Dasatinib and Low Intensity Chemotherapy for Ph+ Acute Lymphoblastic Leukemia
- Registration Number
- NCT02888990
- Lead Sponsor
- Versailles Hospital
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 71
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment Arm Dasatinib standard treatment + dasatinib
- Primary Outcome Measures
Name Time Method Progression free survival at 12 months 12 months
- Secondary Outcome Measures
Name Time Method 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
Trial Locations
- Locations (62)
Cliniques Universitaires Saint-Luc
🇧🇪Bruxelles, Belgium
CHU Ambroise Paré
🇧🇪Mons, Belgium
Centre Hospitalier Départemental FELIX GUYON
🇫🇷St Denis, La Reunion, France
Ch D'Aix En Provence
🇫🇷Aix en provence, France
Groupe Hospitalier Sud
🇫🇷Amiens, France
CHU Angers
🇫🇷Angers, France
Chr Annecienne
🇫🇷Annecy, France
CHG D'Avignon Henri Duffaut
🇫🇷Avignon, France
Ch Victor Dupouy
🇫🇷Argenteuil, France
IGR
🇫🇷Villejuif, France
Ospedale San Gerardo
🇮🇹Monza, Italy
Hôpital de la Source
🇫🇷Orléans, France
Cochin
🇫🇷Paris, France
Necker
🇫🇷Paris, France
Pitie Salpetrière
🇫🇷Paris, France
St Antoine
🇫🇷Paris, France
CHU Mileterie
🇫🇷Poitiers, France
Hopital R Debre
🇫🇷Reims, France
CH Victor PROVO
🇫🇷Roubaix, France
Centre HENRI BECQUEREL
🇫🇷Rouen, France
Institut de Cancérologie de la Loire
🇫🇷Saint-priest-en-jarez, France
centre rene Huguenin
🇫🇷St Cloud, France
CHU Hautepierre
🇫🇷Strasbourg, France
CHU Tours
🇫🇷Tours, France
CH Brabois
🇫🇷Vandoeuvre Les Nancy, France
Hôpital de PURPAN
🇫🇷Toulouse, France
C.H. de la Côte Basque
🇫🇷Bayonne, France
Hôpital JEAN MINJOZ
🇫🇷Besancon, France
Avicenne
🇫🇷Bobigny, France
Hôpital CLEMENCEAU
🇫🇷Caen, France
Hôpital PASTEUR
🇫🇷Colmar, France
Hôpital du BOCAGE
🇫🇷Dijon, France
CH Versailles
🇫🇷Le Chesnay, France
IPC
🇫🇷Marseille, France
CH E Muller
🇫🇷Mulhouse, France
CHU Nimes
🇫🇷Nimes, France
Ospedali Riuniti di Bergamo
🇮🇹Bergamo, Italy
HIA Percy
🇫🇷Clamart, France
CH Dunkerque
🇫🇷Dunkerque, France
Hôpital A. MICHALLON
🇫🇷Grenoble, France
Archet 1
🇫🇷Nice, France
Robert Bosch-Krankenhaus
🇩🇪Stuttgart, Germany
Hotel Dieu
🇫🇷Valenciennes, France
CH Blois
🇫🇷Blois, France
CHU Brest
🇫🇷Brest, France
Centre Hospitalier Sud Francilien
🇫🇷Corbeil Essonnes, France
Hôpital LAPEYRONIE
🇫🇷Montpellier, France
CH Meaux
🇫🇷Meaux, France
Hôpital Notre Dame de Bon Secours
🇫🇷Metz, France
Hopital Lyon Sud
🇫🇷Pierre Benite, France
Hôpital de PONTCHAILLOU
🇫🇷Rennes, France
Hopital St louis
🇫🇷Paris, France
Henry Mondor
🇫🇷Creteil, France
CH Lens
🇫🇷Lens, France
Hopital Claude Huriez
🇫🇷Lille, France
Hôpital Dupuytren
🇫🇷Limoges, France
CH Perpignan
🇫🇷Perpignan, France
Hôpital du HAUT LEVEQUE
🇫🇷Pessac, France
Edouard Herriot
🇫🇷Lyon, France
HIA Ste Anne
🇫🇷Toulon, France
St. Johannes-Hospital
🇩🇪Duisburg, Germany
Dipartimento Oncologico La Maddalena
🇮🇹Palermo, Italy