Fletcher); and Cycle for Survival and the Shuman Family Fund for GIST Research (R

Fletcher); and Cycle for Survival and the Shuman Family Fund for GIST Research (R.G. emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose routine was 50 mg/d for 4 weeks followed by 2 weeks off treatment. Around the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally moderate to moderate in severity. Conclusion Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy. Gastrointestinal stromal tumor (GIST) represents an ideal solid tumor model to apply the understanding of aberrant transmission transduction to drug discovery and development. Most GISTs (~95%) express the KIT receptor tyrosine kinase (RTK), and activating gene mutations represent a key etiologic mechanism in 80% to 85% of GIST patients (1). Approximately 8% of GIST patients have activating mutations in the gene encoding the related RTK platelet-derived growth factor receptor- (PDGFRA; refs. 2, 3). In ~10% of patients, no kinase mutations are detectable in either of these two genes, although uncontrolled KIT kinase activation has been noted even in the absence of mutation (2, 4). The survival of metastatic GIST patients was dramatically improved by treatment with the KIT and PDGFRA inhibitor imatinib mesylate (Gleevec; refs. 5, 6). However, imatinib resistance emerges due most commonly to development of secondary or mutations (7C10). Therefore, systemic therapies are needed for GIST patients once imatinib resistance appears and for the small subset who are imatinib intolerant. Sunitinib malate (SUTENT) is an oral, multitargeted tyrosine kinase inhibitor with potent activity against KIT, PDGFRs, vascular endothelial growth factor receptors (VEGFRs), and several other RTKs (11C15). Sunitinib may exert antitumor activity in imatinib-resistant GIST by inhibiting imatinib-resistant RTK mutants and/or RTKs involved in tumor angiogenesis (including VEGFRs Octopamine hydrochloride and PDGFRB). Here, we present the final analysis of security, pharmacokinetics (PK), and clinical and biological activity of sunitinib in a phase I/II trial of GIST patients after imatinib failure due to resistance or intolerance, following earlier reports from this study (16, 17). These results supported both the subsequent randomized, placebo-controlled, phase III study that confirmed the clinical benefit of sunitinib (18) and multinational approval of sunitinib in this patient population (19). Materials and Methods Patients Adults with histologically confirmed metastatic and/or unresectable GIST with documented imatinib failure due to resistance or intolerance were eligible for the study. Inclusion criteria included measurable disease, Eastern Cooperative Oncology Group overall performance status 0 to 2 (amended to 0 to 1 1), adequate nutritional and hematologic status, and adequate major organ function. Discontinuation of imatinib 2 wk before initiating sunitinib was required. The study was approved by the institutional review boards of the participating institutions; written informed consent was obtained from all patients. Procedures This was an open-label, single-arm, sequential cohort, dose-escalation phase I and early phase II trial to establish a phase II sunitinib dosing routine based on security, PK, and preliminary biological and clinical activity. Secondary objectives included doing [18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), histologic review, assessments of KIT phosphorylation and tumor cell proliferation, and tumor kinase genotyping to explore possible correlations with clinical activity. The partnership between kinase genotype and sunitinib activity with this research continues to be reported somewhere else (20). Separate affected person cohorts received sunitinib orally using one of three cyclical treatment schedules: Plan 2/2 (2 wk on sunitinib, 2 wk off), Plan 4/2 (4 wk on, 2 wk off), or Plan 2/1 (2 wk on, 1 wk off). Plan 2/2 dosing began at 25, 50, or 75 mg/d; Schedules 4/2 and 2/1 began at 50 mg/d. Individuals experiencing clinical advantage [full response (CR), incomplete response (PR), or steady disease (SD).Remaining ventricular ejection fraction declines had been reversible with medical administration generally; however, some individuals demonstrated transient elevations in serum TnI amounts, without symptoms generally. in tumor biopsies (indicating focus on modulation). The suggested dosage plan was 50 mg/d for four weeks followed by 14 days off treatment. For the 50-mg dosage across all schedules, 79% of PK-evaluable individuals achieved total medication trough concentrations above the prospective focus (50 ng/mL) within 2 weeks of dosing. Furthermore, adverse events had been generally gentle to moderate in intensity. Summary Cellular and molecular analyses demonstrated that sunitinib medical activity is connected with inhibition of Package in GIST pursuing imatinib failing, illustrating the logical approach used to build up a therapy targeted at the root oncogenic signaling pathway aberrancy. Gastrointestinal stromal tumor (GIST) represents a perfect solid tumor model to use the knowledge of aberrant sign transduction to medication discovery and advancement. Many GISTs (~95%) communicate the Package receptor tyrosine kinase (RTK), and activating gene mutations represent an integral etiologic system in 80% to 85% of GIST individuals (1). Around 8% of GIST individuals possess activating mutations in the gene encoding the related RTK platelet-derived development element receptor- (PDGFRA; refs. 2, 3). In ~10% of individuals, no kinase mutations are detectable in either of the two genes, although uncontrolled Package kinase activation continues to be noted actually in the lack of mutation (2, 4). The success of metastatic GIST individuals was significantly improved by treatment using the Package and PDGFRA inhibitor imatinib mesylate (Gleevec; refs. 5, 6). Nevertheless, imatinib level of resistance emerges due mostly to advancement of supplementary or mutations (7C10). Consequently, systemic therapies are necessary for GIST individuals once imatinib level of resistance appears as well as for the tiny subset who are imatinib intolerant. Sunitinib malate (SUTENT) can be an dental, multitargeted tyrosine kinase inhibitor with powerful activity against Package, PDGFRs, vascular endothelial development element receptors (VEGFRs), and many additional RTKs (11C15). Sunitinib may exert antitumor activity in imatinib-resistant GIST by inhibiting imatinib-resistant RTK mutants and/or RTKs involved with tumor angiogenesis (including VEGFRs and PDGFRB). Right here, we present the ultimate analysis of protection, pharmacokinetics (PK), and medical and natural activity of sunitinib inside a stage I/II trial of GIST individuals after imatinib failing due to level of resistance or intolerance, pursuing earlier reports out of this research (16, 17). These outcomes supported both following randomized, placebo-controlled, stage III research that verified the clinical good thing about sunitinib (18) and multinational authorization of sunitinib with this individual population (19). Components and Methods Individuals Adults with histologically verified metastatic and/or unresectable GIST with recorded imatinib failure because of level of resistance or intolerance had been eligible for the analysis. Inclusion requirements included measurable disease, Eastern Cooperative Oncology Group efficiency position 0 to 2 (amended to 0 Octopamine hydrochloride to at least one 1), adequate dietary and hematologic position, and adequate main body organ function. Discontinuation of imatinib 2 wk before initiating sunitinib was needed. The analysis was authorized by the institutional review planks of the taking part institutions; written educated consent was from all individuals. Procedures This is an open-label, single-arm, sequential cohort, dose-escalation stage I and early stage II trial to determine a stage II sunitinib dosing plan based on protection, PK, and initial biological and clinical activity. Secondary objectives included doing [18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), histologic review, assessments of KIT phosphorylation and tumor cell proliferation, and tumor kinase genotyping to explore possible correlations with clinical activity. The relationship between kinase genotype and sunitinib activity in this study has been reported elsewhere (20). Separate patient cohorts received sunitinib orally on one of three cyclical treatment schedules: Schedule 2/2 (2 wk on sunitinib, 2 wk off), Schedule 4/2 (4 wk on, 2 wk off), or Schedule 2/1 (2 wk on, 1 wk off). Schedule 2/2 dosing started at 25, 50, or 75 mg/d; Schedules 4/2 and 2/1 started at 50 mg/d. Patients experiencing clinical benefit [complete response (CR), partial response (PR), or stable disease (SD) 6 mo] at study end were eligible for extended treatment in a treatment continuation study. Patients underwent regular physical examinations and evaluations of performance status, body weight, complete blood counts, and serum biochemistry. Cardiac monitoring included serial weekly measurements of cardiac troponin (TnT and/or TnI) and total creatinine kinase, electrocardiograms, and determination of left PDGFA ventricular ejection fraction (by electrocardiogram or multigated acquisition scan) in each cycle. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria, version 2.0 (21). Tumor imaging and response assessments Objective response was assessed by computed tomography (CT) or magnetic resonance imaging at baseline and the end of every even-numbered cycle. Disease status.By day 14, 79% of patients on 50 mg/d had achieved total drug trough concentrations above 50 ng/mL, the concentration providing target RTK inhibition in preclinical studies (12). concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity. Conclusion Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy. Gastrointestinal stromal tumor (GIST) represents an ideal solid tumor model to apply the understanding of aberrant signal transduction to drug discovery and development. Most GISTs (~95%) express the KIT receptor tyrosine kinase (RTK), and activating gene mutations represent a key etiologic mechanism in 80% to 85% of GIST patients (1). Approximately 8% of GIST patients have activating mutations in the gene encoding the related RTK platelet-derived growth factor receptor- (PDGFRA; refs. 2, 3). In ~10% of patients, no kinase mutations are detectable in either of these two genes, although uncontrolled KIT kinase activation has been noted even in the absence of mutation (2, 4). The survival of metastatic GIST patients was dramatically improved by treatment with the KIT and PDGFRA inhibitor imatinib mesylate (Gleevec; refs. 5, 6). However, imatinib resistance emerges due most commonly to evolution of secondary or mutations (7C10). Therefore, systemic therapies are needed for GIST patients once imatinib resistance appears and for the small subset who are imatinib intolerant. Sunitinib malate (SUTENT) is an oral, multitargeted tyrosine kinase inhibitor with potent activity against KIT, PDGFRs, vascular endothelial growth factor receptors (VEGFRs), and several other RTKs (11C15). Sunitinib may exert antitumor activity in imatinib-resistant GIST by inhibiting imatinib-resistant RTK mutants and/or RTKs involved in tumor angiogenesis (including VEGFRs and PDGFRB). Here, we present the final analysis of safety, pharmacokinetics (PK), and clinical and biological activity of sunitinib in a phase I/II trial of GIST patients after imatinib failure due to resistance or intolerance, following earlier reports from this study (16, 17). These results supported both the subsequent randomized, placebo-controlled, phase III study that confirmed the clinical benefit of sunitinib (18) and multinational approval of sunitinib in this patient population (19). Materials and Methods Patients Adults with histologically confirmed metastatic and/or unresectable GIST with documented imatinib failure due to resistance or intolerance were eligible for the study. Inclusion criteria included measurable disease, Eastern Cooperative Oncology Group performance status 0 to 2 (amended to 0 to 1 1), adequate nutritional and hematologic status, and adequate major organ function. Discontinuation of imatinib 2 wk before initiating sunitinib was required. The study was approved by the institutional review boards of the participating institutions; written informed consent was obtained from all patients. Procedures This was an open-label, single-arm, sequential cohort, dose-escalation phase I and early phase II trial to establish a phase II sunitinib dosing schedule based on safety, PK, and preliminary biological and clinical activity. Secondary objectives included doing [18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), histologic review, assessments of KIT phosphorylation and tumor cell proliferation, and tumor kinase genotyping to explore possible correlations with clinical activity. The relationship between kinase genotype and sunitinib activity in this study has been reported elsewhere (20). Separate patient cohorts received sunitinib orally on one of three cyclical treatment schedules: Schedule 2/2 (2 wk on sunitinib, 2 wk off), Schedule 4/2 (4 wk on, 2 wk off), or Schedule 2/1.Protein concentrations were determined using the Bio-Rad Protein Assay (Bio-Rad Laboratories). was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target focus (50 ng/mL) within 2 weeks of dosing. Furthermore, adverse events had been generally light to moderate in intensity. Bottom line Cellular and molecular analyses demonstrated that sunitinib scientific activity is connected with inhibition of Package in GIST pursuing imatinib failing, illustrating the logical approach used to build up a therapy targeted at the root oncogenic signaling pathway aberrancy. Gastrointestinal stromal tumor (GIST) represents a perfect solid tumor model to use the knowledge of aberrant indication transduction to medication discovery and advancement. Many GISTs (~95%) exhibit the Package receptor tyrosine kinase (RTK), and activating gene mutations represent an integral etiologic system in 80% to 85% of GIST sufferers (1). Around 8% of GIST sufferers have got activating mutations in the gene encoding the related RTK platelet-derived development aspect receptor- (PDGFRA; refs. 2, 3). In ~10% of sufferers, no kinase mutations are detectable in either Octopamine hydrochloride of the two genes, although uncontrolled Package kinase activation continues to be noted also in the lack of mutation (2, 4). The success of metastatic GIST sufferers was significantly improved by treatment using the Package and PDGFRA inhibitor imatinib mesylate (Gleevec; refs. 5, 6). Nevertheless, imatinib level of resistance emerges due mostly to progression of supplementary or mutations (7C10). As a result, systemic therapies are necessary for GIST sufferers once imatinib level of resistance appears as well as for the tiny subset who are imatinib intolerant. Sunitinib malate (SUTENT) can be an dental, multitargeted tyrosine kinase inhibitor with powerful activity against Package, PDGFRs, vascular endothelial development aspect receptors (VEGFRs), and many various other RTKs (11C15). Sunitinib may exert antitumor activity in imatinib-resistant GIST by inhibiting imatinib-resistant RTK mutants and/or RTKs involved with tumor angiogenesis (including VEGFRs and PDGFRB). Right here, we present the ultimate analysis of basic safety, pharmacokinetics (PK), and scientific and natural activity of sunitinib within a stage I/II trial of GIST sufferers after imatinib failing due to level of resistance or intolerance, pursuing earlier reports out of this research (16, 17). These outcomes supported both following randomized, placebo-controlled, stage III research that verified the clinical advantage of sunitinib (18) and multinational acceptance of sunitinib within this individual population (19). Components and Methods Sufferers Adults with histologically verified metastatic and/or unresectable GIST with noted imatinib failure because of level of resistance or intolerance had been eligible for the analysis. Inclusion requirements included measurable disease, Eastern Cooperative Oncology Group functionality position 0 to 2 (amended to 0 to at least one 1), adequate dietary and hematologic position, and adequate main body organ function. Discontinuation of imatinib 2 wk before initiating sunitinib was needed. The analysis was accepted by the institutional review planks of the taking part institutions; written up to date consent was extracted from all sufferers. Procedures This is an open-label, single-arm, sequential cohort, dose-escalation stage I and early stage II trial to determine a stage II sunitinib dosing timetable based on basic safety, PK, and primary biological and scientific activity. Secondary goals included carrying out [18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), histologic review, assessments of Package phosphorylation and tumor cell proliferation, and tumor kinase genotyping to explore feasible correlations with scientific activity. The partnership between kinase genotype and sunitinib activity within this research continues to be reported somewhere else (20). Separate affected individual cohorts received sunitinib orally using one of three cyclical treatment schedules: Timetable 2/2 (2 wk on sunitinib, 2 wk off), Timetable 4/2 (4 wk on, 2 wk off), or Timetable 2/1 (2 wk on, 1 wk off). Timetable 2/2 dosing began at 25, 50, or.M.C. sufferers achieved total medication trough concentrations above the mark focus (50 ng/mL) within 2 weeks of dosing. Furthermore, adverse events had been generally light to moderate in intensity. Bottom line Cellular and molecular analyses demonstrated that sunitinib scientific activity is connected with inhibition of Package in GIST pursuing imatinib failing, illustrating the logical approach used to build up a therapy targeted at the root oncogenic signaling pathway aberrancy. Gastrointestinal stromal tumor (GIST) represents a perfect solid tumor model to use the knowledge of aberrant indication transduction to medication discovery and advancement. Many GISTs (~95%) exhibit the Package receptor tyrosine kinase (RTK), and activating gene mutations represent an integral etiologic system in 80% to 85% of GIST sufferers (1). Around 8% of GIST sufferers have got activating mutations in the gene encoding the related RTK platelet-derived development aspect receptor- (PDGFRA; refs. 2, 3). In ~10% of sufferers, no kinase mutations are detectable in either of the two genes, although uncontrolled KIT kinase activation has been noted even in the absence of mutation (2, 4). The survival of metastatic GIST patients was dramatically improved by treatment with the KIT and PDGFRA inhibitor imatinib mesylate (Gleevec; refs. 5, 6). However, imatinib resistance emerges due most commonly to evolution of secondary or mutations (7C10). Therefore, systemic therapies are needed for GIST patients once imatinib resistance appears and for the small subset who are imatinib intolerant. Sunitinib malate (SUTENT) is an oral, multitargeted tyrosine kinase inhibitor with potent activity against KIT, PDGFRs, vascular endothelial growth factor receptors (VEGFRs), and several other RTKs (11C15). Sunitinib may exert antitumor activity in imatinib-resistant GIST by inhibiting imatinib-resistant RTK mutants and/or RTKs involved in tumor angiogenesis (including VEGFRs and PDGFRB). Here, we present the final analysis of safety, pharmacokinetics (PK), and clinical and biological activity of sunitinib in a phase I/II trial of GIST patients after imatinib failure due to resistance or intolerance, following earlier reports from this study (16, 17). These results supported both the subsequent randomized, placebo-controlled, phase III study that confirmed the clinical benefit of sunitinib (18) and multinational approval of sunitinib in this patient population (19). Materials and Methods Patients Adults with histologically confirmed metastatic and/or unresectable GIST with documented imatinib failure due to resistance or intolerance were eligible for the study. Inclusion criteria included measurable disease, Eastern Cooperative Oncology Group performance status 0 to 2 (amended to 0 to 1 1), adequate nutritional and hematologic status, and adequate major organ function. Discontinuation of imatinib 2 wk before initiating sunitinib was required. The study was approved by the institutional review boards of the participating institutions; written informed consent was obtained from all patients. Procedures This was an open-label, single-arm, sequential cohort, dose-escalation phase I and early phase II trial to establish a phase II sunitinib dosing schedule based on safety, PK, and preliminary biological and clinical activity. Secondary objectives included doing [18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), histologic review, assessments of KIT phosphorylation and tumor cell proliferation, and tumor kinase genotyping to explore possible correlations with clinical activity. The relationship between kinase genotype and sunitinib activity in this study has been reported elsewhere (20). Separate patient cohorts received sunitinib orally on one of three cyclical treatment schedules: Schedule 2/2 (2 wk on sunitinib, 2 wk off), Schedule.