Evaluation of Efficacy and Safety of Nilotinib in Combination With Chemotherapy in Elderly Patients With Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

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)

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.

Study Overview

• Status: Completed
• Conditions: Philadelphia Chromsome Positive Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Nilotinib

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • AMIENS Cedex 1, France, 80054
    • CHU d'Amiens - Hôpital Sud
  • ANGERS Cedex 09, France, 49933
    • CHU Angers
  • Aix-en-Provence cedex 1, France, 13616
    • Centre Hospitalier du Pays d'Aix
  • Argenteuil Cedex, France, 95107
    • Centre Hospitalier Victor Dupouy
  • BESANÇON Cedex, France, 25030
    • CHU de Besancon - Hopital Jean Minjoz
  • BREST Cedex, France, 29609
    • CHU de Brest - Hôpital Morvan
  • Bayonne, France, 64100
    • Centre Hospitalier de la Cote Basque
  • Caen, France, 14000
    • "CHU Cote de nacre "
  • Clermont Ferrand, France, 63003
    • CHU Estaing
  • Creteil, France, 94010
    • AP-HP - Hôpital Henri Mondor
  • DIJON Cedex, France, 21079
    • CHRU de Dijon
  • Grenoble cedex 9, France, 38043
    • Chu de Grenoble
  • LE CHESNAY Cedex, France, 78157
    • Ch de Versailles - Hopital Andre Mignot
  • LILLE Cedex, France, 59037
    • CHRU de Lille
  • LIMOGES Cedex, France, 87042
    • C H U de Limoges - Hôpital Dupuytren
  • Lille Cedex, France, 59020
    • Groupe Hospitalier de l'Institut Catholique de Lille, hôpital Saint-Vincent
  • MEAUX Cedex, France, 77104
    • CH de Meaux
  • MONTPELLIER Cedex 5, France, 34295
    • Hopital Saint-Eloi
  • MULHOUSE Cedex, France, 68070
    • CH de Mulhouse - Hôpital Emile Muller
  • Marseille cedex 9, France, 13273
    • Institut Paoli-Calmettes
  • Nantes, France, 44000
    • CHU Hôtel Dieu, Nantes
  • Nice, France, 06200
    • Chu de Nice - Hôpital L'Archet 1
  • ORLEANS Cedex, France, 45032
    • CHR d'Orléans - hôpital La Source
  • PARIS Cedex 10, France, 75010
    • AP-HP - Hôpital Saint Louis
  • PARIS Cedex 15, France, 75743
    • AP-HP - Hôpital Necker
  • PARIS cedex 12, France, 75571
    • AP-HP - hôpital Saint-Antoine
  • PERPIGNAN cedex 09, France, 66046
    • CH de Perpignan - Hôpital Saint-Jean
  • PESSAC Cedex, France, 33604
    • Chu de Bordeaux - Hopital Haut-Leveque
  • POITIERS Cedex, France, 86021
    • CHU de Poitiers - Hôpital la Milétrie
  • Pierre-Bénite Cedex, France, 69495
    • Centre Hospitalier Lyon Sud
  • Pringy Cedex, France, 74374
    • CH de la région d'Annecy
  • REIMS Cedex, France, 51092
    • CHU de Reims - Hôpital Robert Debré
  • RENNES Cedex 9, France, 35033
    • CHU de Rennes, Hopital Pontchaillou
  • Rouen Cedex 1, France, 76038
    • Centre Henri Becquerel, Rouen
  • SAINT DENIS Cedex, France, 97405
    • CHU de la Réunion - Hôpital Felix Guyon
  • STRASBOURG Cedex, France, 67098
    • CHRU de Strasbourg - Hôpital Hautepierre
  • TOULON Cedex 9, France, 83041
    • HIA Sainte Anne
  • TOURS Cedex 9, France, 37044
    • CHRU de Tours - Hôpital Bretonneau
  • Toulouse, France, 31100
    • "Institut Universitaire du Cancer (CHU de Toulouse - Hôpital Purpan)"
  • VALENCIENNES Cedex, France, 59322
    • Centre hospitalier de valenciennes
  • Vandoeuvre Les Nancy, France, 54511
    • CHU de Nancy - Hôpital Brabois
• Germany
  • Aachen, Germany, 52074
    • Uniklinik Aachen
  • Berlin, Germany, 13353
    • Charité Universitätsmedizin Berlin
  • Düsseldorf, Germany, 40225
    • University Hospital Düsseldorf
  • Göttingen, Germany, 37075
    • Universitätsklinikum Göttingen
  • Hamburg, Germany, 20099
    • Asklepios Klinik St. Georg
  • Kiel, Germany, 24116
    • Universitätsklinikum Schleswig-Holstein Campus Kiel
  • Leipzig, Germany, 04103
    • Universität Leipzig, José-Carreras-Haus
  • Mainz, Germany, 55101
    • Universitätskliniken Mainz
  • Mannheim, Germany, 68167
    • Klinikum Mannheim
  • München, Germany, 81377
    • Universitätsklinikum Großhadern
  • Nürnberg, Germany, 90419
    • Klinikum Nürnberg Nord
  • Oldenburg, Germany, 26133
    • Klinikum Oldenburg
  • Rostock, Germany, 18055
    • Universität Rostock
  • Ulm, Germany, 89070
    • Medizinische Universitätsklinik Ulm
  • Würzburg, Germany, 97080
    • Universität Würzburg
  • Baden-Württemberg
    • Stuttgart, Baden-Württemberg, Germany, 70376
      • Robert Bosch Krankenhaus
  • Bayern
    • Regensburg, Bayern, Germany, 93042
      • Klinikum der Universität Regensburg
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • University Hospital of Frankfurt, Medical Dept. II
  • NRW
    • Essen, NRW, Germany, 45147
      • Universitätsklinikum Essen
    • Münster, NRW, Germany, 48149
      • Universitätsklinik Münster
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Universitatsklinik Dresden
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Barcelona, Spain, 08916
    • Hospital Universitario Germans Trias i Pujol (ICO - Badalona)
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre (Madrid)
  • Salamanca, Spain, 37007
    • Hospital Clínico Universitario de Salamanca
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío (Sevilla)
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico La Fe (Valencia)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of efficacy of a nilotinib-based induction and consolidation therapy	rate of patients without event	after 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival
Progression free survival
Event free survival
Relapse free survival
complete haematological remission	The rate of complete haematological remission after induction treatment	after induction treatment (week 5)
major molecular response in bone marrow	major molecular response defined by a BCR-ABL/ABL < 0.1% in bone marrow
complete molecular response	complete molecular response defined by a BCR-ABL/ABL < 0.001% in bone marrow
undetectable BCR-ABL level	The proportion of patients with confirmed undetectable BCR-ABL level with a test sensitivity of at least 4.5 log.
T315I or p-loop Mutations	Detection of a T315I or p-loop BCR-ABL TK domain mutation
molecular relapse or progression	The proportion of patients with molecular relapse or progression
Tolerability	Tolerability as determined by descriptive assessment of adverse events and discontinuation due to treatment-related SAEs
Death during induction	(all patients who started treatment)	End of induction (week 5)
Death in complete remission

Collaborators and Investigators

• Sponsor: Goethe University
• Investigators: Principal Investigator: Heike Pfeifer, Dr.med., Johann Wolfgang Goethe University Hospital

Publications and helpful links

Helpful Links

• Trial register of University Cancer Center Frankfurt, additional trial information

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): March 10, 2020
• Study Completion (Actual): March 10, 2020

Study Registration Dates

• First Submitted: February 3, 2012
• First Submitted That Met QC Criteria: February 3, 2012
• First Posted (Estimate): February 7, 2012

Study Record Updates

• Last Update Posted (Actual): July 30, 2020
• Last Update Submitted That Met QC Criteria: July 29, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: ALL; Nilotinib; BCR-ABL; acute lymphoblastic leukemia; Tasigna; Philadelphia chromsome
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Chromosome Aberrations; Translocation, Genetic; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Philadelphia Chromosome
• Other Study ID Numbers: EWALL-PH-02; 2010-022855-46 (EudraCT Number)