Leukemia, Lymphoblastic, Acute Clinical Trial
Official title:
An Open Label Phase II Study to Evaluate the Efficacy and Safety of Induction and Consolidation Therapy With Dasatinib in Combination With Chemotherapy in Patients Aged 55 Years and Over With Philadelphia Chromosome Positive (Ph+ or BCR-ABL+) Acute Lymphoblastic Leukemia (ALL).
1. The use of imatinib in combination or in association with chemotherapy is now
considered as the gold standard for the treatment of Ph+ ALL. The complete remission
(CR) rate is 90% versus 20% to 40% with chemotherapy alone. The combination of
imatinib, vincristine and dexamethasone is a well tolerated regimen in aged patients
and is also associated with a high CR rate of 80% to 90% in patient aged 55 years and
over.
2. However, despite high CR rates, the progression free survival rate at 12 months of
patients treated with the combination of imatinib and chemotherapy is 30% to 50%.
Relapses remain frequent and only patients intensified with allogenic haematopoietic
stem cell transplantation are in long term remission. This strategy is not fully
applicable to most patients aged 55 years and over.
3. Relapses after or during imatinib therapy in patients with Ph+ ALL are associated with
BCR-ABL tyrosine kinase domain mutation in 80% of cases, predominantly of the p-loop.
The exact incidence of the T315I mutation is controversial and can be estimated to be
near 50%. Conversely, the detection of the T315I or F317 mutation in a patient is a
very strong predictor of relapse.
4. Dasatinib is a potent SCR and BCR-ABL tyrosine kinase inhibitor with preserved in vitro
activity in most of the BCR-ABL mutated cell lines, except for the T315I and F317
mutations. This is also the case in vivo, with patients harbouring BCR-ABL TK domain
mutations remaining sensitive to dasatinib. The CHR rate in Ph+ ALL resistant to
imatinib is 33% and the median progression-free survival is 3.7 months. Progression
free survival (PFS) rate at 12 months is 22%.
The goal of this trial is to evaluate the efficacy and the tolerance of the combination of
dasatinib with chemotherapy in the front-line setting as induction and consolidation therapy
in Ph+ ALL patient aged 55 years and over. A European consensus has been reached to adopt a
common chemotherapeutic schedule for patients aged 55 years and over. This schedule will be
used in this trial with the addition of dasatinib as concomitant therapy during induction
and alternating with chemotherapy during consolidation and maintenance. A CR rate of 90% and
a progression free survival of 60% at 12 months are expected. The patients will be
prospectively monitored for minimal residual disease and mutation.
n/a
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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