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.

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.