Safety and Efficacy of Ponatinib Followed by Imatinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase

NCT ID: NCT04070443

Last Updated: 2025-11-18

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 170 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-13
• Study Completion Date: 2029-06-01

Brief Summary

The investigators hypothesize that, in newly diagnosed de novo chronic phase CML patients, an induction treatment with ponatinib for 6 months should increase the rate of patients reaching a stable MR4.5 allowing cessation of imatinib treatment.

The investigators proposal is to conduct a multicenter, Phase II trial to evaluate the safety, clinical and biological activity of an induction treatment with ponatinib for 6 months, followed by a consolidation treatment with imatinib in newly diagnosed de novo chronic phase CML patients.

Detailed Description

TREATMENT PLAN :

All eligible patients will be treated:

• During the induction Phase (Month 1 to Month 6) with ponatinib (30mg/day) single agent; then
• During the consolidation Phase (Month 7 to Month 36) with imatinib (400mg/day) single agent; then
• From M36 :

• Patients with stable MR4.5 (i.e. since at least 2 years) will enter in the TFR phase and will stop imatinib treatment. Thereafter, in case of MMR loss, imatinib will be re-introduced as per investigator judgement (including for dose).
• Patients without stable MR4.5 will continue imatinib treatment until stable MR4.5, or M60, PD, death, withdrawal of consent or overall trial completion. Such patients will be allowed to enter into the TFR phase as soon as a stable 2-year MR4.5 is reached: however, they will be considered as a failure for the primary endpoint analysis.

STATISTICS :

A total of 170 patients will be enrolled in this study.

According to a Fleming design, with a P0=20% as minimal efficacy rate and P1=30% as an expected target, 156 patients should be enrolled, assuming an unilateral type I error alpha of 5% and 90% power. At the time of analysis, if at least 40 successes are observed among the 156 evaluable patients, the treatment will be considered as interesting for further investigation in this indication. Considering that some patients may withdraw their consent before 36 months (about 10%), the investigators plan to enrol 170 patients in total.

DATA ENTRY, DATA MANAGEMENT AND STUDY MONITORING All the data concerning the patients will be recorded in the electronic case report form (eCRF) throughout the study. Serious adverse event (SAE) and Adverse Event of Specific Interest (AESI) reporting will be also paper-based by e-mail and/or Fax.

The sponsor will perform the study monitoring and will help the investigators to conduct the study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local law requirements.

Conditions

Philadelphia Chromosome Positive CML; BCR-ABL Positive Chronic Myelogenous Leukemia

Study Design

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

Study Groups

Induction phase with Ponatinib followed by Imatinib

Ponatinib (Iclusig®) : Tyrosine Kinase Inhibitor (BCR-ABL); oral (tablets) : 30mg/day during 6 months (induction phase); Takeda & Incyte Biosciences.

Imatinib (either Glivec® or any generic form) : Tyrosine Kinase Inhibitor (BCR-ABL, ABL, KIT and PDGFRA receptor tyrosine kinases); oral : 400 mg/day during at least 30 months (then, depending of MR4.5)

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

30mg/day; 6 months. Dose adaptation procedures are planned in case of toxicity.

Imatinib

Intervention Type: DRUG

400 mg/day; at least 30 months (M7 to M36), then depending of MR4.5 . Dose adaptation procedures are planned in case of toxicity.

Interventions

Ponatinib

30mg/day; 6 months. Dose adaptation procedures are planned in case of toxicity.

Intervention Type: DRUG

Imatinib

400 mg/day; at least 30 months (M7 to M36), then depending of MR4.5 . Dose adaptation procedures are planned in case of toxicity.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Male or female patients aged ≥18 and ≤65 years at time of inform consent signature.
• Cytologically confirmed CML, Philadelphia chromosome positive with or without additional chromosomal abnormalities and/or BCR-ABL positive (Major BCR (M-BCR) transcript exclusively), i. e. Cryptic Philadelphia chromosome patients can be enrolled:

• diagnosed within the past 3 months prior to D1 (i.e. within 60 days [± 7 days] since the date of first cytogenetic analysis),
• in chronic phase defined by i) <15 % blasts in peripheral blood and bone marrow, ii) < 30% blast plus promyelocytes in peripheral blood and bone marrow; iii) < 20 % basophils in peripheral blood and iv) ≥100 X 109 platelets/L in peripheral blood,
• no extra-medullary disease.
• All EUTOS long-term survival Scores.
• No prior treatment for CML with any tyrosine kinase inhibitor (eg. imatinib, dasatinib, nilotinib or bosutinib), or busulphan; interferon-alpha; homoharringtonine; cytosine arabinoside; or any other investigational agent; with the exception of hydroxyurea and/or anagrelide which are the only authorized prior treatments.

Note: Hydroxyurea should be stopped at least 24 hours prior the initiation of ponatinib.

• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2.
• Adequate organ functions as defined below according to lab tests performed within 7 days before Day 1:

Renal function:

• Serum creatinine clearance ≥ 50 mL/min/1.73m2 according to CKD-EPDI formula or serum creatinine ≤ 2 upper limit of normal (ULN).

Hepatic function:

• Serum bilirubin < 1.5 × ULN, with the following exception: Patients with known Gilbert disease who have serum bilirubin level ≤ 3 ULN may be enrolled.
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤ 2.5 ULN.
• Amylase or Lipase ≤ 1.5 × ULN Total cholesterol ≤1.5 ULN

• Women of child-bearing potential must have a negative serum pregnancy test within 7 days before study drug start and must agree to use an effective form of contraception from the time of the negative pregnancy test up to 3 months after the last dose of study treatments.
• Fertile men must agree to use an effective method of contraception during the study and for up to 3 months after the last dose of study treatments.
• Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
• Patients must be covered by a medical insurance.

Exclusion Criteria

• Any form of prior auto- or allo-hemopoietic stem cell transplant.
• Hypersensitivity to the active substance or to any of the excipients of ponatinib and imatinib (see respective IB/SmPC).
• Inability to take oral medication including malabsorption syndrome or other illness that could affect oral absorption of the study treatments (hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption).
• Patients using, or requiring to use while on the study of any not permitted concomitant medications:

• Any approved anti-cancer systemic treatment including chemotherapy, targeted therapy, immunotherapy or any biological therapy,
• Any investigational agents,
• Any treatment able to induce " torsades de pointes ",
• Any strong inducers and inhibitors of CYP3A4.
• Patients with a malignancy other than CP-CML within 5 years prior to Day 1 with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated in situ carcinoma of the cervix, basal or squamous cell skin cancer, localised prostate cancer or ductal in situ carcinoma treated surgically with curative intent).
• Patients with active B or C hepatitis infection. Notes: Patients with past Hepatitis B Virus (HBV) infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen (HBsAg) test and a positive hepatitis B core antibody (HBcAb) test) are eligible.

Patients with a positive HBcAb test must have a negative HBV DNA test at screening.

Patients positive for Hepatitis C Virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

• Patients with significant cardiovascular disease, such as New York Heart Association cardiac disease Class II or greater, myocardial infarction within 3 months prior to D1, unstable arrhythmias, unstable angina, peripheral arterial occlusive disease, venous thromboembolism or pulmonary embolism, brain stroke, evolutive ischemic cardiopathy; prolonged corrected QT interval (QTc) interval on baseline electrocardiogram (>450 msec on the Fridericia's correction) despite correction of predisposants factors; long congenital QT syndrome.
• Any of the following medical conditions despite adequate therapeutic management:

• Uncontrolled HTA despite adequate ongoing treatment.
• Diabetes with documented target organ damage.
• Pregnant or lactating women.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre Leon Berard

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Franck-Emmanuel NICOLINI, MD

Role: PRINCIPAL_INVESTIGATOR

Centre Leon Berard

Locations

Chu Amiens Picardie

Amiens, , France

CHU d'Angers

Angers, , France

Centre Hospitalier Annecy-Genevois

Annecy, , France

CH d'Avignon

Avignon, , France

Chru Besançon

Besançon, , France

Institut Bergonie

Bordeaux, , France

Chru Brest

Brest, , France

Institut D'Hematologie de Basse Normandie

Caen, , France

Chu D'Estaing

Clermont-Ferrand, , France

Centre Hospitalier Sud Francilien

Corbeil-Essonnes, , France

Hopital Henri Mondor

Créteil, , France

CHU de Grenoble

Grenoble, , France

CH de Versailles - Hôpital André Mignot

Le Chesnay, , France

Hôpital Claude Huriez - CHRU de Lille

Lille, , France

CHU Limoges - Hôpital Dupuytren

Limoges, , France

Centre Léon Bérard

Lyon, , France

Institut Paoli Calmettes

Marseille, , France

Hopital Saint Eloi

Montpellier, , France

Chu Hotel Dieu

Nantes, , France

CHU Nîmes Caremeau - Institut de Cancérologie du Gard

Nîmes, , France

Hopital Saintantoine

Paris, , France

Chu Poitiers

Poitiers, , France

Chu - Hopital de Pontchaillou

Rennes, , France

Institut de Cancérologie Lucien Neuwirth

Saint-Priest-en-Jarez, , France

CHU Strasbourg

Strasbourg, , France

Iuct Toulouse - Oncopole

Toulouse, , France

CHRU Nancy/Brabois

Vandœuvre-lès-Nancy, , France

Hopital Paul Brousse

Villejuif, , France

Countries

France

Other Identifiers

ET18000120 (TIPI)

Identifier Type: -

Identifier Source: org_study_id