Ponatinib for FLT3-ITD Acute Myelogenous Leukemia (PONATINIB-AML)

August 6, 2020 updated by: Philippe ROUSSELOT, Versailles Hospital

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

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 14.5%); 2) FLT3-ITD with wild type CEBPA, TET2, DNMT3 and MLL-PTD (3-year OS 35.2%) 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: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (O'Hare T, Cancer Cell 2009). Despite low activity against FLT3 based on the IC50 value (FLT3 IC50: 12.6 nM compared to BCR IC50: 0.37 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 mg/kg 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 51.1 nM. Cmax was increased to 111 nM and 149 nM in the 30 mg and 45 mg cohorts respectively. The trough concentrations were 55.3 nM and 61.9 nM for the 30 mg and 45 mg doses respectively (Ariad clinical investigator's 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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
49

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Aix-en-Provence, France, 13600
        • Dr Abdelaziz CHAIB
      • Amiens, France, 80054
        • CHU Amiens
      • Angers, France, 49033
        • CHU d'Angers
      • Argenteuil, France, 95107
        • Hôpital Victor Dupouy
      • Bayonne, France, 64100
        • Dr Edouard RANDIAMALALA
      • Besançon, France, 25030
        • CHU de Besançon
      • Bobigny, France, 93000
        • Dr Thorsten BRAUN
      • Boulogne Sur Mer cedex, France, 62321
        • CHU Boulogne sur Mer
      • Caen Cedex, France, 14033
        • CHR Clemenceau
      • Clamart, France, 92141
        • Hopital D'Instruction Des Armees Percy
      • Corbeil-essonnes, France, 91100
        • Dr Stéphanie HAÏAT
      • Créteil, France, 94010
        • Hôpital Henri Mondor
      • Dijon, France, 21079
        • CHU de Dijon
      • Le Chesnay cedex, France, 78157
        • Centre Hospitalier de Versailles
      • Lille cedex, France, 59037
        • Hopital Claude Huriez
      • Limoges cedex, France, 87042
        • CHRU Dupuytren
      • Lyon cedex 03, France, 69437
        • Hôpital Edouard Herriot
      • Marseille, France, 13000
        • Dr Regis COSTELLO
      • Meaux, France, 77104
        • Centre Hospitalier de Meaux
      • Mulhouse, France, 68000
        • Dr Mario OJEDA-URIBE
      • Nantes, France, 44000
        • Dr Jacques DELAUNAY
      • Nice cedex 3, France, 06202
        • CHU Nice, Hôpital Archet 1
      • Nîmes, France, 30029
        • CHU de Nîmes
      • Paris, France, 75010
        • Hôpital Saint Louis
      • Paris, France, 75013
        • Hopital La Pitie Salpetriere
      • Paris cedex 12, France, 75751
        • Hôpital Saint Antoine
      • Paris cedex 15, France, 75743
        • Hopital Necker Enfants Malades
      • Perpignan, France, 66000
        • Dr Laurence SANHES
      • Pessac, France, 33604
        • Dr Arnaud PIGNEUX
      • Pontoise Cedex, France, 95303
        • Centre Hospitalier René Dubos
      • Rennes, France, 35000
        • Marc BERNARD
      • Rouen, France, 76000
        • Dr Emilie LEMASLE
      • Saint Cloud, France, 92210
        • Centre Hospitalier René Huguenin
      • Saint-Priest-en-Jarez, France, 42270
        • Institut de Cancerologie de La Loire
      • Saint-Quentin, France, 02100
        • Dr Réda GARIDI
      • Toulouse, France, 31000
        • Dr Christian RECHER
      • Valenciennes, France, 59322
        • Centre Hospitalier de Valenciennes

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 70 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. a. Patients aged 18 to 55-60 years: Cohort A b. Patients aged 55-60 to 70 years: Cohort B
  2. Signed informed consent
  3. Acute myeloid leukemia in first complete remission
  4. Platelets ≥ 100 Giga/l; Neutrophils ≥ 1 Giga/l
  5. Intermediate risk karyotype with FLT3-ITD activating mutant detected at diagnosis (mutant FLT3/wild-type allelic ratio higher than 10%) (appendix 16)
  6. Induction with intensive chemotherapy, dose dense sequential induction or 3 + 7 like regimen (daunorubicin or idarubicin) for Cohort A and inclusion in the ALFA backbone for cohort B.
  7. Pancreatic functions within the normal range
  8. AST or ALT less or equal to 2.5 fold upper normal range, bilirubin less or equal to 1.5 fold upper normal range
  9. Serum creatinine less or equal to 1.5 fold upper normal range
  10. Two planned consolidation courses with high-dose cytarabine (HDAC, Cohort A) or intermediate dose cytarabine (IDAC, Cohort B).

Exclusion Criteria:

  1. Acute promyelocytic leukemia
  2. Transformation of myeloproliferative or myelodysplastic syndromes
  3. Known central nervous system involvement
  4. Uncontrolled bacterial, viral or fungal infection
  5. Other active malignancy
  6. Previous episode of pancreatitis
  7. Hypertriglyceridemia > 4.5 g/L
  8. Lipase > 1.5 × ULN, amylase > 1.5 x ULN not related to leukemia
  9. QTc > 470 ms (Bazett formula, see Appendix 1)

  10. Patients at high or very high risk of cardiovascular disease with any of the following f) Established cardiovascular disease

    • Cardiac disease:

      • Congestive heart failure greater than class II NYHA or
      • Left ventricular ejection fraction (LVEF) < 50% or
      • Unstable angina (anginal symptoms at rest) or
      • New onset angina (began within the last 3 months) or
      • Myocardial infarction, coronary/peripheral artery disease, congestive heart failure, cerebrovascular accident including transient ischemic attack within the past 12 months or
      • History of thrombolic or embolic events

    • Arrhythmias

      - Any history of clinically significant cardiac arrhythmias requiring anti-arrhythmic therapy.

      g) Diabetes Mellitus untreated or not equilibrated with therapy h) Arterial Hypertension,

    • - Uncontrolled hypertension defined as systolic blood pressure greater than 140 mmHg or diastolic pressure greater than 90 mmHg, despite optimal medical management and optimal measurement (http://www.has-sante.fr/portail/display.jsp?id=c_272459)

    • - Any history of hypertension with

      • Hypertensive encephalopathy
      • Posterior leucoencephalopathy
      • Aortic or artery dissection i) Familial dysplipidemia. j) Taking medications that are known to be associated with Torsades de Pointes (see Appendix 11)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Ponatinib arm
dose-escalation Arm _ 15, 30, 45mg Ponatinib per day. Each cohort will consist of 3 evaluable patients
Drug: Ponatinib and Cytarabine
Prospective, non-randomized, open-label, multicenter, dose-escalation phase I-II trial; an adaptive Bayesian logistic regression dose-escalation model incorporating escalation with overdose control will be used (Babb 1998, Tighiouart 2005). Each cohort will consist of 3 evaluable patients

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
dose-limiting toxicity (DLT) of ponatinib during consolidation 1 with HDAC or IDAC
Time Frame: 12 months
assess the safety of increased doses of ponatinib in combination with high or intermediate -dose cytarabine in AML FLT3-ITD patients in first complete remission
12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 5 years
To determine disease-free survival from achievement of first complete remission
5 years
Relapse-free survival
Time Frame: 5 years
To determine overall survival from achievement of first complete remission
5 years
Event-free survival
Time Frame: 5 years
To determine overall survival from diagnosis
5 years
Minimal residual disease based on FLT3-ITD quantification, WT1 expression and/or NPM1 mutation quantification
Time Frame: 18 months
To study minimal residual disease after induction and consolidation courses based on the quantification of the FLT3-ITD signal and /or WT1, NPM if available
18 months
relationship between minimal residual disease and outcome
Time Frame: 18 months
To study the relationship between minimal residual disease and outcome
18 months
To study ponatinib resistance mechanisms
Time Frame: 18 months
To assess FLT3-ITD mutant before and after ponatinib treatment
18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Versailles Hospital

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Rousselot Philippe, Pr, CH Versailles

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 1, 2013

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 1, 2020

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 1, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 2, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 28, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 29, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 10, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 6, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2013-000268-27

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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