. Emerging efficacy data as single agent and in combination with chemotherapy is encouraging yet too early for firm conclusions. This manuscript reviews the role of the IGF system in human malignancy and its interactions with other signaling pathways, and summarizes the available data of IGF-1R inhibitors currently in clinical trials.

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A phase I study of AVE1642, a humanized monoclonal antibody IGF-1R (insulin like growth factor1 receptor) antagonist, in patients(pts) with advanced solid tumor(ST)

Cited by 28 publications

References 0 publications

The Type 1 Insulin-Like Growth Factor Receptor Pathway

The Type 1 Insulin-Like Growth Factor Receptor Pathway

BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR

The insulin-like growth factor pathway as a target for cancer therapy

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