A Phase l/ll Study of AMN107 in Adult Patients With Glivec-intolerant CML or Relapsed-refractory Ph+ALL

This study will investigate if nilotinib provides an improved safety and efficacy profile over that seen in patients receiving Imatinib.


Eligibility Criteria:
Inclusion Criteria:

* Diagnosed as Ph+ ALL who are either relapsed after or refractory to standard therapy
* Diagnosed as CML in blast crisis or accelerated phase or chronic phase who are resistant or intolerant to imatinib
* Performance status is normal or ambulatory and capable of all self-care Exclusion Criteria
* A history of significant or serious uncontrolled cardiovascular disease
* Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib
* Patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control

Exclusion Criteria:

* Cytopathologically confirmed CNS infiltration NB: in absence of suspicion of CNS involvement, lumbar puncture is not required
* Impaired cardiac function, including any one of the following

  * LVEF \< 45% as determined by echocardiogram
  * Complete left bundle branch block
  * Use of a cardiac pacemaker
  * ST depression of \> 1mm in 2 or more leads and/or T-wave inversions in 2 or more contiguous leads
  * Congenital long QT syndrome
  * History of or presence of significant ventricular or atrial tachyarrhythmias
  * Clinically significant resting bradycardia (\< 50 beats per minute)
  * QTc \> 480 msec on screening ECG (using the QTcF formula)
  * Right bundle branch block plus left anterior hemiblock, bifascicular block
  * Myocardial infarction within 3 months prior to starting AMN107
  * Uncontrolled angina pectoris
* Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
* Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of AMN107 (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
* Use of therapeutic warfarin
* Acute or chronic liver or renal disease considered unrelated to tumor (e.g., hepatitis, cirrhosis, renal insufficiency, etc.)
* Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
* Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF) ≤ 1 week prior to starting study drug.
* Patients who are currently receiving treatment with any of the medications listed in (cf. Post-text suppl. 5) that cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in (cf. Post-text suppl. 5) have the potential to prolong the Q-T interval.
* Patients who have received chemotherapy ≤ 1 week or who are within 5 half-lives of their last dose chemotherapy (6 weeks for nitrosurea or mitomycin-C) prior to starting study drug or who have not recovered from side effects of such therapy. Hydroxyurea is permitted at the investigator's discretion prior to enrollment.
* Patients who have received Glivec® ≤ 1 week or who have not recovered from side effects of such therapy.
* Patients who have received immunotherapy ≤ 1 week prior to starting study drug or who have not recovered from side effects of such therapy.
* Patients who have received any investigational drug (excluding STI571/Glivec) ≤ 4 weeks or investigational cytotoxic agent within 1 week (or who are within 5 half-lives of a previous investigational cytotoxic agent) prior to starting study drug or who have not recovered from side effects of such therapy.
* Patients who have received wide field radiotherapy ≤ 4 week or limited field radiation for palliation ≤ 2 week prior to starting study drug or who have not recovered from side effects of such therapy.
* Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
* Patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of AMN107). Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug
* Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
* Patients unwilling or unable to comply with the protocol

Other protocol-defined inclusion and exclusion criteria may apply.