Clinical trial NCT02428543: Ponatinib for FLT3-ITD Acute Myelogenous Leukemia
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Lukemia
Keywords: FLT3-ITD patients in first complete remission
Lead sponsor: Versailles Hospital
Sponsor class: OTHER
First posted: 2015-04-29
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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)

Primary outcomes:
measure: dose-limiting toxicity (DLT) of ponatinib during consolidation 1 with HDAC or IDAC
timeFrame: 12 months
Secondary outcomes:
measure: Overall survival
timeFrame: 5 years
measure: Relapse-free survival
timeFrame: 5 years
measure: Event-free survival
timeFrame: 5 years
measure: Minimal residual disease based on FLT3-ITD quantification, WT1 expression and/or NPM1 mutation quantification
timeFrame: 18 months
measure: relationship between minimal residual disease and outcome
timeFrame: 18 months
measure: To study ponatinib resistance mechanisms
timeFrame: 18 months
Other outcomes:
Locations:
city: Aix-en-Provence
country: France
facility: Dr Abdelaziz CHAIB
city: Amiens
country: France
facility: Chu Amiens
city: Angers
country: France
facility: CHU d'Angers
city: Argenteuil
country: France
facility: Hôpital VICTOR DUPOUY
city: Bayonne
country: France
facility: Dr Edouard RANDIAMALALA
city: Besançon
country: France
facility: CHU de Besançon
city: Bobigny
country: France
facility: Dr Thorsten BRAUN
city: Boulogne Sur Mer cedex
country: France
facility: CHU Boulogne Sur Mer
city: Caen Cedex
country: France
facility: Chr Clemenceau
city: Clamart
country: France
facility: Hôpital d'Instruction des Armées PERCY
city: Corbeil-essonnes
country: France
facility: Dr Stéphanie HAÏAT
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: CHU de Dijon
city: Le Chesnay cedex
country: France
facility: Centre hospitalier de Versailles
city: Lille cedex
country: France
facility: Hôpital Claude Huriez
city: Limoges cedex
country: France
facility: CHRU Dupuytren
city: Lyon cedex 03
country: France
facility: Hôpital Edouard Herriot
city: Marseille
country: France
facility: Dr Regis COSTELLO
city: Meaux
country: France
facility: Centre Hospitalier de Meaux
city: Mulhouse
country: France
facility: Dr Mario OJEDA-URIBE
city: Nantes
country: France
facility: Dr Jacques DELAUNAY
city: Nice cedex 3
country: France
facility: CHU Nice, Hôpital Archet 1
city: Nîmes
country: France
facility: CHU de Nîmes
city: Paris cedex 12
country: France
facility: Hôpital Saint Antoine
city: Paris cedex 15
country: France
facility: Hôpital Necker Enfants Malades
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hôpital La Pitié Salpêtrière
city: Perpignan
country: France
facility: Dr Laurence SANHES
city: Pessac
country: France
facility: Dr Arnaud PIGNEUX
city: Pontoise Cedex
country: France
facility: Centre Hospitalier René Dubos
city: Rennes
country: France
facility: Marc BERNARD
city: Rouen
country: France
facility: Dr Emilie LEMASLE
city: Saint Cloud
country: France
facility: Centre Hospitalier René Huguenin
city: Saint-Priest-en-Jarez
country: France
facility: Institut de Cancérologie de la Loire
city: Saint-Quentin
country: France
facility: Dr Réda GARIDI
city: Toulouse
country: France
facility: Dr Christian RECHER
city: Valenciennes
country: France
facility: Centre Hospitalier de Valenciennes
Study officials:
affiliation: CH Versailles
name: Rousselot Philippe, Pr
role: PRINCIPAL_INVESTIGATOR
References: