Ignite Creation Date:
2024-05-06 @ 3:59 AM
Last Modification Date:
2024-10-26 @ 11:42 AM
Study NCT ID:
NCT02428543
Status:
UNKNOWN
Last Update Posted:
2020-08-10
First Post:
2013-08-02
Brief Title:
Ponatinib for FLT3-ITD Acute Myelogenous Leukemia
Sponsor:
Versailles Hospital
Organization:
Versailles Hospital
Study Overview
Official Title:
A Phase I - II Study to Assess Safety and Efficacy of the Combination of Ponatinib With High or Intermediate-Dose Cytarabine as Consolidation Therapy for Patients With Intermediate-Risk Cytogenetic FLT3-ITD AML iIn First Complete Remission
Status:
UNKNOWN
Status Verified Date:
2020-08
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PONATINIB-AML
Brief Summary:
This project is part of a joint ALFA and GOELAM strategy aiming to improve the survival of patients with newly diagnosed Acute Myeloid Leukemia AML aged 18-70 years The basis of this strategy is to evaluate intensified conventional chemotherapy and targeted drugs in selected disease-risk subgroups of adult patients with non promyelocytic AML Participation will be proposed to almost all adult patients in France aged 18-70 years and diagnosed with AML
FLT3 genetic alterations include FLT3 somatic point mutations within the second tyrosine kinase domain and internal duplications of the juxta-membrane domain This alteration is refered to as FLT3-ITD The FLT3-ITD mutation is found in around 30 of patients with cytogenetically normal AML Patients with the FLT3-ITD genotype have been reported to have a poor outcome when treated with conventional chemotherapy with an estimated 4-year relapse-free survival of 25 Schlenk et al N Engl J Med 2008 More recently the prognostic relevance of FLT3-ITD has been studied in the context of integrated genetic profiling This confirmed the genetic complexity of AML and also that FLT3-ITD was associated with reduced overall survival in intermediate-risk AML A multivariate analysis of several genetic alterations revealed that FLT3-ITD was the primary predictor of patient outcome FLT3-ITD mutations were classified in 3 categories 1 FLT3-ITD with 8 TET2 DNMT3A or MLL-PTD mutations 3-year OS 145 2 FLT3-ITD with wild type CEBPA TET2 DNMT3 and MLL-PTD 3-year OS 352 and 3 FLT3-ITD with CEBPA mutations 3-year OS 42 Patel JP et al N Engl J Med 2012 However FLT3-ITD was not a predictor of response to induction therapy allowing the introduction of targeted therapies after the induction course
Several FLT3 inhibitors have been evaluated or are currently being tested in the setting of relapsing AML In most trials to date patients were only eligible if the FLT3-ITD mutation was present Disappointing results were reported with the first generation of FLT3 inhibitors including lestaurtinib CEP-701 midostaurin PKC-412 and sorafenib Second generation FLT3 inhibitors such as quizartinib AC220 are currently under investigation with promising results However the hematologic toxicity of AC220 will likely present a major limitation in evaluating AC220 combined with standard or high-dose chemotherapy
Ponatinib AP24534 is a third generation tyrosine kinase inhibitor targeting the BCR-ABL tyrosine kinase domain Ponatinib was rationally designed with an extensive network of optimized molecular contacts and triple bonds to accommodate the T315I mutation a major cause of resistance to tyrosine kinase inhibitors in chronic and advanced phase chronic myelogenous leukemia CML Ponatinib also inhibits SRC IC50 54 nM and members of the VEGFR FGFR and PDGFR families of receptor tyrosine kinases OHare T Cancer Cell 2009 Despite low activity against FLT3 based on the IC50 value FLT3 IC50 126 nM compared to BCR IC50 037 nM ponatinib has recently been reported to have significant cellular activity against the MV4-11 cell line which harbors an FLT3-ITD activating mutation Ponatinib-induced apoptosis was maximal at 10 nM in vitro and a single dose of 5 and 10 mgkg had a strong inhibitory effect in vivo in mice bearing MV4-11 xenografts Primary blast cells from 4 FLT3-ITD AML patients were also tested and ponatinib reduced their viability IC50 4 nM whereas no activity was shown on FLT3-ITD-negative blast cells Gozgit JM et al Mol Cancer Ther 2011
Preliminary data from the phase I clinical trial showed that 15 mg ponatinib was associated with a Cmax of 511 nM Cmax was increased to 111 nM and 149 nM in the 30 mg and 45 mg cohorts respectively The trough concentrations were 553 nM and 619 nM for the 30 mg and 45 mg doses respectively Ariad clinical investigators brochure version 3 Results from the ongoing phase II trial in CML patients suggest that the hematological toxicity profile of ponatinib is comparable with that of nilotinib or dasatinib both of which have been successfully combined with conventional chemotherapy
Investigators thus aim to combine ponatinib with cytarabine in FLT3-ITD AML patients in first complete remission
FLT3 genetic alterations include FLT3 somatic point mutations within the second tyrosine kinase domain and internal duplications of the juxta-membrane domain This alteration is refered to as FLT3-ITD The FLT3-ITD mutation is found in around 30 of patients with cytogenetically normal AML Patients with the FLT3-ITD genotype have been reported to have a poor outcome when treated with conventional chemotherapy with an estimated 4-year relapse-free survival of 25 Schlenk et al N Engl J Med 2008 More recently the prognostic relevance of FLT3-ITD has been studied in the context of integrated genetic profiling This confirmed the genetic complexity of AML and also that FLT3-ITD was associated with reduced overall survival in intermediate-risk AML A multivariate analysis of several genetic alterations revealed that FLT3-ITD was the primary predictor of patient outcome FLT3-ITD mutations were classified in 3 categories 1 FLT3-ITD with 8 TET2 DNMT3A or MLL-PTD mutations 3-year OS 145 2 FLT3-ITD with wild type CEBPA TET2 DNMT3 and MLL-PTD 3-year OS 352 and 3 FLT3-ITD with CEBPA mutations 3-year OS 42 Patel JP et al N Engl J Med 2012 However FLT3-ITD was not a predictor of response to induction therapy allowing the introduction of targeted therapies after the induction course
Several FLT3 inhibitors have been evaluated or are currently being tested in the setting of relapsing AML In most trials to date patients were only eligible if the FLT3-ITD mutation was present Disappointing results were reported with the first generation of FLT3 inhibitors including lestaurtinib CEP-701 midostaurin PKC-412 and sorafenib Second generation FLT3 inhibitors such as quizartinib AC220 are currently under investigation with promising results However the hematologic toxicity of AC220 will likely present a major limitation in evaluating AC220 combined with standard or high-dose chemotherapy
Ponatinib AP24534 is a third generation tyrosine kinase inhibitor targeting the BCR-ABL tyrosine kinase domain Ponatinib was rationally designed with an extensive network of optimized molecular contacts and triple bonds to accommodate the T315I mutation a major cause of resistance to tyrosine kinase inhibitors in chronic and advanced phase chronic myelogenous leukemia CML Ponatinib also inhibits SRC IC50 54 nM and members of the VEGFR FGFR and PDGFR families of receptor tyrosine kinases OHare T Cancer Cell 2009 Despite low activity against FLT3 based on the IC50 value FLT3 IC50 126 nM compared to BCR IC50 037 nM ponatinib has recently been reported to have significant cellular activity against the MV4-11 cell line which harbors an FLT3-ITD activating mutation Ponatinib-induced apoptosis was maximal at 10 nM in vitro and a single dose of 5 and 10 mgkg had a strong inhibitory effect in vivo in mice bearing MV4-11 xenografts Primary blast cells from 4 FLT3-ITD AML patients were also tested and ponatinib reduced their viability IC50 4 nM whereas no activity was shown on FLT3-ITD-negative blast cells Gozgit JM et al Mol Cancer Ther 2011
Preliminary data from the phase I clinical trial showed that 15 mg ponatinib was associated with a Cmax of 511 nM Cmax was increased to 111 nM and 149 nM in the 30 mg and 45 mg cohorts respectively The trough concentrations were 553 nM and 619 nM for the 30 mg and 45 mg doses respectively Ariad clinical investigators brochure version 3 Results from the ongoing phase II trial in CML patients suggest that the hematological toxicity profile of ponatinib is comparable with that of nilotinib or dasatinib both of which have been successfully combined with conventional chemotherapy
Investigators thus aim to combine ponatinib with cytarabine in FLT3-ITD AML patients in first complete remission
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None