Phase III Trial Evaluating the Effectiveness of a Dose Adjustment of Imatinib Mesylate on the Molecular Response

Study Overview
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Brief Summary
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The Imatinib Mesylate at a dose of 400 mg / day is the standard treatment for patients with CML-CP. Recent studies show that the quality of response rate (complete cytogenetic response and major molecular response rate) is dependent on the residual plasma Imatinib.

Detailed Description
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The Imatinib Mesylate at a dose of 400 mg / day is the standard treatment for patients with CML-CP. Recent studies show that the quality of response rate (complete cytogenetic response and major molecular response rate) is dependent on the residual plasma Imatinib. This study aims to evaluate the effectiveness of a strategy for dose adjustment of Imatinib Mesylate based on the measurement of the residual plasma imatinib in patients treated for at least 2 years Imatinib 400 mg / d in complete cytogenetic response for at least 1 year.

Official Title
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Phase III Trial Evaluating the Effectiveness of a Dose Adjustment of IM on the Molecular Response in Patients With LMC in Chronic Phase Treated With IM 400 mg / Day for at Least Two Years, Complete Cytogenetic Response for at Least One Year

Conditions
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Leukemia, Myeloid, Chronic-Phase

Intervention / Treatment
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* Drug: Imatinib Mesylate 600 MG Oral Tablet
* Drug: Imatinib Mesylate 400 MG Oral Tablet
* Drug: Imatinib Mesylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with CML-CP treated for at least two years by Imatinib Mesylate 400 mg / d, Patients in complete cytogenetic response for at least 1 year Patients with residual disease detectable by quantitative RT-PCR (RQ-PCR) ECOG ≤ 2, Age ≥ 18 years Signed informed consent, Membership of a social security system Exclusion Criteria: Patients with CML-CP Philadelphia chromosome negative diagnosis. Patients previously treated with Imatinib Mesylate at doses above 400 mg / day Patient with non-hematologic toxicity of grade III or IV in Imatinib Mesylate 400mg / d Patient with a medical condition endocrine, psychiatric, neurological, renal, hepatic or cardiac progressive uncontrolled by medical treatment Pregnant or breastfeeding women, women of childbearing potential not using a contraceptive method effective Known HIV positive Patients previously treated with another tyrosine kinase inhibitor Patient participating in another interventional clinical trial History of non-compliance to Imatinib Mesylate

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: IM concentration < 1000ng/mL Randomized Cohort : adapted strategy versus standard strategy / IM concentration >= 1000ng/mL Parallel Cohort: standard strategy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imatinib 600 (Randomized trial)<br>Randomized Cohort: Adapted strategy of dosage of Imatinib Mesylate : 600mg/d po | Drug: Imatinib Mesylate 600 MG Oral Tablet<br>* Imatinib Mesylate for CP CML<br>* Other names: GLIVEC;|
| Active Comparator: Imatinib 400 (Randomized trial)<br>Randomized Cohort: Standard strategy of dosage of Imatinib Mesylate : 400mg/d po | Drug: Imatinib Mesylate 400 MG Oral Tablet<br>* Imatinib Mesylate for CP CML<br>* Other names: GLIVEC;|
| Other: Imatinib400 (Cohort)<br>Parallel Cohort: Standard strategy of dosage of Imatinib Mesylate : 400mg/d po | Drug: Imatinib Mesylate<br>* Imatinib Mesylate for CP CML<br>* Other names: GLIVEC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Presenting a Decline of the BCR-ABL Transcript Rate at 12 Months From Baseline - Randomised Study | The BCR-ABL transcript rate was analysed by molecular biology by RQ-PCR at study entry, 3 months, 6 months, 9 months and 12 months. Treatment is considered effective at 12 months if: for patients with an inclusion transcript rate less than 0.1%: the transcript rate at 12 months is less or equal to 0.001% or undetectable. for patients with an inclusion transcript rate greater than 0.1% : the transcript rate at 12 months is less or equal to 0.1% or undetectable. If BCR-ABL transcript level was unavailable at M12, the treatment was considered ineffective. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Decline of 2-log of the BCR-ABL Transcript Rate at 3 ,6, 9 and 12 Months From Baseline - Randomised Study | The BCR-ABL transcript rate was analysed by molecular biology by RQ-PCR at study entry, 3 months, 6 months, 9 months and 12 months. Efficacy was also evaluated at 3, 6, 9 and 12 months in terms of decreasing the rate of BCR-ABL transcripts of 2 logarithms, relative to the initial value (inclusion). The lack of data on the transcript rate was considered as failure (no decrease). | 3, 6, 9 and 12 months | 
| Molecular Response at 3, 6, 9 and 12 Months | The molecular response is defined by the measurement of BCR-ABL transcript rate by quantitative RT-PCR (RQ-PCR) on peripheral venous blood according to international standards. It is defined as: Major Molecular Response (MMR): BRC-ABL transcript rate ≤ 0.1% Complete Molecular Response (CMR): transcript BCR-ABL undetectable and non quantifiable. | 3, 6, 9 and 12 months | 
| Time to Complete Molecular Response (CMR) and Major Molecular Response (MMR) | Time to complete molecular response was defined by the time from inclusion/randomization and the first CMR. | From date of randomization until the date of complete molecular response (up to 12 months) | 
| Rate of BCR-ABL Undetectable | The BCR-ABL transcript rate was analysed by molecular biology by RQ-PCR at study entry, 3 months, 6 months, 9 months and 12 months. | 12 first months | 
| Time to the First BCR-ABL Undetectable | The BCR-ABL transcript rate was analysed by molecular biology by RQ-PCR at study entry, 3 months, 6 months, 9 months and 12 months. Time to the first BCR-ABL undetectable was defined by the time from inclusion/randomization and the first CMR. | within 12 months following randomization | 
| Overall Survival | Overall survival is defined by the time from de date of inclusion/randomization to the date of death (of any cause). | First 12 months | 
| Progression-free Survival | Progression-free survival was defined by the time from the date of inclusion and the date of progression. Progression was defined as : Death, Passage into the acceleration phase defined by one of the following criteria: % of blood or medullary blasts greater than 15% but less than 30%, blasts plus promyelocytes greater than 30% in the blood or marrow, basophils greater than 20% in the blood, thrombocytopenia less than 100x10^9/L unrelated to treatment, clonal evolution) Passage to the blast transformation phase defined by one of the following criteria: % of blasts of blood or bone marrow greater than 30%, occurrence of extramedullary damage other than histologically proven hepato-splenic. Increase in BCR-ABL transcripts greater than or equal to 2-log compared to the previous values (this increase must be confirmed within 3 months). | First 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic myeloid leukemia in chronic phase, residual plasma IM concentration, adapted strategy