Nilotinib and Imatinib Mesylate After Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00702403
First received: June 19, 2008
Last updated: April 25, 2014
Last verified: April 2014
  Purpose

This phase I/II trial is studying the side effects and best way to give nilotinib when given together with 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.


Condition Intervention Phase
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
Drug: nilotinib
Drug: imatinib mesylate
Other: pharmacological study
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • 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 [ Time Frame: Up to 365 days post-transplant ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Molecular minimal residual disease (MRD) as determined by polymerase chain reaction (PCR) analysis [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Will be depicted graphically for the group as a function over time.

  • Survival, relapse, and relapse-free-survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be displayed graphically.

  • Efficacy of nilotinib therapy in patients with imatinib-sensitive leukemia [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    To be considered a treatment success post-transplant the patient's bone marrow must demonstrate complete hematological remission, absence of the Philadelphia chromosome, and not satisfy any of the criteria for treatment failure.


Estimated Enrollment: 40
Study Start Date: April 2008
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (prophylactic inhibition of BCR-ABL tyrosine kinase)

Beginning after engraftment and blood counts recover (21 to 28 days after allogeneic stem cell transplant), patients with imatinib-sensitive leukemia receive imatinib mesylate PO QD until day 80 and then nilotinib PO 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.

Drug: nilotinib
Given PO
Other Names:
  • AMN 107
  • Tasigna
Drug: imatinib mesylate
Given PO
Other Names:
  • CGP 57148
  • Gleevec
  • Glivec
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00702403

Locations
United States, California
Stanford University Hospitals and Clinics
Stanford, California, United States, 94305
United States, Florida
H Lee Moffitt Cancer Center and Research Institute Phase 2 Consortium
Tampa, Florida, United States, 33612
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Paul Carpenter Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00702403     History of Changes
Other Study ID Numbers: 2223.00, NCI-2010-00402, P30CA015704, P01CA018029
Study First Received: June 19, 2008
Last Updated: April 25, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Blast Crisis
Leukemia
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myeloid, Accelerated Phase
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Philadelphia Chromosome
Abnormal Karyotype
Neoplasms by Histologic Type
Neoplasms
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Pathologic Processes
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Translocation, Genetic
Chromosome Aberrations
Imatinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on August 21, 2014