Ponatinib for FLT3-ITD Acute Myelogenous Leukemia

NCT ID: NCT02428543

Last Updated: 2020-08-10

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 49 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-07-31
• Study Completion Date: 2023-11-30

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 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.

Conditions

Acute Myeloid Lukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ponatinib arm

dose-escalation Arm \_ 15, 30, 45mg Ponatinib per day. Each cohort will consist of 3 evaluable patients

Group Type: EXPERIMENTAL

Ponatinib and Cytarabine

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Versailles Hospital

OTHER

Sponsor Role: lead

Responsible Party

Philippe ROUSSELOT

Clinical coordinator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Rousselot Philippe, Pr

Role: PRINCIPAL_INVESTIGATOR

CH Versailles

Locations

Dr Abdelaziz CHAIB

Aix-en-Provence, , France

Chu Amiens

Amiens, , France

CHU d'Angers

Angers, , France

Hôpital VICTOR DUPOUY

Argenteuil, , France

Dr Edouard RANDIAMALALA

Bayonne, , France

CHU de Besançon

Besançon, , France

Dr Thorsten BRAUN

Bobigny, , France

CHU Boulogne Sur Mer

Boulogne-sur-Mer, , France

Chr Clemenceau

Caen, , France

Hôpital d'Instruction des Armées PERCY

Clamart, , France

Dr Stéphanie HAÏAT

Corbeil-Essonnes, , France

Hôpital Henri Mondor

Créteil, , France

CHU de Dijon

Dijon, , France

Centre hospitalier de Versailles

Le Chesnay, , France

Hôpital Claude Huriez

Lille, , France

CHRU Dupuytren

Limoges, , France

Hôpital Edouard Herriot

Lyon, , France

Dr Regis COSTELLO

Marseille, , France

Centre Hospitalier de Meaux

Meaux, , France

Dr Mario OJEDA-URIBE

Mulhouse, , France

Dr Jacques DELAUNAY

Nantes, , France

CHU Nice, Hôpital Archet 1

Nice, , France

CHU de Nîmes

Nîmes, , France

Hôpital Saint Louis

Paris, , France

Hôpital La Pitié Salpêtrière

Paris, , France

Hôpital Necker Enfants Malades

Paris, , France

Hôpital Saint Antoine

Paris, , France

Dr Laurence SANHES

Perpignan, , France

Dr Arnaud PIGNEUX

Pessac, , France

Centre Hospitalier René Dubos

Pontoise, , France

Marc BERNARD

Rennes, , France

Dr Emilie LEMASLE

Rouen, , France

Centre Hospitalier René Huguenin

Saint-Cloud, , France

Institut de Cancérologie de la Loire

Saint-Priest-en-Jarez, , France

Dr Réda GARIDI

Saint-Quentin, , France

Dr Christian RECHER

Toulouse, , France

Centre Hospitalier de Valenciennes

Valenciennes, , France

Countries

France

Other Identifiers

2013-000268-27

Identifier Type: -

Identifier Source: org_study_id