Chronic Myelogenous Leukemia, BCR/ABL Positive
Conditions
Brief summary
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.
Interventions
DRUGDasatinib
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
Sponsors
Versailles Hospital
Maisonneuve-Rosemont Hospital
University Hospital, Bordeaux
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patient ≥ 18 years 2. ECOG Performance Status score 0-2 3. Philadelphia chromosome positive newly diagnosed (≤ 3 months) CP-CML 4. patients not previously treated except with hydroxyurea or imatinib (less than 4 weeks for imatinib) 5. Signed written inform consent 6. 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). 7. Adequate renal function defined as serum creatinine ≤ 3 times the institutional ULN. 8. Women of childbearing potential (WOCBP) must be using an adequate method of contraception.
Exclusion criteria
1. Patients with BCR-ABL positive, Philadelphia negative CML 2. Patient previously treated with a tyrosine kinase inhibitor (TKI) except with imatinib during less than 4 weeks. 3. Pregnancy 4. Active malignancy 5. Uncontrolled or significant cardiovascular disease 6. Patients with QTc \> 450 ms 7. Significant bleeding disorder unrelated to CML 8. Concurrent severe diseases which exclude the administration of therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative rate of significant AE | 12 months therapy | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of treatment interruptions | 12 months therapy | To compare the rate of treatment interruptions |
| Cumulative duration of dasatinib interruption | 12 months therapy | To compare the cumulative duration of dasatinib interruption C. To compare the median dose of dasatinib administered during the first 12 months |
| Mean dose of dasatinib | 12 months therapy | To compare the mean dose of dasatinib administered during the first 12 months |
| Cumulative rate of complete cytogenetic response | 12 months therapy | To compare the cumulative rate of complete cytogenetic response (CCR) at 6, 12 and 18 months, and every 12 months thereafter |
| Cumulative rate of major molecular response | 12 months therapy | To compare the cumulative rate of major molecular response (MMR) at 3, 6, 12, and 18 months, and every 6 months thereafter |
| Median dose of dasatinib administered | 12 months therapy | To compare the median dose of dasatinib administered during the first 12 months |
| Cumulative rate of complete molecular response | 12 months therapy | To compare the cumulative rate of complete molecular response at 3, 6, 12 and 18 months, and every 6 months thereafter |
| Time to molecular response | 12 months therapy | To compare the time to molecular response (major or complete) |
| Relationship between peak plasmatic level and efficacy | 12 months therapy | To analyse the relationship between peak plasmatic level (Cmax) and efficacy in the three arms |
| Relationship between through plasmatic level and efficacy | 12 months therapy | To analyse the relationship between through plasmatic level (Cmin) and efficacy in the three arms |
| Progression-free survival at 5 years | 12 months therapy | To compare the progression-free survival (PFS) at 5 years in the three arms |
| Overall survival at 5 years | 12 months therapy | To compare the overall survival at 5 years in the three arms |
| Lymphocyte populations before and during dasatinib therapy | 12 months therapy | To analyse lymphocyte populations before and during dasatinib therapy (for French participating centers - see appendix 14). |
| Rate of sustained major molecular remission after dasatinib discontinuation in patients in complete molecular response | 12 months therapy | 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) |
Countries
Canada, France
Contacts
PRINCIPAL_INVESTIGATORPhilippe ROUSSELOT, Professeur hémato-oncologie
Versailles Hospital
Outcome results
None listed