Clinical trial NCT01528085: Evaluation of Efficacy and Safety of Nilotinib in Combination With Chemotherapy in Elderly Patients With Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Official title: An Open Label Phase II Study to Evaluate the Efficacy and Safety of Induction and Consolidation Therapy With Nilotinib 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: Philadelphia Chromsome Positive Acute Lymphoblastic Leukemia
Keywords: Philadelphia chromsome
BCR-ABL
ALL
acute lymphoblastic leukemia
Nilotinib
Tasigna
Lead sponsor: Goethe University
Sponsor class: OTHER
First posted: 2012-02-07
Enrollment: 79
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: The goal of this trial is to evaluate the efficacy and the tolerance of the combination of nilotinib 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 nilotinib as concomitant therapy during induction, consolidation and maintenance. The patients will be prospectively monitored for minimal residual disease and bcr-abl tyrosine kinase domain mutations.


Eligibility criteria: Inclusion Criteria:

1. Male or female patients \> 55 years
2. Philadelphia chromosome- or BCR-ABL positive acute lymphoblastic leukemia
3. Not previously treated except with corticosteroids or single dose vincristine (three doses cyclophosphamide accepted)
4. With or without documented CNS involvement
5. WHO performance status \< 2
6. Normal serum levels \> LLN (lower limit of normal) of potassium, magnesium, total calcium corrected for serum albumin; or corrected to within normal limits with supplements, prior to the first dose of study medication
7. Signed written inform consent
8. Molecular evaluation for BCR-ABL performed
9. Willingness of male subjects whose sexual partners are women of child-bearing potential (WOCBP), to use an effective form of contraception (pearl index \< 1%), such as complete sexual abstinence, combined oral contraceptive, hormone IUCD, vaginal hormone ring, transdermal contraceptive patch, contraceptive implant or depot contraceptive injection in combination with a second method of contraception like a condom or a cervical cap / diaphragm with spermicide or surgical sterilisation (vasectomy) in male patients during the study and at least 6 months thereafter. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months).

Exclusion Criteria:

1. Patient previously treated with tyrosine kinase inhibitors
2. Known impaired cardiac function, including any of the following:

   * LVEF \< 45%
   * Complete left bundle branch block
   * Right bundle branch block plus left anterior hemiblock, bifascicular block
   * Use of a ventricular-paced pacemaker
   * Congenital long QT syndrome
   * History of or presence of clinically significant ventricular or atrial tachyarrhythmias
   * Clinically significant resting bradycardia (\< 50 beats per minute)
   * QTcF\>450 msec on screening ECG. If QTc \> 450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion.
   * Myocardial infarction with 12 months prior to starting nilotinib
   * Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
3. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
4. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or known infection with Hepatitis B or C
5. Treatment with any, other investigational agent or participating in another trial within 30 days prior to entering this study
6. Inadequate hepatic functions defined as ASAT or ALAT \> 2,5 times the institutional upper limit of normal or \> 5 times ULN if considered due to leukemia
7. Total bilirubin \> 2 fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht
8. Concurrent severe diseases which exclude the administration of therapy
9. Past history of acute or chronic pancreatits
10. Patients unwilling or unable to comply with the protocol.e branch block; Right bundle branch block plus left anterior hemiblock, bifascicular block; Use of a ventricular-paced pacemaker; congenital long QT syndrome

    * History of or presence of clinically significant ventricular or atrial tachyarrhythmias
    * Clinically significant resting bradycardia (\< 50 beats per minute)
    * QTcF\>450 msec on screening ECG. If QTc \> 450 msec and electrolytes are not within normal ranges before nilotinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion.
    * Myocardial infarction with 12 months prior to starting nilotinib
    * Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)

      * Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
      * Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or known infection with Hepatitis B 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 or \> 5 times ULN if considered due to leukemia
      * Total bilirubin \> 2 fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht
      * Concurrent severe diseases which exclude the administration of therapy
      * Past history of acute or chronic pancreatits
      * Patients unwilling or unable to comply with the protocol.

Primary outcomes:
measure: Evaluation of efficacy of a nilotinib-based induction and consolidation therapy
timeFrame: after 12 months
Secondary outcomes:
measure: complete haematological remission
timeFrame: after induction treatment (week 5)
measure: major molecular response in bone marrow
measure: complete molecular response
measure: undetectable BCR-ABL level
measure: Event free survival
measure: Relapse free survival
measure: Progression free survival
measure: T315I or p-loop Mutations
measure: molecular relapse or progression
measure: Overall survival
measure: Tolerability
measure: Death during induction
timeFrame: End of induction (week 5)
measure: Death in complete remission
Other outcomes:
Locations:
city: Aix-en-Provence cedex 1
country: France
facility: Centre Hospitalier du Pays d'Aix
city: AMIENS Cedex 1
country: France
facility: CHU d'Amiens - Hôpital Sud
city: ANGERS Cedex 09
country: France
facility: Chu Angers
city: Argenteuil Cedex
country: France
facility: Centre Hospitalier Victor Dupouy
city: Bayonne
country: France
facility: Centre Hospitalier de la Côte Basque
city: BESANÇON Cedex
country: France
facility: CHU de Besançon - Hôpital Jean Minjoz
city: BREST Cedex
country: France
facility: CHU de Brest - Hôpital Morvan
city: Caen
country: France
facility: "CHU Cote de nacre "
city: Clermont Ferrand
country: France
facility: CHU Estaing
city: Creteil
country: France
facility: AP-HP - Hôpital Henri Mondor
city: DIJON Cedex
country: France
facility: CHRU de Dijon
city: Grenoble cedex 9
country: France
facility: CHU de Grenoble
city: LE CHESNAY Cedex
country: France
facility: CH de Versailles - Hôpital André Mignot
city: Lille Cedex
country: France
facility: Groupe Hospitalier de l'Institut Catholique de Lille, hôpital Saint-Vincent
city: LILLE Cedex
country: France
facility: CHRU de Lille
city: LIMOGES Cedex
country: France
facility: C H U de Limoges - Hôpital Dupuytren
city: Marseille cedex 9
country: France
facility: Institut Paoli-Calmettes
city: MEAUX Cedex
country: France
facility: CH de Meaux
city: MONTPELLIER Cedex 5
country: France
facility: Hôpital Saint-Eloi
city: MULHOUSE Cedex
country: France
facility: CH de Mulhouse - Hôpital Emile Muller
city: Nantes
country: France
facility: CHU Hôtel Dieu, Nantes
city: Nice
country: France
facility: CHU de Nice - Hôpital l'Archet 1
city: ORLEANS Cedex
country: France
facility: CHR d'Orléans - Hôpital La Source
city: PARIS Cedex 10
country: France
facility: AP-HP - Hôpital Saint Louis
city: PARIS cedex 12
country: France
facility: AP-HP - Hôpital SAINT-ANTOINE
city: PARIS Cedex 15
country: France
facility: AP-HP - Hôpital Necker
city: PERPIGNAN cedex 09
country: France
facility: CH de Perpignan - Hôpital Saint-Jean
city: PESSAC Cedex
country: France
facility: CHU de Bordeaux - Hôpital Haut-Lévêque
city: Pierre-Bénite Cedex
country: France
facility: Centre Hospitalier Lyon Sud
city: POITIERS Cedex
country: France
facility: CHU de Poitiers - Hôpital La Milétrie
city: Pringy Cedex
country: France
facility: CH de la Région d'Annecy
city: REIMS Cedex
country: France
facility: CHU de Reims - Hôpital Robert Debré
city: RENNES Cedex 9
country: France
facility: CHU de Rennes, Hôpital Pontchaillou
city: Rouen Cedex 1
country: France
facility: Centre Henri Becquerel, Rouen
city: SAINT DENIS Cedex
country: France
facility: CHU de La Réunion - Hôpital Félix Guyon
city: STRASBOURG Cedex
country: France
facility: CHRU de Strasbourg - Hôpital Hautepierre
city: TOULON Cedex 9
country: France
facility: HIA Sainte Anne
city: Toulouse
country: France
facility: "Institut Universitaire du Cancer (CHU de Toulouse - Hôpital Purpan)"
city: TOURS Cedex 9
country: France
facility: CHRU de Tours - Hôpital Bretonneau
city: VALENCIENNES Cedex
country: France
facility: Centre Hospitalier de Valenciennes
city: Vandoeuvre Les Nancy
country: France
facility: CHU de Nancy - Hôpital Brabois
city: Stuttgart
country: Germany
facility: Robert Bosch Krankenhaus
state: Baden-Württemberg
city: Regensburg
country: Germany
facility: Klinikum der Universität Regensburg
state: Bayern
city: Frankfurt
country: Germany
facility: University Hospital of Frankfurt, Medical Dept. II
state: Hessen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Essen
country: Germany
facility: Universitätsklinikum Essen
state: NRW
city: Münster
country: Germany
facility: Universitätsklinik Münster
state: NRW
city: Dresden
country: Germany
facility: Universitätsklinik Dresden
state: Sachsen
city: Aachen
country: Germany
facility: Uniklinik Aachen
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Düsseldorf
country: Germany
facility: University Hospital Düsseldorf
city: Göttingen
country: Germany
facility: Universitätsklinikum Göttingen
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Campus Kiel
city: Leipzig
country: Germany
facility: Universität Leipzig, José-Carreras-Haus
city: Mainz
country: Germany
facility: Universitätskliniken Mainz
city: Mannheim
country: Germany
facility: Klinikum Mannheim
city: München
country: Germany
facility: Universitätsklinikum Großhadern
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg Nord
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Rostock
country: Germany
facility: Universität Rostock
city: Ulm
country: Germany
facility: Medizinische Universitätsklinik Ulm
city: Würzburg
country: Germany
facility: Universität Würzburg
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol (ICO - Badalona)
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre (Madrid)
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío (Sevilla)
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe (Valencia)
Study officials:
affiliation: Johann Wolfgang Goethe University Hospital
name: Heike Pfeifer, Dr.med.
role: PRINCIPAL_INVESTIGATOR
References: