Nilotinib and Imatinib Mesylate After Donor Stem Cell Transplant in Treating Patients With ALL or CML

A Multicenter Phase I/II Study of the Prophylactic Inhibition of BCR-ABL Tyrosine Kinase by Tasigna ® (Nilotinib) After Hematopoietic Cell Transplantation for Philadelphia Chromosome-Positive Leukemias.

This phase I/II trial is studying the side effects and best way to give nilotinib when given alone or sequentially after imatinib mesylate after donor stem cell transplant in treating patients with acute lymphoblastic leukemia or chronic myelogenous leukemia. Nilotinib and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the safety of the administration of nilotinib between Day 81 and Day 365 after hematopoietic cell transplantation (HCT) in patients with Philadelphia chromosome positive (Ph+) leukemia.

SECONDARY OBJECTIVES:

I. To quantify the breakpoint cluster region (BCR)/Abelson murine leukemia (ABL) transcript load after HCT during tyrosine kinase inhibitor therapy in patients with Ph+ leukemia treated sequentially with imatinib (imatinib mesylate) and nilotinib from the time of engraftment.

II. To evaluate survival at 1 year in patients with Ph+ leukemia who received sequential imatinib and nilotinib from the time of engraftment.

III. To determine if imatinib can be co-administered with nilotinib for patients with rising levels of BCR/ABL on 2 consecutive occasions after HCT.

IV. To confirm that imatinib can be delivered at an average daily dose of 400 mg at least 85% of the time in the majority of adults during the first 80 days after HCT.

V. To determine whether nilotinib can be administered safely at a daily dose of at least 300 mg (175 mg/m^2 in children < 17 years) at least 70% of the time to patients with imatinib resistant Ph+ leukemia during the first 80 days after HCT.

VI. To determine treatment efficacy success at 1 year post-transplant as demonstrated by complete hematological remission, absence of Philadelphia chromosome, and not satisfying any of the criteria for treatment failure.

OUTLINE:

Beginning after engraftment and blood count recovery (21-28 days after allogeneic stem cell transplant), patients with imatinib-sensitive leukemia receive imatinib mesylate orally (PO) once daily (QD) until day 80 and then nilotinib PO twice daily (BID) on days 81-445. Patients with imatinib-resistant leukemia receive nilotinib PO BID beginning after engraftment and blood count recovery until day 445.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

• Body surface area >= 1 m^2
• Allogeneic HCT
• Acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia (CML) characterized by the p190 and/or p210 BCR/ABL gene rearrangement
• CML in accelerated phase, blast crisis, or blast crisis remission as defined by World Health Organization (WHO) criteria
• CML in chronic phase if patient age =< 17 years or a patient of any age with CML in second chronic phase or beyond
• Patients with minimal residual disease (MRD) that is not declining in response to tyrosine kinase inhibitor therapy must be screened for the T315I and other mutations
• An appropriately matched related or unrelated donor
• Signed informed consent
• Patient must have a life expectancy of at least 2 months
• Stated willingness of the patient to comply with study procedures and reporting requirements
• Creatinine =< 2.0 x upper limit normal (ULN)
• Platelets > 20 x 10^9 /L
• Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN, conjugated bilirubin < 3 x ULN
• Serum potassium phosphorus, magnesium, and calcium >= lower limit normal (LLN) or correctable with supplements prior to first dose of study drug; calcium levels may be corrected for hypoalbuminemia
• Serum amylase and lipase < 1.5 x ULN
• Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing; postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; male and female patients of reproductive potential 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
• Careful rationalization with a view to discontinuing or considering alternatives to any concomitant medications that have potential to prolong the QT interval

Exclusion Criteria:

• Autologous transplant

• Non-myeloablative transplant

• Patient age > 17 years with CML in first chronic phase

• Aberrant antigen expression on marrow leukemic blasts >= 5% by multidimensional flow cytometric assay immediately before conditioning (CML patients in chronic phase exempt from flow cytometry screening)

• Ph+ ALL without complete cytogenetic remission immediately before conditioning

• Known T315I mutation

• Hypersensitivity to Gleevec or Tasigna

• Patients who are Tasigna-resistant or intolerant

• Central nervous system (CNS) involvement with leukemia at baseline (pre-imatinib therapy); CML chronic phase (CP), accelerated phase (AP) patients exempt from CNS involvement screening

• Female patients who are pregnant, breast-feeding, or of childbearing potential without a negative serum pregnancy test at screening; male or female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial; post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential

• Life expectancy severely limited by diseases other than leukemia

• Myocardial infarction within one year prior to starting nilotinib

• Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, unstable angina)

• Absolute neutrophil count (ANC) less than 1500 per microliter at study entry despite the use of filgrastim (G-CSF)

• Impaired cardiac function, including any one of the following:

  • Complete left bundle branch block or bifascicular block (right bundle branch block plus left anterior hemiblock) or use of ventricular-paced pacemaker
  • Congenital long QT syndrome or a family history of long QT syndrome
  • History of or presence of significant ventricular or atrial tachyarrhythmias
  • Clinically significant resting bradycardia (< 50 beats per minute)

• Corrected QT interval (QTc) > 450 milliseconds on screening electrocardiogram (ECG); if QTc > 450 and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient rescreened for QTc