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

STATUS

Recruiting
End date

Jun 1, 2029
participants needed

170
sponsor

Centre Leon Berard

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Updated on 18 February 2022

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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	Philadelphia Chromosome Positive CML, BCR-ABL Positive Chronic Myelogenous Leukemia
Treatment	Imatinib, Ponatinib
Clinical Study Identifier	NCT04070443
Sponsor	Centre Leon Berard
Last Modified on	18 February 2022

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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 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
	Note: Hydroxyurea should be stopped at least 24 hours prior the initiation of
	homoharringtonine; cytosine arabinoside; or any other investigational agent
	ponatinib
	Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2
	with the exception of hydroxyurea and/or anagrelide which are the only
	Adequate organ functions as defined below according to lab tests performed within 7 days before Day 1
	authorized prior treatments
	Renal function
	Hepatic function
	Serum creatinine clearance ≥ 50 mL/min/1.73m2 according to CKD-EPDI formula or serum creatinine ≤ 2 upper limit of normal (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
	Serum bilirubin < 1.5 × ULN, with the following exception: Patients with known Gilbert disease who have serum bilirubin level ≤ 3 ULN may be enrolled
	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
	Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤ 2.5 ULN
	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
	Amylase or Lipase ≤ 1.5 × ULN Total cholesterol ≤1.5 ULN
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 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 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
	Any of the following medical conditions despite adequate therapeutic management
	of the cervix, basal or squamous cell skin cancer, localised prostate cancer
	or ductal in situ carcinoma treated surgically with curative intent)
	Uncontrolled HTA despite adequate ongoing treatment
	Diabetes with documented target organ damage
	Pregnant or lactating women
	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

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