A Prospective Randomized Phase II Study Evaluating the Monitoring of Imatinib Mesylate Plasmatic Through Level in Patients Newly Diagnosed With CP-CML

Study Overview
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Brief Summary
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Imatinib mesylate (Gleevec/Glivec, IM) is currently the gold standard or CML-CP front line therapy. The recommended dose of IM is 400 mg/day. The rates of complete cytogenetic responses at 3, 6 and 12 months are 27%, 50% and 69% respectively. The optimal IM daily dose is not yet determined and randomized studies addressing this question are on-going. First results from the TOPS trial (EHA 2008 congress) suggest a more rapid kinetic of response for patients treated with imatinib high dose. Recent studies revealed that initial Imatinib plasmatic dosage is predictive for achieving complete cytogenetic responses (CCR) and that a dosage of 1000 ng/ml is associated with a higher proportion of major molecular responses (MMR) (Picard et al., Blood 2007, Larson et al. Blood 2007). Results from the study of Larson et al. indicate that around 40% of the patients had a trough plasmatic level below 1000 ng/ml after day 28 of imatinib 400 mg/d. The major molecular response rate at 12 months for the patients with the lower plasmatic through level is 25.4% compared to 40.1% for the patients with a plasmatic dosage over 800 to 1000 ng/ml. Investigators propose to adapt the imatinib daily dose in case of imatinib through plasmatic level at day 28 below 1000 ng/ml. Patients with a trough plasmatic dosage ≤ 1000 ng/ml will be randomized between a prospective adaptation strategy of the imatinib daily dose (cohort 1) versus observation only (cohort 2). The patients with adequate imatinib dosage (> 1000 ng/ml) will be followed up according the ELN recommendation (cohort 3). Imatinib trough plasmatic level will then be rechecked every month thereafter for patients in cohort 1 and cohort 2 and every three months in cohort 3. The first endpoint of the study will be the rate of major molecular response at 12 months in cohort 1. Our hypothesis is to improve the 12 months MMR rate with the optimized strategy (cohort 1) from 25% of MMR at 12 months to 40% of MMR at 12 months.

Official Title
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A Prospective Randomized Phase II Study Evaluating the Monitoring of Imatinib Mesylate (Glivec®) Plasmatic Through Level in Patients Newly Diagnosed With Chronic Phase Chronic Myelogenous Leukaemia (CP-CML).

Conditions
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Intervention / Treatment
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* Drug: Posology dose modification
* Other: active comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient ≥ 18 years Philadelphia chromosome positive newly diagnosed chronic myelogenous leukaemia (≤ 4 months) in first chronic phase. Not previously treated with tyrosine kinase inhibitors other than imatinib Prior treatment with imatinib during less than 13 weeks Signed written inform consent Women of childbearing potential (WOCBP) must be using an adequate method of contraception Exclusion Criteria: Patients with BCR-ABL positive, Philadelphia negative CML Patient previously treated with TKI other than imatinib Pregnancy Active malignancy Concurrent severe diseases which exclude the administration of therapy

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control Arm<br>cohort 3: Imatinib through dosage ≥ 1000 ng/ml | |
| Active Comparator: Active comparator<br>Cohort 2 : Imatinib standard dose Imatinib through dosage < 1000 ng/ml | Other: active comparator<br> <br> * Other names: Cohort 2 : Imatinib standard dose;|
| Experimental: Experimental arm<br>Cohort 1 : dose adjustment based on trough plasmatic level value Imatinib through dosage < 1000 ng/ml | Drug: Posology dose modification<br> <br> * Other names: Cohort 1 : dose adjustment based on trough plasmatic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The major molecular response rate at 12 months in cohort 1. |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete cytogenetic response at 6 and 12 months |  | 12 months | 
| Major molecular response rate at 12 months in cohort 2 and cohort 3. |  | 12 months | 
| Major molecular response at 3, 6, and 9 months |  | 9 months | 
| Complete molecular response 6 and 12 months |  | 12 months | 
| Relationship between plasmatic dosage and efficacy |  | 12 months | 
| Relationship between plasmatic dosage and tolerance |  | 12 months | 
| Progression free survival |  | 5 years | 
| Event free survival |  | 5 years | 
| Overall survival |  | 5 years |