Clinical trial NCT02888990: Dasatinib and Low Intensity Chemotherapy for Ph+ Acute Lymphoblastic Leukemia
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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia, Lymphoblastic, Acute
Lead sponsor: Versailles Hospital
Sponsor class: OTHER
First posted: 2016-09-05
Enrollment: 71
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

1. Patients with ECOG status \> 2
2. Patient previously treated with Tyrosine Kinase Inhibitors
3. Patients with QTc \> 470 ms
4. Heart insufficiency NYHA grade III/IV, LEVF \< 50% and or RF \< 30%, myocardial infarction within the past 6 months prior to study
5. Active secondary malignancy
6. Patients with active bacterial, viral or fungal infection
7. Known infection with HIV, Hepatitis B (except post vaccinal profile) or C
8. Treatment with any, other investigational agent or participating in another trial within 30 days prior to entering this study
9. 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
10. Concurrent severe diseases which exclude the administration of therapy

Primary outcomes:
measure: Progression free survival at 12 months
timeFrame: 12 months
Secondary outcomes:
measure: The proportion of Complete haematological remission
timeFrame: 5 years
measure: The proportion of Major molecular response defined by a BCR-ABL/ABL ≤ 0.1% in bone marrow
timeFrame: 5 years
measure: The proportion of Complete molecular response
timeFrame: 5 years
measure: Event free survival
timeFrame: 5 years
measure: Relapse free survival
timeFrame: 5 years
measure: Progression free survival
timeFrame: 5 years
measure: The proportion of Detection of a T315I or F317 BCR-ABL TK mutation
timeFrame: 5 years
measure: The proportion of Molecular progression
timeFrame: 5 years
measure: Overall survival
timeFrame: 5 years
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 5 years
measure: Death during induction
timeFrame: 2 months
measure: Death in complete remission
timeFrame: 5 years
Other outcomes:
Locations:
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Mons
country: Belgium
facility: CHU Ambroise Paré
city: St Denis
country: France
facility: Centre Hospitalier Départemental FELIX GUYON
state: La Reunion
city: Aix en provence
country: France
facility: Ch D'Aix En Provence
city: Amiens
country: France
facility: Groupe Hospitalier Sud
city: Angers
country: France
facility: CHU Angers
city: Annecy
country: France
facility: Chr Annecienne
city: Argenteuil
country: France
facility: Ch Victor Dupouy
city: Avignon
country: France
facility: CHG D'Avignon Henri Duffaut
city: Bayonne
country: France
facility: C.H. de la Côte Basque
city: Besancon
country: France
facility: Hôpital JEAN MINJOZ
city: Blois
country: France
facility: CH Blois
city: Bobigny
country: France
facility: Avicenne
city: Brest
country: France
facility: CHU Brest
city: Caen
country: France
facility: Hôpital CLEMENCEAU
city: Clamart
country: France
facility: HIA Percy
city: Clermont ferrand
country: France
facility: Hotel Dieu
city: Colmar
country: France
facility: Hôpital PASTEUR
city: Corbeil Essonnes
country: France
facility: Centre Hospitalier Sud Francilien
city: Creteil
country: France
facility: Henry Mondor
city: Dijon
country: France
facility: Hôpital du BOCAGE
city: Dunkerque
country: France
facility: CH Dunkerque
city: Grenoble
country: France
facility: Hôpital A. MICHALLON
city: Le Chesnay
country: France
facility: CH Versailles
city: Lens
country: France
facility: CH Lens
city: Lille
country: France
facility: Hopital Claude Huriez
city: Limoges
country: France
facility: Hôpital Dupuytren
city: Lyon
country: France
facility: Edouard Herriot
city: Marseille
country: France
facility: IPC
city: Meaux
country: France
facility: CH Meaux
city: Metz
country: France
facility: Hôpital Notre Dame de Bon Secours
city: Montpellier
country: France
facility: Hôpital LAPEYRONIE
city: Mulhouse
country: France
facility: CH E Muller
city: Nantes
country: France
facility: Hotel Dieu
city: Nice
country: France
facility: Archet 1
city: Nimes
country: France
facility: CHU Nimes
city: Orléans
country: France
facility: Hôpital de la Source
city: Paris
country: France
facility: Cochin
city: Paris
country: France
facility: Hopital St louis
city: Paris
country: France
facility: Necker
city: Paris
country: France
facility: Pitie Salpetrière
city: Paris
country: France
facility: St Antoine
city: Perpignan
country: France
facility: CH Perpignan
city: Pessac
country: France
facility: Hôpital du HAUT LEVEQUE
city: Pierre Benite
country: France
facility: Hopital Lyon Sud
city: Poitiers
country: France
facility: CHU Mileterie
city: Reims
country: France
facility: Hopital R Debre
city: Rennes
country: France
facility: Hôpital de PONTCHAILLOU
city: Roubaix
country: France
facility: CH Victor PROVO
city: Rouen
country: France
facility: Centre HENRI BECQUEREL
city: Saint-priest-en-jarez
country: France
facility: Institut de Cancérologie de la Loire
city: St Cloud
country: France
facility: centre rene Huguenin
city: Strasbourg
country: France
facility: CHU Hautepierre
city: Toulon
country: France
facility: HIA Ste Anne
city: Toulouse
country: France
facility: Hôpital de PURPAN
city: Tours
country: France
facility: CHU Tours
city: Valenciennes
country: France
facility: Hotel Dieu
city: Vandoeuvre Les Nancy
country: France
facility: CH Brabois
city: Villejuif
country: France
facility: IGR
city: Duisburg
country: Germany
facility: St. Johannes-Hospital
city: Stuttgart
country: Germany
facility: Robert Bosch-Krankenhaus
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Palermo
country: Italy
facility: Dipartimento Oncologico La Maddalena
Study officials:
affiliation: CH Versailles
name: Rousselot Philippe, MD
role: PRINCIPAL_INVESTIGATOR
References: