Dasatinib and Low Intensity Chemotherapy for Ph+ Acute Lymphoblastic Leukemia

Leukemia, Lymphoblastic, Acute Clinical Trial

— EWALLPH01  

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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02888990
• Other study ID #: 2006-005694-21
• Status: Completed
• Phase: Phase 2
• First received: August 19, 2016
• Last updated: August 30, 2016
• Start date: August 2007
• Est. completion date: January 2016

Study information

• Verified date: August 2016
• Source: Central Hospital, Versailles
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santéFrance: Committee for the Protection of Personnes
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 71
• Est. completion date: January 2016
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 55 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoblastic, Acute
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Dasatinib

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc	Bruxelles
Belgium	CHU Ambroise Paré	Mons
France	Ch D'Aix En Provence	Aix en provence
France	Groupe Hospitalier Sud	Amiens
France	CHU Angers	Angers
France	Chr Annecienne	Annecy
France	Ch Victor Dupouy	Argenteuil
France	CHG D'Avignon Henri Duffaut	Avignon
France	C.H. de la Côte Basque	Bayonne
France	Hôpital JEAN MINJOZ	Besancon
France	CH Blois	Blois
France	Avicenne	Bobigny
France	CHU Brest	Brest
France	Hôpital CLEMENCEAU	Caen
France	HIA Percy	Clamart
France	Hotel Dieu	Clermont ferrand
France	Hôpital PASTEUR	Colmar
France	Centre Hospitalier Sud Francilien	Corbeil Essonnes
France	Henry Mondor	Creteil
France	Hôpital du BOCAGE	Dijon
France	CH Dunkerque	Dunkerque
France	Hôpital A. MICHALLON	Grenoble
France	CH Versailles	Le Chesnay
France	CH Lens	Lens
France	Hopital Claude Huriez	Lille
France	Hôpital Dupuytren	Limoges
France	Edouard Herriot	Lyon
France	IPC	Marseille
France	CH Meaux	Meaux
France	Hôpital Notre Dame de Bon Secours	Metz
France	Hôpital LAPEYRONIE	Montpellier
France	CH E Muller	Mulhouse
France	Hotel Dieu	Nantes
France	Archet 1	Nice
France	CHU Nimes	Nimes
France	Hôpital de la Source	Orléans
France	Cochin	Paris
France	Hopital St louis	Paris
France	Necker	Paris
France	Pitie Salpetrière	Paris
France	St Antoine	Paris
France	CH Perpignan	Perpignan
France	Hôpital du HAUT LEVEQUE	Pessac
France	Hopital Lyon Sud	Pierre Benite
France	CHU Mileterie	Poitiers
France	Hopital R Debre	Reims
France	Hôpital de PONTCHAILLOU	Rennes
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	Centre Hospitalier Départemental FELIX GUYON	St Denis	La Reunion
France	CHU Hautepierre	Strasbourg
France	HIA Ste Anne	Toulon
France	Hôpital de PURPAN	Toulouse
France	CHU Tours	Tours
France	Hotel Dieu	Valenciennes
France	CH Brabois	Vandoeuvre Les Nancy
France	IGR	Villejuif
Germany	St. Johannes-Hospital	Duisburg
Germany	Robert Bosch-Krankenhaus	Stuttgart
Italy	Ospedali Riuniti di Bergamo	Bergamo
Italy	Ospedale San Gerardo	Monza
Italy	Dipartimento Oncologico La Maddalena	Palermo

Sponsors (1)

Lead Sponsor	Collaborator
Central Hospital, Versailles

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival at 12 months		12 months	No
Secondary	The proportion of Complete haematological remission		5 years	No
Secondary	The proportion of Major molecular response defined by a BCR-ABL/ABL = 0.1% in bone marrow		5 years	No
Secondary	The proportion of Complete molecular response		5 years	No
Secondary	Event free survival		5 years	No
Secondary	Relapse free survival		5 years	No
Secondary	Progression free survival		5 years	No
Secondary	The proportion of Detection of a T315I or F317 BCR-ABL TK mutation		5 years	No
Secondary	The proportion of Molecular progression		5 years	No
Secondary	Overall survival		5 years	No
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0		5 years	Yes
Secondary	Death during induction		2 months	Yes
Secondary	Death in complete remission		5 years	Yes