Phase I study of SCH 900105 (SC), an anti-hepatocyte growth factor (HGF) monoclonal antibody (MAb), as a single agent and in combination with erlotinib (E) in patients (pts) with advanced solid tumors.

Patnaik, Amita; Weiss, Glen J.; Papadopoulos, K.; Tibes, Raoul; Tolcher, Anthony W.; Payumo, Francis; Cotreau, Monette M.; Jac, J.; Isaacs, Robin; Ramanathan, R. K.

doi:10.1200/jco.2010.28.15_suppl.2525

Cited by 27 publications

(24 citation statements)

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“…Although no measurable increase in tumor HGF expression levels was observed for the 2-or 10-mg/kg cohorts, the increase was observed in serum by 2.66-and 3.51-fold, respectively, by the same time postdose. Increased serum HGF after ficlatuzumab administration, indicating target engagement, is consistent with previous observations (26). The increase in HGF in tumor and more pronounced and consistent increase in serum is likely due to the stabilization of HGF upon complex formation with ficlatuzumab and/or compensatory increase in HGF production (39).…”

Section: Discussionsupporting

confidence: 78%

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A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases

Tabernero

Elez

Herranz

et al. 2014

Clinical Cancer Research

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Purpose: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases. Patients and Methods: Patients with p-Met (phosphorylated c-Met)–positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed. Results: No dose-limiting toxicities occurred in the 19 patients enrolled (n = 6, 2 mg/kg; n = 7, 10 mg/kg; n = 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n = 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (−53%), p-ERK (−43%), p-Akt (−2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4–10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease >1 year. Conclusions: Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle. Clin Cancer Res; 20(10); 2793–804. ©2014 AACR.

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Section: Discussionsupporting

confidence: 78%

“…In a first-in-human dose-escalation study, ficlatuzumab 20 mg/kg once every 14-day cycle was established as the recommended phase II dose (RP2D; ref. 26). Ficlatuzumab is in development for the treatment of solid tumors, including a phase Ib/II study in NSCLC (27,28).…”

Section: Introductionmentioning

confidence: 99%

A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases

Tabernero

Elez

Herranz

et al. 2014

Clinical Cancer Research

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“…SCH900195 has been demonstrated to be efficacious in advanced solid cancers in a Phase I trial [65].…”

Section: Antibodiesmentioning

confidence: 99%

Targeting the MET oncogene in cancer and metastases

Stella

Benvenuti

Comoglio

2010

Expert Opinion on Investigational Drugs

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Importance of the field: 'Invasive growth' is a genetic program involved in embryonic development and adult organ regeneration and usurped by cancer cells. Although its control is complex, tumor-and context-specific and regulated by several cytokines and growth factors, the role played by the MET oncogene is well documented. In human cancers the contribution of MET to invasive growth is mainly through overexpression, driven by unfavorable microenvironmental conditions. MET activation confers a selective advantage to neoplastic cells in tumor progression and drug resistance. A subset of tumors feature alterations of the MET gene and a consequent MET-addicted phenotype. Areas covered in this review: The molecular basis and rationale of MET inhibition in cancer and metastases are discussed. A number of molecules designed to block MET signaling are under development and several Phase II trials are ongoing. What the reader will gain: Knowledge of the state of the art of anti-MET targeted approaches and the molecular basis and strategies to select patients eligible for treatment with MET inhibitors. Take home message: Due to its versatile functions MET is a promising candidate for cancer therapy. Understanding molecular mechanisms of sensitization and resistance to MET inhibitors is a priority to guide tailored therapies and select patients that are most likely to achieve a clinical benefit.

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“…Notably, grade 3 mucositis has been seen in one of the patients who had received single-agent AV-229. 103 The usual adverse effects for conjunction therapy with AV-229 are reported to be diarrhea and rash. The conjunction of AV-229 with a medication named gefitinib has indicated a trend for improved overall response rate (ORR) and PFS in some groups of patients with EGFR-sensitizing mutations as well as patients with low Met biomarker levels.…”

Section: Anti-hgf Monoclonal Antibodiesmentioning

confidence: 99%

The c-Met receptor: Implication for targeted therapies in colorectal cancer

et al. 2017

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c-Met (mesenchymal-epithelial transition factor) is a tyrosine kinase receptor activated by hepatocyte growth factor and regulates multiple biological processes, such as cell scattering, survival, and proliferation. Aberrant c-Met signaling has been implicated in a variety of cancer types, including colorectal cancer. c-Met is genetically altered through various mechanisms that is associated with colorectal cancer progression and metastasis. Especially, in colorectal cancer, preclinical evidence for the aberrant activation of the c-Met signaling exists. Accordingly, molecular targeting of c-Met receptor could be a promising strategy, in the treatment of colorectal cancer patients. Recently, it was also shown that crosstalk between c-Met and other cell surface receptors attributes to tumorigenesis and development of therapeutic resistance. Characterization of the molecular mechanisms through which c-Met crosstalks with other receptors in favor of tumor formation and progression remains to explore. This review will describe the mechanisms of aberrant c-Met signaling in colorectal cancer and discuss on additional roles for c-Met receptor through crosstalk with other tyrosine kinase receptors and cell surface proteins in colorectal cancer. Novel therapeutic approaches for c-Met pathway targeting will also be discussed.

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Phase I study of SCH 900105 (SC), an anti-hepatocyte growth factor (HGF) monoclonal antibody (MAb), as a single agent and in combination with erlotinib (E) in patients (pts) with advanced solid tumors.

Cited by 27 publications

References 0 publications

A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases

A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases

Targeting the MET oncogene in cancer and metastases

The c-Met receptor: Implication for targeted therapies in colorectal cancer

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