OPTIM DASATINIB (Optimized Tyrosine Kinase Inhibitors Monotherapy)

Study Overview
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Brief Summary
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This protocol is a multicentric interventional phase II study from the French CML Intergroup (FILMC). The core of the protocol is to explore the efficacy and safety of an optimization strategy consisting in the modulation of the dasatinib daily dose according to the results of repeated plasmatic levels of dasatinib. The objective of this strategy is to improve the overall results of the treatment of early CP-CML in order to avoid the development of resistance and BCR-ABL tyrosine kinase mutations. The study will be conducted in selected FILMC and Canadian centers. The study is sponsored by the Hôpitaux de Versailles and supported by Bristol-Myers Squibb. The dasatinib treatment will be provided by Bristol-Myers Squibb until marketing authorization is granted in that indication.

Official Title
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A PROSPECTIVE RANDOMIZED PHASE II STUDY EVALUATING THE OPTIMIZATION OF THE RESIDUAL PLASMATIC LEVEL OF DASATINIB (SPRYCEL®) IN PATIENTS NEWLY DIAGNOSED WITH CHRONIC PHASE CHRONIC MYELOGENOUS LEUKAEMIA (CP-CML).

Conditions
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Chronic Myelogenous Leukemia, BCR/ABL Positive

Intervention / Treatment
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* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient ≥ 18 years ECOG Performance Status score 0-2 Philadelphia chromosome positive newly diagnosed (≤ 3 months) CP-CML patients not previously treated except with hydroxyurea or imatinib (less than 4 weeks for imatinib) Signed written inform consent Adequate hepatic function defined as: total bilirubin ≤ 2.0 times the institutional ULN; ALT and AST ≤ 2.5 times the institutional upper limit of normal (ULN). Adequate renal function defined as serum creatinine ≤ 3 times the institutional ULN. 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 a tyrosine kinase inhibitor (TKI) except with imatinib during less than 4 weeks. Pregnancy Active malignancy Uncontrolled or significant cardiovascular disease Patients with QTc > 450 ms Significant bleeding disorder unrelated to CML 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1<br>Arm A1: Dasatinib dose adjustment based on Cmin ≥3nM value analysed on blood after 7-10 days dasatinib 100mg intake | Drug: Dasatinib<br>* Dasatinib is a multitargeted tyrosine kinase inhibitor with a 300-fold more potent activity on the BCR-ABL tyrosine kinase in vitro compared to imatinib mesylate<br>* Other names: Sprycel®;|
| Active Comparator: A2<br>Arm A2: Dasatinib standard dose (100mg/d) with Cmin ≥ 3nM analysed on blood after 7-10 days dasatinib 100mg intake | Drug: Dasatinib<br>* Dasatinib is a multitargeted tyrosine kinase inhibitor with a 300-fold more potent activity on the BCR-ABL tyrosine kinase in vitro compared to imatinib mesylate<br>* Other names: Sprycel®;|
| Active Comparator: B<br>Arm B : Dasatinib standard dose with Cmin < 3nM analysed on blood after 7-10 days dasatinib 100mg intake | Drug: Dasatinib<br>* Dasatinib is a multitargeted tyrosine kinase inhibitor with a 300-fold more potent activity on the BCR-ABL tyrosine kinase in vitro compared to imatinib mesylate<br>* Other names: Sprycel®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative rate of significant AE | The cumulative rate of serious AEs defined by grade 3-4 fluid retention, all grade pleural effusion, haematological grade 3-4 AEs related to dasatinib and/or all AE leading to dasatinib discontinuation within the first year of therapy | 12 months therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of treatment interruptions | To compare the rate of treatment interruptions | 12 months therapy | 
| Cumulative duration of dasatinib interruption | To compare the cumulative duration of dasatinib interruption C. To compare the median dose of dasatinib administered during the first 12 months | 12 months therapy | 
| Mean dose of dasatinib | To compare the mean dose of dasatinib administered during the first 12 months | 12 months therapy | 
| Cumulative rate of complete cytogenetic response | To compare the cumulative rate of complete cytogenetic response (CCR) at 6, 12 and 18 months, and every 12 months thereafter | 12 months therapy | 
| Cumulative rate of major molecular response | To compare the cumulative rate of major molecular response (MMR) at 3, 6, 12, and 18 months, and every 6 months thereafter | 12 months therapy | 
| Median dose of dasatinib administered | To compare the median dose of dasatinib administered during the first 12 months | 12 months therapy | 
| Cumulative rate of complete molecular response | To compare the cumulative rate of complete molecular response at 3, 6, 12 and 18 months, and every 6 months thereafter | 12 months therapy | 
| Time to molecular response | To compare the time to molecular response (major or complete) | 12 months therapy | 
| Relationship between peak plasmatic level and efficacy | To analyse the relationship between peak plasmatic level (Cmax) and efficacy in the three arms | 12 months therapy | 
| Relationship between through plasmatic level and efficacy | To analyse the relationship between through plasmatic level (Cmin) and efficacy in the three arms | 12 months therapy | 
| Progression-free survival at 5 years | To compare the progression-free survival (PFS) at 5 years in the three arms | 12 months therapy | 
| Overall survival at 5 years | To compare the overall survival at 5 years in the three arms | 12 months therapy | 
| Lymphocyte populations before and during dasatinib therapy | To analyse lymphocyte populations before and during dasatinib therapy (for French participating centers - see appendix 14). | 12 months therapy | 
| Rate of sustained major molecular remission after dasatinib discontinuation in patients in complete molecular response | To evaluate the rate of sustained major molecular remission after dasatinib discontinuation in patients in complete molecular response, CMR (undetectable BCR-ABL transcript, BCR-ABL/ABL IS ratio < 1x10-5) | 12 months therapy |