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).

Versailles Hospital62 sites in 2 countries71 target enrollmentAugust 2007

ConditionsLeukemia, Lymphoblastic, Acute

InterventionsDasatinib

DrugsDasatinib

Overview

Phase: Phase 2
Intervention: Dasatinib
Conditions: Leukemia, Lymphoblastic, Acute
Sponsor: Versailles Hospital
Enrollment: 71
Locations: 62
Primary Endpoint: Progression free survival at 12 months
Status: Completed
Last Updated: 9 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

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.
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.
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.
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.

Registry

clinicaltrials.gov

Start Date

August 2007

End Date

January 2016

Last Updated

9 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Versailles Hospital

Responsible Party

Principal Investigator

Philippe ROUSSELOT

study coordinator

Versailles Hospital

Eligibility Criteria

Inclusion Criteria

•Male or female patients ≥ 55 years
•Philadelphia chromosome or BCR-ABL positive acute lymphoblastic leukaemia
•Not previously treated except with corticosteroids or single dose vincristine (three doses cyclophosphamide accepted but not recommended)
•With or without documented CNS involvement
•Signed written inform consent
•Molecular evaluation for BCR-ABL done

Exclusion Criteria

•Patients with ECOG status \> 2
•Patient previously treated with Tyrosine Kinase Inhibitors
•Patients with QTc \> 470 ms
•Heart insufficiency NYHA grade III/IV, LEVF \< 50% and or RF \< 30%, myocardial infarction within the past 6 months prior to study
•Active secondary malignancy
•Patients with active bacterial, viral or fungal infection
•Known infection with HIV, Hepatitis B (except post vaccinal profile) or C
•Treatment with any, other investigational agent or participating in another trial within 30 days prior to entering this study
•Inadequate hepatic functions defined as ASAT or ALAT \> 2,5 times the institutional upper limit of normal and total bilirubin \> 2 fold the institutional upper limit unless considered to be due to organ involvement by the leukemia
•Concurrent severe diseases which exclude the administration of therapy

Arms & Interventions

Treatment Arm

standard treatment + dasatinib

Intervention: Dasatinib

Outcomes

Primary Outcomes

Progression free survival at 12 months

Time Frame: 12 months

Secondary Outcomes

The proportion of Complete haematological remission(5 years)
The proportion of Major molecular response defined by a BCR-ABL/ABL ≤ 0.1% in bone marrow(5 years)
The proportion of Complete molecular response(5 years)
Event free survival(5 years)
Relapse free survival(5 years)
Progression free survival(5 years)
The proportion of Detection of a T315I or F317 BCR-ABL TK mutation(5 years)
The proportion of Molecular progression(5 years)
Overall survival(5 years)
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0(5 years)
Death during induction(2 months)
Death in complete remission(5 years)