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

  • STATUS
    Recruiting
  • End date
    Jun 1, 2027
  • participants needed
    170
  • sponsor
    Centre Leon Berard
Updated on 22 July 2021
imatinib
tyrosine
philadelphia chromosome
busulfan
hydroxyurea
cytarabine
dasatinib
ponatinib
bosutinib
lipase
interferon
leukemia
kinase inhibitor
nilotinib
anagrelide
chronic phase chronic myeloid leukemia
basophils

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.

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.

Details
Condition Chronic myeloid leukemia, Philadelphia Chromosome Positive CML, philadelphia chromosome positive chronic myelogenous leukemia
Treatment Imatinib, Ponatinib
Clinical Study IdentifierNCT04070443
SponsorCentre Leon Berard
Last Modified on22 July 2021

Eligibility

Yes No Not Sure

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 2 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 or triglycerides 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
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