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Laurel M Adams - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics modeling and analysis of Foretinib in adult patients with advanced solid tumors
The Journal of Clinical Pharmacology, 2015Co-Authors: Rajendra P Singh, Howard Kallender, Bela Patel, Lone H Ottesen, Laurel M AdamsAbstract:: Foretinib is a multikinase inhibitor that inhibits multiple receptor tyrosine kinases, including MET and VEGFR, with the potential for treatment of solid tumors. Hepatocellular carcinoma (HCC) pathogenesis is associated with overexpression of MET, and physiologic changes in the livers of HCC patients may decrease CYP3A isozyme-mediated metabolism of Foretinib. A population pharmacokinetic model of Foretinib was developed to explore the effect of tumor type, formulation, and other covariates. Data from 1 HCC study in Asia and 3 non-HCC studies in the United States with varying Foretinib regimens and formulations were used for analysis. A 2-compartment model with a linear first-order absorption and elimination and lag time in absorption adequately described Foretinib pharmacokinetics in 132 advanced non-HCC and HCC patients and identified an effect of formulations on bioavailability. The bisphosphate salt capsules and freebase tablets had a relative bioavailability 37% and 20% higher, respectively, than the solution formulation. HCC patients had ≈19.6% lower mean clearance (70.14 L/h), ≈16% lower mean volume of distribution (1725.6 L), and higher dose-normalized exposure compared with non-HCC patients. This could be a result of differences in metabolism in HCC patients, body weight, or activity of CYP3A isozymes between Asian and Western cancer patients.
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erratum to a phase 1 dose escalation study of the safety and pharmacokinetics of once daily oral Foretinib a multi kinase inhibitor in patients with solid tumors
Investigational New Drugs, 2013Co-Authors: Geoffrey I Shapiro, Laurie Sherman, Stewart W Mccallum, Laurel M Adams, Steve Weller, Suzanne Swann, Harold KeerAbstract:Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, Foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral Foretinib once daily. Dose escalation was planned as a conventional “3 + 3” design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg Foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P < 0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P < 0.03). The MTD of Foretinib bisphosphate salt was determined to be 80 mg once daily.
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phase ii and biomarker study of the dual met vegfr2 inhibitor Foretinib in patients with papillary renal cell carcinoma
Journal of Clinical Oncology, 2013Co-Authors: Toni K Choueiri, Ulka N Vaishampayan, Jonathan E Rosenberg, Theodore F Logan, Andrea L Harzstark, Brian I Rini, Sandy Srinivas, Ronald M Bukowski, Mark N Stein, Laurel M AdamsAbstract:Purpose Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of Foretinib in patients with PRCC. Patients and Methods Patients were enrolled onto the study in two cohorts with different dosing schedules of Foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a...
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Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma
Journal of Clinical Oncology, 2012Co-Authors: Toni K Choueiri, Ulka N Vaishampayan, Jonathan E Rosenberg, Theodore F Logan, Andrea L Harzstark, Brian I Rini, Sandy Srinivas, Ronald M Bukowski, Mark N Stein, Laurel M AdamsAbstract:Purpose Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of Foretinib in patients with PRCC. Patients and Methods Patients were enrolled onto the study in two cohorts with different dosing schedules of Foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a...
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A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral Foretinib, a multi-kinase inhibitor, in patients with solid tumors.
Investigational new drugs, 2012Co-Authors: Geoffrey I Shapiro, Harold Keer, Laurie Sherman, Dale Miles, Laurel M Adams, Steve Weller, Suzanne Swann, Stewart Mccallum, Thomas Müller, Patricia LorussoAbstract:Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, Foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral Foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg Foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P
Claudia C Faria - One of the best experts on this subject based on the ideXlab platform.
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Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma
Cancer Research, 2015Co-Authors: Claudia C Faria, Adrian M Dubuc, Marc Remke, Brian Golbourn, Roberto J Diaz, Sameer Agnihotri, Amanda Luck, Nesrin Sabha, Samantha Olsen, Xiaochong WuAbstract:Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)–driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor Foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood–brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, Foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate Foretinib as an effective therapy for patients with SHH-driven medulloblastoma. Cancer Res; 75(1); 134–46. ©2014 AACR.
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Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma
Neuro-oncology, 2014Co-Authors: Christian A Smith, Claudia C Faria, Adrian M Dubuc, Marc Remke, Brian Golbourn, Roberto J Diaz, Sameer Agnihotri, Amanda Luck, Nesrin Sabha, Samantha OlsenAbstract:BACKGROUND: (blind field). METHODS: Expression profiling, molecular subgrouping and analysis of somatic copy number alterations were conducted on multiple independent cohorts of patient tumour samples to examine intermediates of the MET signaling pathway in medulloblastoma. To examine the in vitro and in vivo effects of Foretinib treatment; MET signalling biochemical analysis; migration and invasion assays; and Foretinib pharmacokinetic studies were performed. Medulloblastoma xenografts and transgenic mouse models were used to evaluate Foretinib treatment in vivo. RESULTS: We analyzed three large non-overlapping cohorts of medulloblastoma patients (discovery cohort, n = 199; validation cohort 1, n = 439; validation cohort 2, n = 285) and demonstrated that cMET, known to be involved in tumor progression and dissemination, is a marker of sonic hedgehog (SHH) medulloblastoma. Importantly, immunohistochemical analysis of activated cMET (phosphorylated cMET) in another independent patient cohort (n = 385) revealed that cMET activation correlates with increased tumor relapse and a poor survival in pediatric patients with SHH medulloblastomas, thus defining a subset of patients that may benefit from cMET targeted therapy. We show that Foretinib, an FDA approved inhibitor of cMET, suppresses cMET activation, decreases proliferation and induces apoptosis, both in medulloblastoma cell lines and in SHH medulloblastoma xenografts. Furthermore Foretinib penetrates the blood-brain barrier and is effective both in the primary and in the metastatic compartments. Treatment of mouse xenografts and of an aggressive transgenic model of metastatic SHH medulloblastoma with Foretinib reduced primary medulloblastoma growth, decreased the incidence of metastases by 36% and increased survival by 45%. CONCLUSIONS: Our results provide strong rationale for advancing Foretinib into clinical trials for SHH-driven medulloblastomas. SECONDARY CATEGORY: Tumor Biology.
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abstract 847 Foretinib a multi kinase inhibitor of cmet and pdgfrα in the treatment of disseminated medulloblastoma
Cancer Research, 2012Co-Authors: Claudia C Faria, Christian A Smith, Brian Golbourn, James T RutkaAbstract:Medulloblastoma (MB) is the most common malignant brain tumor in childhood accounting for around 10% of all pediatric cancer deaths. Dissemination occurs in 30% of the patients at the time of diagnosis and essentially defines children with incurable disease given that metastatic disease is refractory to current treatments. Therefore, there is an urgent need for new therapies to treat metastatic MB. The hepatocyte growth factor (HGF)/cMET signaling pathway has been recently implicated in the pathogenesis of MB. Overexpression of cMET and HGF is associated with group C tumors which have high incidence of metastasis and poor outcome. Moreover, overexpression of the platelet-derived growth factor receptor (PDGFR) was also identified in metastatic MB. Using Foretinib, a multi-kinase inhibitor of cMET and PDGFRα, we aimed to target two important pathways involved in MB dissemination. Using three MB cell lines (Daoy, ONS - 76 and D425) that express different amounts of the receptors (cMET and PDGF), we performed dose-response experiments with Foretinib, measuring downstream targets of cMET and PDGFRα activation. We showed that Foretinib inhibits proliferation, migration, invasion and anchorage independent growth of MB cell lines in a dose-dependent manner. By immunofluorecence, we observed that Foretinib induces polyploidy and using flow cytometry analysis we found that it also induces apoptosis and cell cycle arrest in G2-M phase. To test the efficacy of Foretinib in vivo we have created a disseminated mouse model of MB injecting MB cells in the fourth ventricle of nude mice, mimicking the process of dissemination in children. The cells were previously transfected with a luciferase expressing vector allowing weekly monitoring of tumor growth and dissemination by bioluminescence imaging. Foretinib was able to reduce tumor growth and metastasis in xenografts, increasing survival when compared to controls. Altogether these results suggest that small molecule inhibitors of cMET and PDGFR may represent a new therapeutic strategy in the treatment of disseminated MB. Given that Foretinib is already being tested in clinical trials for other forms of cancer, the findings from our experiments may lead to the design of identical trials in children with metastatic medulloblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 847. doi:1538-7445.AM2012-847
Stewart W Mccallum - One of the best experts on this subject based on the ideXlab platform.
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erratum to a phase 1 dose escalation study of the safety and pharmacokinetics of once daily oral Foretinib a multi kinase inhibitor in patients with solid tumors
Investigational New Drugs, 2013Co-Authors: Geoffrey I Shapiro, Laurie Sherman, Stewart W Mccallum, Laurel M Adams, Steve Weller, Suzanne Swann, Harold KeerAbstract:Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, Foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral Foretinib once daily. Dose escalation was planned as a conventional “3 + 3” design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg Foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P < 0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P < 0.03). The MTD of Foretinib bisphosphate salt was determined to be 80 mg once daily.
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phase ii trial of single agent Foretinib gsk1363089 in patients with recurrent or metastatic squamous cell carcinoma of the head and neck
Investigational New Drugs, 2013Co-Authors: Tanguy Y Seiwert, Howard Kallender, Harold Keer, Stewart W Mccallum, John Sarantopoulos, George R BlumenscheinAbstract:Background Foretinib is a small-molecule, oral multikinase inhibitor primarily targeting the mesenchymal epithelial transition (MET) factor receptor, and the vascular endothelial growth factor receptor 2. We conducted a phase II study to evaluate the single-agent activity and tolerability of Foretinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods An open-label, single-arm, multicenter trial employing a Simon 2-stage design was conducted with a total of 41 patients planned for the study. One or more responses in the first 14 patients were required in order to progress to the second stage. Foretinib was administered as 240 mg orally for 5 consecutive days of a 14-day treatment cycle (5/9 schedule) to patients with recurrent and/or metastatic SCCHN. Results Fourteen patients were enrolled. The study did not meet criteria for continuing to the second stage. A maximum of 30 cycles were administered (median = 4.0). Fifty percent of patients (7/14) showed stable disease (SD), 43 % of patients (6/14) experienced tumor shrinkage and two patients had prolonged disease stabilization for ≥13 months. The most common adverse events were fatigue, constipation and hypertension, which were manageable with additional medication or adjustments to the dosing schedule. Conclusion Foretinib 240 mg on a 5/9 schedule was generally well tolerated. SD was the best-observed outcome, with minor tumor shrinkage detected in nearly half of all patients. The efficacy results, prolonged disease stabilization and tolerable side-effect profile, support further investigation, possibly in combination with other targeted agents or cytotoxic chemotherapy for SCCHN.
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a phase i study of Foretinib a multi targeted inhibitor of c met and vascular endothelial growth factor receptor 2
Clinical Cancer Research, 2010Co-Authors: Joseph Paul Eder, Harold Keer, Laurie Sherman, Stewart W Mccallum, Dale Miles, Geoffrey I Shapiro, Leonard Joseph Appleman, Belinda Cancilla, S Hitchcockbryan, Elisabeth I HeathAbstract:Purpose: Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral Foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of Foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity. Experimental Design: Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received Foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional “3+3” design. Results: Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non–dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses. Conclusions: The recommended dose of Foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials. Clin Cancer Res; 16(13); 3507–16. ©2010 AACR.
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abstract a8 final results of a phase i dose escalation study of the safety and pharmacokinetics of Foretinib administered orally daily to patients with solid tumors
Molecular Cancer Therapeutics, 2009Co-Authors: Patricia Lorusso, Fabiola Cecchi, Daniel C Rabe, Donald P Bottaro, Joseph Paul Eder, Laurie Sherman, Stewart W Mccallum, Dale Miles, Geoffrey I ShapiroAbstract:Foretinib is a potent, orally available, small‐molecule inhibitor of MET and VEGFR2. Significant tumor cell growth inhibition was observed preclinically following treatment in multiple tumor models. Antitumor activity was observed in a previous phase I study in which Foretinib was dosed intermittently on days 1–5 every 14 days. This phase I dose‐escalation study to evaluate daily oral administration of Foretinib was conducted in adults with solid tumors. Foretinib was orally administered until disease progression or toxicity mandated removal from the study. Dose‐limiting toxicities (DLTs) that occurred during the first 28 days of treatment were used to determine the maximum tolerated dose (MTD). Safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) were evaluated. Tumor volume was assessed every 8 weeks by RECIST. A total of 37 patients (pts) were treated across 4 dose levels in the following order: 60 mg/d (6 pts), 80 mg/d (12 pts), 120 mg/d (3 pts), 100 mg/d (3 pts), and 80 mg/d (13 pts, PK expansion). Reported DLTs were hypertension and dehydration at 120 mg/d and diarrhea at 100 mg/d. The MTD of Foretinib was determined to be 80 mg. With chronic dosing, 12 of 25 pts (48%) on 80 mg required a dose reduction to 60 mg between 21 days and 4 months on treatment. Frequent AEs associated with Foretinib were hypertension (62%), fatigue (51%), nausea (43%), diarrhea (41%), proteinuria (30%), increased lactate dehydrogenase (27%), vomiting (24%), anorexia (22%), increased aspartate transaminase (19%), rash (16%), increased GGT (16%), and increased lipase (16%), primarily CTCAE grades 1 and 2. The Foretinib plasma PK (at MTD) was characterized by a t max of ≈4 hours, a steady‐state oral clearance (CL/F) of ≈83 L/h, and ≈3.8‐fold accumulation at steady state (achieved by ≈day 15). At steady state, values of C max and AUC 0–24 were ≈45.7 ng/mL and ≈805 h · ng/mL, respectively, and the C min was ≈52% of C max . Plasma PD markers were measured during cycle 1 in 19 pts treated at the MTD. Shed Met (sMET) and VEGF showed increases, whereas sVEGFR2 showed a decrease. No pts had confirmed partial response or complete response, but stable disease (SD) (range, 2.1–18.1 months) was seen in 23 pts (74.2%). 11 pts had tumor regression from baseline, with tumor shrinkage ranging from 1%–21%. Disease progression was seen in 8 pts (25.8%). Overall, 35.5% of pts were event‐free at 6 months, and 12.9% of pts (diagnoses included medullary thyroid, hepatocellular, and papillary renal cell carcinomas, and alveolar soft part sarcoma) were event‐free at 12 months. 62% percent of pts withdrew due to progressive disease, 8% due to AEs, 5% due to death, and 24% due to consent withdrawal/investigator discretion/other. Foretinib can be safely administered at the oral daily dose of 80 mg (MTD); however, with chronic administration, dose reductions were not uncommon. The safety profile observed with daily dosing of Foretinib is similar to that seen with intermittent dosing. Plasma PK results indicate that exposure to Foretinib was well maintained over the daily dosing interval. PD results are similar to that seen with intermittent dosing and indicate that sMET, VEGF, and sVEGFR2 are promising markers for monitoring biological activity of Foretinib. Prolonged SD and tumor regression in pts with various cancers suggest that Foretinib has promise as an anticancer therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A8.
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abstract b6 a phase ii study of the efficacy and safety of Foretinib a novel receptor tyrosine kinase inhibitor given on an intermittent 5 days on 9 days off 5 9 schedule in patients with recurrent or metastatic squamous cell cancer of the head and n
Molecular Cancer Therapeutics, 2009Co-Authors: Tanguy Y Seiwert, Stewart W Mccallum, Suzanne Swann, Peter L Bonate, Hazel Kurz, John SarantopoulosAbstract:Foretinib (also known as GSK1363089 and XL880) is a small‐molecule, spectrum‐specific receptor tyrosine kinase inhibitor, with potent activity against MET, VEGFR2, and multiple additional tyrosine kinases with tumor growth‐promoting and angiogenic properties. Antitumor activity has been observed in 2 previous phase I studies. This phase II study was conducted to evaluate responses in squamous cell cancer of the head and neck (SCCHN). An open‐label, single‐arm, multicenter trial employing a Simon 2‐stage design was conducted, with a total of 41 patients to be enrolled in the study. One or more responses in the first 14 subjects were required to progress to the second stage. Foretinib was administered as a 240‐mg oral dose once daily on days 1–5 of a 14‐day cycle to subjects with recurrent and/or metastatic SCCHN. Other eligibility requirements included measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 1 or 0, and no history of uncontrolled tumor bleeding. Exclusions included more than 1 prior therapy for recurrent or metastatic disease, history of brain metastasis, and rapid progression within 6 months after curative‐intent therapy for local/loco‐regional disease. Endpoints were objective response rate, safety, duration of response, progression‐free survival (PFS), overall survival (OS), and characterization of the pharmacokinetics. Tumor volume was assessed every 8 weeks by Response Evaluation Criteria in Solid Tumors. This study did not meet the predefined criteria for continuing to the second stage. Response and safety data are available for 14 patients with a data cut off date of July 24 2009 (median age = 59.0; males/female = 13/1: ECOG PS 0/1 = 9/5 patients). A maximum of 30 cycles was administered (median = 4.5). The most common reason for withdrawal was progressive disease. Treatment‐emergent adverse events occurring in >25% of individuals included (# [%]): fatigue (7 [50%]), constipation (5 [36%]), hypertension (5 [36%]), anorexia (4 [29%]), dysphagia (4 [29%]), weight loss (4 [29%]), increased alanine transaminase (4 [29%]), increased aspartate transaminase (4 [29%]), dyspnea (4 [29%]), headache (4 [29%]), and mucosal inflammation (4 [29%]). Investigator‐assessed median PFS (95% confidence interval) was 3.65 (3.42, 5.32) months; median OS was 5.59 (3.71, not reported) months. The best overall response was stable disease (SD), with a median duration of 4.11 (3.65–13.86) months. Foretinib 240 mg on a 5/9 schedule was generally well tolerated. SD was the best observed response. The safety and efficacy results support further investigation in combination with other targeted agents or cytotoxic chemotherapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B6.
Samantha Olsen - One of the best experts on this subject based on the ideXlab platform.
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Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma
Cancer Research, 2015Co-Authors: Claudia C Faria, Adrian M Dubuc, Marc Remke, Brian Golbourn, Roberto J Diaz, Sameer Agnihotri, Amanda Luck, Nesrin Sabha, Samantha Olsen, Xiaochong WuAbstract:Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)–driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor Foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood–brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, Foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate Foretinib as an effective therapy for patients with SHH-driven medulloblastoma. Cancer Res; 75(1); 134–46. ©2014 AACR.
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Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma
Neuro-oncology, 2014Co-Authors: Christian A Smith, Claudia C Faria, Adrian M Dubuc, Marc Remke, Brian Golbourn, Roberto J Diaz, Sameer Agnihotri, Amanda Luck, Nesrin Sabha, Samantha OlsenAbstract:BACKGROUND: (blind field). METHODS: Expression profiling, molecular subgrouping and analysis of somatic copy number alterations were conducted on multiple independent cohorts of patient tumour samples to examine intermediates of the MET signaling pathway in medulloblastoma. To examine the in vitro and in vivo effects of Foretinib treatment; MET signalling biochemical analysis; migration and invasion assays; and Foretinib pharmacokinetic studies were performed. Medulloblastoma xenografts and transgenic mouse models were used to evaluate Foretinib treatment in vivo. RESULTS: We analyzed three large non-overlapping cohorts of medulloblastoma patients (discovery cohort, n = 199; validation cohort 1, n = 439; validation cohort 2, n = 285) and demonstrated that cMET, known to be involved in tumor progression and dissemination, is a marker of sonic hedgehog (SHH) medulloblastoma. Importantly, immunohistochemical analysis of activated cMET (phosphorylated cMET) in another independent patient cohort (n = 385) revealed that cMET activation correlates with increased tumor relapse and a poor survival in pediatric patients with SHH medulloblastomas, thus defining a subset of patients that may benefit from cMET targeted therapy. We show that Foretinib, an FDA approved inhibitor of cMET, suppresses cMET activation, decreases proliferation and induces apoptosis, both in medulloblastoma cell lines and in SHH medulloblastoma xenografts. Furthermore Foretinib penetrates the blood-brain barrier and is effective both in the primary and in the metastatic compartments. Treatment of mouse xenografts and of an aggressive transgenic model of metastatic SHH medulloblastoma with Foretinib reduced primary medulloblastoma growth, decreased the incidence of metastases by 36% and increased survival by 45%. CONCLUSIONS: Our results provide strong rationale for advancing Foretinib into clinical trials for SHH-driven medulloblastomas. SECONDARY CATEGORY: Tumor Biology.
Harold Keer - One of the best experts on this subject based on the ideXlab platform.
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erratum to a phase 1 dose escalation study of the safety and pharmacokinetics of once daily oral Foretinib a multi kinase inhibitor in patients with solid tumors
Investigational New Drugs, 2013Co-Authors: Geoffrey I Shapiro, Laurie Sherman, Stewart W Mccallum, Laurel M Adams, Steve Weller, Suzanne Swann, Harold KeerAbstract:Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, Foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral Foretinib once daily. Dose escalation was planned as a conventional “3 + 3” design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg Foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P < 0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P < 0.03). The MTD of Foretinib bisphosphate salt was determined to be 80 mg once daily.
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phase ii trial of single agent Foretinib gsk1363089 in patients with recurrent or metastatic squamous cell carcinoma of the head and neck
Investigational New Drugs, 2013Co-Authors: Tanguy Y Seiwert, Howard Kallender, Harold Keer, Stewart W Mccallum, John Sarantopoulos, George R BlumenscheinAbstract:Background Foretinib is a small-molecule, oral multikinase inhibitor primarily targeting the mesenchymal epithelial transition (MET) factor receptor, and the vascular endothelial growth factor receptor 2. We conducted a phase II study to evaluate the single-agent activity and tolerability of Foretinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods An open-label, single-arm, multicenter trial employing a Simon 2-stage design was conducted with a total of 41 patients planned for the study. One or more responses in the first 14 patients were required in order to progress to the second stage. Foretinib was administered as 240 mg orally for 5 consecutive days of a 14-day treatment cycle (5/9 schedule) to patients with recurrent and/or metastatic SCCHN. Results Fourteen patients were enrolled. The study did not meet criteria for continuing to the second stage. A maximum of 30 cycles were administered (median = 4.0). Fifty percent of patients (7/14) showed stable disease (SD), 43 % of patients (6/14) experienced tumor shrinkage and two patients had prolonged disease stabilization for ≥13 months. The most common adverse events were fatigue, constipation and hypertension, which were manageable with additional medication or adjustments to the dosing schedule. Conclusion Foretinib 240 mg on a 5/9 schedule was generally well tolerated. SD was the best-observed outcome, with minor tumor shrinkage detected in nearly half of all patients. The efficacy results, prolonged disease stabilization and tolerable side-effect profile, support further investigation, possibly in combination with other targeted agents or cytotoxic chemotherapy for SCCHN.
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phase ii study evaluating 2 dosing schedules of oral Foretinib gsk1363089 cmet vegfr2 inhibitor in patients with metastatic gastric cancer
PLOS ONE, 2013Co-Authors: Manish A Shah, Fabiola Cecchi, Howard Kallender, Daniel C Rabe, Zev A Wainberg, Daniel V T Catenacci, Howard S Hochster, James M Ford, Pamela L Kunz, Harold KeerAbstract:Purpose: The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of Foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma. Patients and Methods: Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha=0.10 and beta=0.2 to test the alternative hypothesis that single-agent Foretinib would result in an ORR of $25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of Foretinib activity. Results: From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25–88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9–7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET:total MET protein ratio decreased with Foretinib treatment. Conclusion: These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by Foretinib, single-agent Foretinib lacked efficacy in unselected patients with metastatic gastric cancer.
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A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral Foretinib, a multi-kinase inhibitor, in patients with solid tumors.
Investigational new drugs, 2012Co-Authors: Geoffrey I Shapiro, Harold Keer, Laurie Sherman, Dale Miles, Laurel M Adams, Steve Weller, Suzanne Swann, Stewart Mccallum, Thomas Müller, Patricia LorussoAbstract:Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, Foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral Foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg Foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P
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a phase i study of Foretinib a multi targeted inhibitor of c met and vascular endothelial growth factor receptor 2
Clinical Cancer Research, 2010Co-Authors: Joseph Paul Eder, Harold Keer, Laurie Sherman, Stewart W Mccallum, Dale Miles, Geoffrey I Shapiro, Leonard Joseph Appleman, Belinda Cancilla, S Hitchcockbryan, Elisabeth I HeathAbstract:Purpose: Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral Foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of Foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity. Experimental Design: Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received Foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional “3+3” design. Results: Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non–dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses. Conclusions: The recommended dose of Foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials. Clin Cancer Res; 16(13); 3507–16. ©2010 AACR.