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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.


Phase 1/Phase 2
N/A
N/A
Open (Enrolling)
Both
Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Lymphoblastic Leukemia in Remission, Blastic Phase Chronic Myelogenous Leukemia, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood Chronic Myelogenous Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase Chronic Myelogenous Leukemia, Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia, Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Relapsing Chronic Myelogenous Leukemia, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Childhood Acute Lymphoblastic Leukemia

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Trial Information

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.


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 counts recover (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 counts recover 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)

- 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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety and tolerability of nilotinib therapy in patients with imatinib-sensitive leukemia graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0

Outcome Description:

Treatment safety failure is defined for patients with imatinib sensitive Ph+ leukemia as the inability to be able to deliver at least 400 milligrams per day of nilotinib in adults, and 230 milligrams/m2 per day in children, for at least 85% of the time interval between 81 and 365 days after transplant because of toxicity.

Outcome Time Frame:

Up to 365 days post-transplant

Safety Issue:

Yes

Principal Investigator

Paul Carpenter

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Institutional Review Board

Study ID:

2223.00

NCT ID:

NCT00702403

Start Date:

April 2008

Completion Date:

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Adult Acute Lymphoblastic Leukemia in Remission
  • Blastic Phase Chronic Myelogenous Leukemia
  • Childhood Acute Lymphoblastic Leukemia in Remission
  • Childhood Chronic Myelogenous Leukemia
  • Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Chronic Phase Chronic Myelogenous Leukemia
  • Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia
  • Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Untreated Adult Acute Lymphoblastic Leukemia
  • Untreated Childhood Acute Lymphoblastic Leukemia
  • Blast Crisis
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myeloid, Chronic-Phase
  • Philadelphia Chromosome

Name

Location

H. Lee Moffitt Cancer Center and Research InstituteTampa, Florida  33612
Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109
Oregon Health and Science UniversityPortland, Oregon  97201
Stanford University Hospitals and ClinicsStanford, California  94305
H Lee Moffitt Cancer Center and Research Institute Phase 2 ConsortiumTampa, Florida  33612