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Yu-nien Sun - One of the best experts on this subject based on the ideXlab platform.
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Exploratory modeling and simulation to support development of Motesanib in Asian patients with non-small cell lung cancer based on MONET1 study results
Clinical pharmacology and therapeutics, 2014Co-Authors: Claret L, Yu-nien Sun, Bruno R, Cheng-pang HsuAbstract:The Motesanib phase III MONET1 study failed to show improvement in overall survival (OS) in non-small cell lung cancer, but a subpopulation of Asian patients had a favorable outcome. We performed exploratory modeling and simulations based on MONET1 data to support further development of Motesanib in Asian patients. A model-based estimate of time to tumor growth was the best of tested tumor size response metrics in a multivariate OS model (P < 0.00001) to capture treatment effect (hazard ratio, HR) in Asian patients. Significant independent prognostic factors for OS were baseline tumor size (P < 0.0001), smoking history (P < 0.0001), and ethnicity (P < 0.00001). The model successfully predicted OS distributions and HR in the full population and in Asian patients. Simulations indicated that a phase III study in 500 Asian patients would exceed 80% power to confirm superior efficacy of Motesanib combination therapy (expected HR: 0.74), suggesting that Motesanib combination therapy may benefit Asian patients.
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Exploratory modeling and simulation to support development of Motesanib in Asian patients with non-small cell lung cancer (NSCLC) based on MONET1 study results.
Journal of Clinical Oncology, 2013Co-Authors: Rene Bruno, Laurent Claret, Cheng-pang Hsu, Yu-nien SunAbstract:e19103 Background: Motesanib failed to improve overall survival (OS) in the MONET1 phase III study when combined to carboplatin/paclitaxel (CP) vs. CP in first-line NSCLC cancer patients (JCO 30:28...
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Simulations using a drug-disease modeling framework and phase II data predict phase III survival outcome in first-line non-small-cell lung cancer.
Clinical pharmacology and therapeutics, 2012Co-Authors: Claret L, Cheng-pang Hsu, Bruno R, Yu-nien SunAbstract:Simulations were performed for carboplatin/paclitaxel (C/P) plus Motesanib or bevacizumab vs. C/P as first-line treatment for advanced non-small-cell lung cancer (NSCLC) using a published drug-disease model. With 700 patients in each arm, simulated hazard ratios for Motesanib (0.87; 95% confidence interval [CI], 0.71-1.1) and bevacizumab (0.89; 95% CI, 0.73-1.1) agreed with results from the respective phase III studies but did not discriminate between failed and successful studies. The current model may require further enhancement to improve its utility for predicting phase III outcomes.
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Safety and pharmacokinetics of Motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study
BMC cancer, 2011Co-Authors: Dusan Kotasek, Adeboye H Adewoye, Niall C. Tebbutt, Jayesh Desai, Stephen Welch, Lillian L. Siu, S. Mccoy, Yu-nien Sun, Jessica Johnson, Timothy J. PriceAbstract:This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of Motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors. Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with Motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with Motesanib (100 or 125 mg QD; cohorts 5 and 6). Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of Motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring Motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of Motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or Motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease. Treatment with Motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. ClinicalTrials.gov NCT01235416.
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safety and pharmacokinetics of Motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors a phase 1b study
BMC Cancer, 2011Co-Authors: D Kotasek, Adeboye H Adewoye, Niall C. Tebbutt, Jayesh Desai, Stephen Welch, Lillian L. Siu, S. Mccoy, Yu-nien Sun, Jessica Johnson, Timothy J. PriceAbstract:Background: This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of Motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors. Methods: Patients received weekly intravenous gemcitabine (1000 mg/m 2 ) and erlotinib (100 mg QD) alone (control cohort) or in combination with Motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 14); or erlotinib (150 mg QD) in combination with Motesanib (100 or 125 mg QD; cohorts 5 and 6). Results: Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of Motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring Motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of Motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or Motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease. Conclusions: Treatment with Motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Trial Registration: ClinicalTrials.gov NCT01235416
Rene Bruno - One of the best experts on this subject based on the ideXlab platform.
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Exploratory modeling and simulation to support development of Motesanib in Asian patients with non-small cell lung cancer (NSCLC) based on MONET1 study results.
Journal of Clinical Oncology, 2013Co-Authors: Rene Bruno, Laurent Claret, Cheng-pang Hsu, Yu-nien SunAbstract:e19103 Background: Motesanib failed to improve overall survival (OS) in the MONET1 phase III study when combined to carboplatin/paclitaxel (CP) vs. CP in first-line NSCLC cancer patients (JCO 30:28...
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Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by Motesanib in thyroid cancer patients.
Cancer chemotherapy and pharmacology, 2010Co-Authors: Laurent Claret, Rebeca Melara, Liviawati Sutjandra, Mita Kuchimanchi, Rene Bruno, Yu-nien SunAbstract:Objective To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between Motesanib exposure and tumor response in a phase 2 study of Motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer.
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population pharmacokinetic pharmacodynamic modeling for the time course of tumor shrinkage by Motesanib in thyroid cancer patients
Cancer Chemotherapy and Pharmacology, 2010Co-Authors: Laurent Claret, Rebeca Melara, Liviawati Sutjandra, Mita Kuchimanchi, Rene Bruno, Yu-nien SunAbstract:Objective To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between Motesanib exposure and tumor response in a phase 2 study of Motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer.
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Development of a modeling framework to simulate efficacy endpoints for Motesanib in patients with thyroid cancer
Cancer chemotherapy and pharmacology, 2010Co-Authors: Laurent Claret, Yu-nien Sun, Rene BrunoAbstract:To develop a modeling framework that simulates clinical endpoints (objective response rate and progression-free survival) to support development of Motesanib. The framework was evaluated using results from a phase 2 study of Motesanib in thyroid cancer. Models of probability and duration of dose modifications and overall survival were developed using data from 93 patients with differentiated thyroid cancer and 91 patients with medullary thyroid cancer, who received Motesanib 125 mg once daily. The models, combined with previously developed population pharmacokinetic and tumor growth inhibition models, were assessed in predicting dose intensity, tumor size over time, objective response rate, and progression-free survival. Dose-response simulations were performed in patients with differentiated thyroid cancer. The predicted objective response rate and median progression-free survival in patients with differentiated thyroid cancer was 15.0% (95% prediction interval, 7.5%-23.7%) and 40 weeks (95% prediction interval, 32-49 weeks), respectively, compared with the observed objective response rate of 14.0% and median progression-free survival of 40 weeks. The simulated median objective response rate increased with Motesanib starting dose from 13.5% at 100 mg once daily to 38.0% at 250 mg once daily. However, simulated median progression-free survival was independent of starting dose, ranging from 40.5 weeks (95% prediction interval, 38.6-46.9 weeks) at 100 mg once daily to 40.0 weeks (95% prediction interval, 38.6-46.8 weeks) at 250 mg once daily. Dose-response simulations confirmed the appropriateness of 125-mg once-daily dosing; no clinically relevant improvement in progression-free survival would be obtained by dose intensification. This modeling framework represents an important tool to simulate clinical response and support clinical development decisions.
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Population pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations for exposure‐;tumor response relationships: Motesanib in a phase II thyroid cancer (TC) trial
Journal of Clinical Oncology, 2009Co-Authors: Laurent Claret, Rebeca Melara, Mita Kuchimanchi, Rene Bruno, L. Sutjandra, Daniel E. Stepan, Yu-nien SunAbstract:e14528 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR; and Kit that is being investigated for its antitumor activity. In a phase 2 monotherapy study, a response rate of 14% (per RECIST) was observed in patients (pts) with differentiated thyroid cancer (DTC; NEJM 359:31–42, 2008) compared with 1% in pts with medullary TC (MTC; Endocr Soc Ann Meeting 2007, abstract OR39–3). We evaluated the relationship between Motesanib PK and tumor response, investigated whether differences in PK between MTC and DTC pts contributed to the observed difference in response, and simulated tumor response with different dose regimens in pts with TC. Methods: Data from the phase 2 TC trial were used for PK/PD modeling. The study enrolled 93 DTC and 91 MTC pts who received Motesanib 125 mg once daily (QD). Motesanib concentrations were fitted to a 2- compartment population PK model. Estimates of pts’ PK parameters were used to calculate concentration and steady-state area under th...
Laurent Claret - One of the best experts on this subject based on the ideXlab platform.
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Exploratory modeling and simulation to support development of Motesanib in Asian patients with non-small cell lung cancer (NSCLC) based on MONET1 study results.
Journal of Clinical Oncology, 2013Co-Authors: Rene Bruno, Laurent Claret, Cheng-pang Hsu, Yu-nien SunAbstract:e19103 Background: Motesanib failed to improve overall survival (OS) in the MONET1 phase III study when combined to carboplatin/paclitaxel (CP) vs. CP in first-line NSCLC cancer patients (JCO 30:28...
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Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by Motesanib in thyroid cancer patients.
Cancer chemotherapy and pharmacology, 2010Co-Authors: Laurent Claret, Rebeca Melara, Liviawati Sutjandra, Mita Kuchimanchi, Rene Bruno, Yu-nien SunAbstract:Objective To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between Motesanib exposure and tumor response in a phase 2 study of Motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer.
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population pharmacokinetic pharmacodynamic modeling for the time course of tumor shrinkage by Motesanib in thyroid cancer patients
Cancer Chemotherapy and Pharmacology, 2010Co-Authors: Laurent Claret, Rebeca Melara, Liviawati Sutjandra, Mita Kuchimanchi, Rene Bruno, Yu-nien SunAbstract:Objective To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between Motesanib exposure and tumor response in a phase 2 study of Motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer.
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Development of a modeling framework to simulate efficacy endpoints for Motesanib in patients with thyroid cancer
Cancer chemotherapy and pharmacology, 2010Co-Authors: Laurent Claret, Yu-nien Sun, Rene BrunoAbstract:To develop a modeling framework that simulates clinical endpoints (objective response rate and progression-free survival) to support development of Motesanib. The framework was evaluated using results from a phase 2 study of Motesanib in thyroid cancer. Models of probability and duration of dose modifications and overall survival were developed using data from 93 patients with differentiated thyroid cancer and 91 patients with medullary thyroid cancer, who received Motesanib 125 mg once daily. The models, combined with previously developed population pharmacokinetic and tumor growth inhibition models, were assessed in predicting dose intensity, tumor size over time, objective response rate, and progression-free survival. Dose-response simulations were performed in patients with differentiated thyroid cancer. The predicted objective response rate and median progression-free survival in patients with differentiated thyroid cancer was 15.0% (95% prediction interval, 7.5%-23.7%) and 40 weeks (95% prediction interval, 32-49 weeks), respectively, compared with the observed objective response rate of 14.0% and median progression-free survival of 40 weeks. The simulated median objective response rate increased with Motesanib starting dose from 13.5% at 100 mg once daily to 38.0% at 250 mg once daily. However, simulated median progression-free survival was independent of starting dose, ranging from 40.5 weeks (95% prediction interval, 38.6-46.9 weeks) at 100 mg once daily to 40.0 weeks (95% prediction interval, 38.6-46.8 weeks) at 250 mg once daily. Dose-response simulations confirmed the appropriateness of 125-mg once-daily dosing; no clinically relevant improvement in progression-free survival would be obtained by dose intensification. This modeling framework represents an important tool to simulate clinical response and support clinical development decisions.
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Population pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations for exposure‐;tumor response relationships: Motesanib in a phase II thyroid cancer (TC) trial
Journal of Clinical Oncology, 2009Co-Authors: Laurent Claret, Rebeca Melara, Mita Kuchimanchi, Rene Bruno, L. Sutjandra, Daniel E. Stepan, Yu-nien SunAbstract:e14528 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR; and Kit that is being investigated for its antitumor activity. In a phase 2 monotherapy study, a response rate of 14% (per RECIST) was observed in patients (pts) with differentiated thyroid cancer (DTC; NEJM 359:31–42, 2008) compared with 1% in pts with medullary TC (MTC; Endocr Soc Ann Meeting 2007, abstract OR39–3). We evaluated the relationship between Motesanib PK and tumor response, investigated whether differences in PK between MTC and DTC pts contributed to the observed difference in response, and simulated tumor response with different dose regimens in pts with TC. Methods: Data from the phase 2 TC trial were used for PK/PD modeling. The study enrolled 93 DTC and 91 MTC pts who received Motesanib 125 mg once daily (QD). Motesanib concentrations were fitted to a 2- compartment population PK model. Estimates of pts’ PK parameters were used to calculate concentration and steady-state area under th...
Angela Coxon - One of the best experts on this subject based on the ideXlab platform.
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Antitumor activity of Motesanib alone and in combination with cisplatin or docetaxel in multiple human non–small-cell lung cancer xenograft models
Molecular cancer, 2012Co-Authors: Angela Coxon, Beth Ziegler, Stephen Kaufman, Hongyu Wang, Joanna Schmidt, Heather Sweet, Charlie Starnes, Dawn Weishuhn, Douglas SaffranAbstract:Non-small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. We investigated the antitumor activity of Motesanib, a selective antagonist of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit, alone and combined with chemotherapy in five human NSCLC xenograft models (A549, Calu-6, NCI-H358, NCI-H1299, and NCI-H1650) containing diverse genetic mutations. Motesanib as a single agent dose-dependently inhibited tumor xenograft growth compared with vehicle in all five of the models (P < 0.05). When combined with cisplatin, Motesanib significantly inhibited the growth of Calu-6, NCI-H358, and NCI-H1650 tumor xenografts compared with either single agent alone (P < 0.05). Similarly, the combination of Motesanib plus docetaxel significantly inhibited the growth of A549 and Calu-6 tumor xenografts compared with either single agent alone (P < 0.05). In NCI-H358 and NCI-H1650 xenografts, Motesanib with and without cisplatin significantly decreased tumor blood vessel area (P < 0.05 vs vehicle) as assessed by anti-CD31 staining. Motesanib alone or in combination with chemotherapy had no effect on tumor cell proliferation in vitro. These data demonstrate that Motesanib had antitumor activity against five different human NSCLC xenograft models containing diverse genetic mutations, and that it had enhanced activity when combined with cisplatin or docetaxel. These effects appeared to be mediated primarily by antiangiogenic mechanisms.
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antitumor activity of Motesanib alone and in combination with cisplatin or docetaxel in multiple human non small cell lung cancer xenograft models
Molecular Cancer, 2012Co-Authors: Angela Coxon, Beth Ziegler, Stephen Kaufman, Hongyu Wang, Joanna Schmidt, Heather Sweet, Charlie Starnes, Douglas Saffran, Dawn Weishuhn, Anthony PolverinoAbstract:Background Non–small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. We investigated the antitumor activity of Motesanib, a selective antagonist of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit, alone and combined with chemotherapy in five human NSCLC xenograft models (A549, Calu-6, NCI-H358, NCI-H1299, and NCI-H1650) containing diverse genetic mutations.
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Anti-tumor activity of Motesanib in a medullary thyroid cancer model.
Journal of endocrinological investigation, 2011Co-Authors: Angela Coxon, James Bready, Steve Kaufman, Juan Estrada, Tao Osgood, Jude Canon, Ling Wang, Robert Radinsky, Rick Kendall, Paul E. HughesAbstract:Medullary thyroid cancer (MTC) is frequently associated with mutations in the tyrosine kinase Ret and with increased expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Motesanib is an investigational, orally administered small molecule antagonist of VEGFR1, 2, and 3; platelet-derived growth factor receptor (PDGFR); Kit; and possibly Ret. The aim of this study was to investigate the effects of Motesanib on wildtype and mutant Ret activity in vitro and on tumor xenograft growth in a mouse model of MTC. In cellular phosphorylation assays, Motesanib inhibited the activity of wild-type Ret (IC(50)=66 nM), while it had limited activity against mutant Ret C634W (IC(50)=1100 nM) or Ret M918T (IC(50)>2500 nM). In vivo, Motesanib significantly inhibited the growth of TT tumor cell xenografts (expressing Ret C634W) and significantly reduced tumor blood vessel area and tumor cell proliferation, compared with control. Treatment with Motesanib resulted in substantial inhibition of Ret tyrosine phosphorylation in TT xenografts and, at comparable doses, in equivalent inhibition of VEGFR2 phosphorylation in both TT xenografts and in mouse lung tissue. The results of this study demonstrate that Motesanib inhibited thyroid tumor xenograft growth predominantly through inhibition of angiogenesis and possibly via a direct inhibition of VEGFR2 and Ret expressed on tumor cells. These data suggest that targeting angiogenesis pathways and specifically the VEGF pathway may represent a novel therapeutic approach in the treatment of MTC.
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anti tumor activity of Motesanib in a medullary thyroid cancer model
Journal of Endocrinological Investigation, 2011Co-Authors: Angela Coxon, James Bready, Steve Kaufman, Juan Estrada, Tao Osgood, Jude Canon, Ling Wang, Robert Radinsky, Rick Kendall, Paul E. HughesAbstract:Background: Medullary thyroid cancer (MTC) is frequently associated with mutations in the tyrosine kinase Ret and with increased expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Motesanib is an investigational, orally administered small molecule antagonist of VEGFR1, 2, and 3; platelet-derived growth factor receptor (PDGFR); Kit; and possibly Ret. Aim: The aim of this study was to investigate the effects of Motesanib on wild-type and mutant Ret activity in vitro and on tumor xenograft growth in a mouse model of MTC. Methods/Results: In cellular phosphorylation assays, Motesanib inhibited the activity of wild-type Ret (IC50=66 nM), while it had limited activity against mutant Ret C634W (IC50=1100 nM) or Ret M918T (IC50>2500 nM). In vivo, Motesanib significantly inhibited the growth of TT tumor cell xenografts (expressing Ret C634W) and significantly reduced tumor blood vessel area and tumor cell proliferation, compared with control. Treatment with Motesanib resulted in substantial inhibition of Ret tyrosine phosphorylation in TT xenografts and, at comparable doses, in equivalent inhibition of VEGFR2 phosphorylation in both TT xenografts and in mouse lung tissue. Conclusions: The results of this study demonstrate that Motesanib inhibited thyroid tumor xenograft growth predominantly through inhibition of angiogenesis and possibly via a direct inhibition of VEGFR2 and Ret expressed on tumor cells. These data suggest that targeting angiogenesis pathways and specifically the VEGF pathway may represent a novel therapeutic approach in the treatment of MTC.
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augmentation of radiation response by Motesanib a multikinase inhibitor that targets vascular endothelial growth factor receptors
Clinical Cancer Research, 2010Co-Authors: Tim J. Kruser, Deric L. Wheeler, Eric A. Armstrong, Mari Iida, Kevin R. Kozak, Albert J. Van Der Kogel, Johan Bussink, Angela Coxon, Anthony Polverino, Paul M. HarariAbstract:Background: Motesanib is a potent inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit receptors. In this report we examine the interaction between Motesanib and radiation in vitro and in head and neck squamous cell carcinoma (HNSCC) xenograft models. Experimental Design: In vitro assays were done to assess the impact of Motesanib on VEGFR2 signaling pathways in human umbilical vein endothelial cells (HUVEC). HNSCC lines grown as tumor xenografts in athymic nude mice were utilized to assess the in vivo activity of Motesanib alone and in combination with radiation. Results: Motesanib inhibited VEGF-stimulated HUVEC proliferation in vitro , as well as VEGFR2 kinase activity. Additionally, Motesanib and fractionated radiation showed additive inhibitory effects on HUVEC proliferation. In vivo combination therapy with Motesanib and radiation showed increased response compared with drug or radiation alone in UM-SCC1 ( P P = 0.001); however, the combination was not significantly more efficacious than radiation alone in UM-SCC6 xenografts. Xenografts treated with Motesanib showed a reduction of vessel penetration into tumor parenchyma, compared with control tumors. Furthermore, triple immunohistochemical staining for vasculature, proliferation, and hypoxia showed well-defined spatial relationships among these parameters in HNSCC xenografts. Motesanib significantly enhanced intratumoral hypoxia in the presence and absence of fractionated radiation. Conclusions: These studies identify a favorable interaction when combining radiation and Motesanib in HNSCC models. The data presented suggest that Motesanib reduces blood vessel penetration into tumors and thereby increases intratumoral hypoxia. These findings suggest that clinical investigations examining combinations of radiation and Motesanib are warranted in HNSCC. Clin Cancer Res; 16(14); 3639–47. ©2010 AACR.
Michael Bass - One of the best experts on this subject based on the ideXlab platform.
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A phase 1b, open-label study of trebananib plus bevacizumab or Motesanib in patients with solid tumours
Oncotarget, 2014Co-Authors: David S. Hong, Razelle Kurzrock, Marilyn Mulay, Erik Rasmussen, Michael Bass, Zhandong D. Zhong, Greg Friberg, Lee S RosenAbstract:To examine the angiopoietin pathway inhibitor trebananib IV plus the anti-VEGF agents bevacizumab or Motesanib in advanced solid tumours. In this open-label phase 1b study, patients received IV trebananib 3 mg kg-1 QW plus bevacizumab 15 mg kg-1 Q3W (cohort 1) or Motesanib orally 75 mg (cohort 2); or trebananib 10 mg kg-1 plus bevacizumab 15 mg kg-1 (cohort 3) or Motesanib 125 mg (cohort 4). If <33% of patients had dose-limiting toxicities (DLTs), dose escalation occurred. Endpoints were treatment-related adverse events (AEs) incidence and pharmacokinetics (primary); anti-trebananib antibodies, biomarkers, and tumour response (secondary). Thirty-six patients received ≥ 1 dose of trebananib (cohorts 1, 2, 3, 4; n = 6, 8, 19, 3). DLT of G3 intestinal perforation and G3 tumor haemorrhage occurred in cohorts 2 and 3, respectively (both n = 1). Across both trebananib plus bevacizumab cohorts, the most common AEs included fatigue (n = 8), diarrhoea (n =4), constipation (n = 3), nausea (n = 3), and epistaxis (n = 3). Three patients across those cohorts had grade ≥ 3 AEs. Across the trebananib plus Motesanib cohorts, the most common AEs included hypertension (n = 4), diarrhoea (n = 4), nausea (n = 3), fatigue (n = 3), vomiting (n = 2), and decreased appetite (n = 2). Two patients had grade ≥ 3 AEs. Trebananib did not markedly affect Motesanib pharmacokinetics. Across the trebananib plus bevacizumab cohorts, two patients had a partial response; 11 patients had stable disease lasting >6 months. Across the trebananib plus Motesanib cohorts, one patient had a partial response; five patients had stable disease lasting >6 months. Trebananib IV 3 mg kg-1 or 10 mg kg-1 plus bevacizumab or Motesanib in advanced solid tumours may be associated with less severe toxicities relative to those emerging when combining two anti-VEGF agents.
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a phase 1b open label study of trebananib plus bevacizumab or Motesanib in patients with solid tumours
Oncotarget, 2014Co-Authors: David S. Hong, Razelle Kurzrock, Marilyn Mulay, Erik Rasmussen, Michael Bass, Zhandong D. Zhong, Greg Friberg, Lee S RosenAbstract:// David S. Hong 1 , Razelle Kurzrock 2 , Marilyn Mulay 3 , Erik Rasmussen 4 , Benjamin M. Wu 5 , Michael B. Bass 6 , Zhandong D. Zhong 7 , Greg Friberg 8 , Lee S. Rosen 9 1 Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX 77230–1402, USA 2 Center for Personalized Cancer Therapy and CTO, Division of Hematology and Oncology, UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC #0658, La Jolla, CA 92093–0658, USA 3 Mulay Educational and Clinical Consulting Associates, 12412 Texas Ave., Suite 206, Los Angeles, CA 90025, USA 4 Department of Biostatistics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 5 Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 6 Department of Molecular Sciences and Computational Biology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 7 Department of Clinical Immunology and Biological Sample Management, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 8 Department of Early Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA 9 Department of Medicine, Division of Hematology and Oncology, UCLA, Santa Monica, CA 90404, USA Correspondence to: David S. Hong, e-mail: dshong@mdanderson.org Keywords: angiogenesis, angiopoietins, Tie2 receptor, vascular endothelial growth factor, angiogenic inhibitors Received: June 19, 2014 Accepted: October 02, 2014 Published: October 23, 2014 ABSTRACT Background: To examine the angiopoietin pathway inhibitor trebananib IV plus the anti-VEGF agents bevacizumab or Motesanib in advanced solid tumours. Methods: In this open-label phase 1b study, patients received IV trebananib 3 mg kg −1 QW plus bevacizumab 15 mg kg −1 Q3W (cohort 1) or Motesanib orally 75 mg (cohort 2); or trebananib 10 mg kg −1 plus bevacizumab 15 mg kg −1 (cohort 3) or Motesanib 125 mg (cohort 4). If 6 months. Across the trebananib plus Motesanib cohorts, one patient had a partial response; five patients had stable disease lasting >6 months. Conclusion: Trebananib IV 3 mg kg −1 or 10 mg kg −1 plus bevacizumab or Motesanib in advanced solid tumours may be associated with less severe toxicities relative to those emerging when combining two anti-VEGF agents.
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Challenges in developing a validated biomarker for angiogenesis inhibitors: the Motesanib experience.
PloS one, 2014Co-Authors: Michael Bass, Bin Yao, Gerard J. Davis, Michael T. Davis, Barbara A. Kaesdorf, Sabrina S. Chan, Y. J. Hei, Scott D. PattersonAbstract:We sought to develop placental growth factor as a predictive pharmacodynamic biomarker for Motesanib efficacy as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer. Placental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of Motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of Motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models. In the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with ≥2.2-fold change from baseline in placental growth factor (n = 18) had significantly longer overall survival than those with <2.2-fold change (n = 19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12-0.74; P = 0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log-transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79-1.22; P = 0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with ≥2.0-fold change in placental growth factor (n = 229) compared with <2.0-fold change (n = 127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67-1.15, P = 0.340). Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies. ClinicalTrials.gov NCT00460317, NCT00369070.
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challenges in developing a validated biomarker for angiogenesis inhibitors the Motesanib experience
PLOS ONE, 2014Co-Authors: Michael Bass, Bin Yao, Gerard J. Davis, Michael T. Davis, Barbara A. Kaesdorf, Sabrina S. Chan, Y. J. Hei, Scott D. PattersonAbstract:Purpose: We sought to develop placental growth factor as a predictive pharmacodynamic biomarker for Motesanib efficacy as first-line therapy in patients with advanced nonsquamous non–small-cell lung cancer. Experimental Design: Placental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of Motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of Motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models. Results: In the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with $2.2-fold change from baseline in placental growth factor (n=18) had significantly longer overall survival than those with ,2.2-fold change (n=19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12–0.74; P=0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log-transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79–1.22; P=0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with $2.0-fold change in placental growth factor (n=229) compared with ,2.0-fold change (n=127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67–1.15, P=0.340). Conclusions: Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies. Trial Registration: ClinicalTrials.gov NCT00460317, NCT00369070
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Biomarkers as Predictors of Response to Treatment with Motesanib in Patients with Progressive Advanced Thyroid Cancer
The Journal of clinical endocrinology and metabolism, 2010Co-Authors: Michael Bass, Yong-jiang Hei, Michael T. Davis, Martin Schlumberger, Steven I. Sherman, Lisa Kivman, Huan Mei Khoo, Kimberly H. Notari, Matthew Peach, Scott D. PattersonAbstract:Context: Antiangiogenic therapies have shown potential in the treatment of advanced thyroid cancer, but it is uncertain which patients are most likely to benefit from therapy. Objective: This prespecified exploratory analysis investigated whether baseline levels and/or changes in circulating biomarkers could predict tumor response and/or progression-free survival (PFS) among patients enrolled in a phase 2 study of Motesanib in advanced thyroid cancer. Design/Setting/Patients: Patients with progressive locally advanced or metastatic medullary or differentiated thyroid cancer received Motesanib 125 mg once daily for up to 48 wk in a phase 2 interventional study. Samples for assessment of circulating biomarkers of angiogenesis or apoptosis were collected at study wk 1 (baseline), 2, 4, 8, 16, 24, 32, 40, 48, and 4 wk after cessation of Motesanib treatment. Tumor response was assessed per Response Evaluation Criteria in Solid Tumors by independent review. Results: Change from baseline in serum placental growt...