Fludarabine and Total-Body Irradiation Followed By Donor Peripheral Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib - Full Text View

Sponsor:	Fred Hutchinson Cancer Research Center
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00036738

Purpose

RATIONALE: Giving imatinib mesylate, dasatinib, or nilotinib low doses of chemotherapy, such as fludarabine, and radiation therapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving immunosuppressive therapy after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well fludarabine and total-body irradiation followed by donor peripheral stem cell transplant work in treating patients with acute lymphoblastic leukemia or chronic myelogenous leukemia that has responded to previous treatment with imatinib mesylate, dasatinib, or nilotinib.

Condition	Intervention	Phase
Leukemia	Biological: therapeutic allogeneic lymphocytes Drug: cyclosporine Drug: dasatinib Drug: fludarabine phosphate Drug: imatinib mesylate Drug: mycophenolate mofetil Drug: nilotinib Procedure: peripheral blood stem cell transplantation Radiation: radiation therapy	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official Title:	Allogeneic Nonmyeloablative Hematopoietic Stem Cell Transplant for Patients With BCR-ABL Tyrosine Kinase Inhibitor Responsive PH+ Acute Leukemia - A Multi-Center Trial

Resource links provided by NLM:

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood

Drug Information available for: Fludarabine Cyclosporine Fludarabine monophosphate Cyclosporin Mycophenolate mofetil hydrochloride Mycophenolate Mofetil Imatinib Imatinib mesylate Dasatinib

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Relapse-free survival < 40% at 1 year [ Designated as safety issue: No ]
Transplant related mortality < 40% at 1 year [ Designated as safety issue: Yes ]

Estimated Enrollment:	25
Study Start Date:	July 2001
Estimated Primary Completion Date:	July 2010 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

Determine whether the rate of leukemic relapse can be decreased for patients with imatinib mesylate, dasatinib, or nilotinib-responsive Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myelogenous leukemia in blast crisis treated with a non-myeloablative conditioning regimen comprising fludarabine and total body irradiation followed by allogeneic peripheral blood stem cell (PBSC) transplantation, compared to historical controls treated with high-dose conventional chemotherapy followed by allogeneic PBSC transplantation.
Determine whether the rate of transplant-related mortality can be decreased in patients treated with this regimen.

Secondary

Evaluate whether donor lymphocyte infusions can be safely used in patients with mixed or full donor chimerism treated with this regimen as preemptive therapy to eliminate minimal residual disease.

OUTLINE: This is a multicenter study.

Patients receive oral imatinib mesylate, dasatinib, or nilotinib once daily beginning before study and continuing until day -2 of study. Patients resume oral imatinib mesylate, dasatinib, or nilotinib once daily beginning on day 14 or when blood counts recover after peripheral blood stem cell (PBSC) transplantation.

Transplantation: Patients receive a non-myeloablative conditioning regimen comprising fludarabine IV on days -4 to -2 and total body irradiation followed by filgrastim (G-CSF)-mobilized allogeneic PBSC transplantation on day 0.
Graft-versus-host-disease (GVHD) prophylaxis: Patients receiving related PBSC receive oral mycophenolate mofetil (MMF) twice daily on days 0-27 without tapering. Patients receiving unrelated PBSC receive oral MMF three times daily on days 0-40 followed by a taper on days 41-96 in the absence of GVHD or disease progression. Adults receiving related PBSC receive cyclosporine (CYSP) orally twice daily on days -3 to 56 followed by a taper on days 57-100. Children receiving related donor PBSC receive CYSP IV twice or three times daily on days -3 to 56 followed by a taper on days 57-100. Adults receiving unrelated donor PBSC receive oral CYSP twice daily on days -3 to 100 followed by a taper on days 101-177. Children receiving unrelated donor PBSC receive CYSP IV twice or three times daily on days -3 to 100 followed by a taper on days 101-177.
CNS prophylaxis: Patients receive six doses of intrathecal methotrexate or cytarabine beginning on day 32 after PBSC transplantation or when there is no evidence of gross systemic leukemia. Patients who have a history of CNS leukemia at any time and have not received prior cranio-spinal irradiation (CSI) before study entry receive CSI for 11 days after PBSC transplantation when there is no evidence of gross systemic leukemia.

Patients with persistent disease and no GVHD after stopping GVHD prophylaxis receive donor lymphocyte infusion IV over 30 minutes once every 28 days for 3 doses.

Patients are followed at 6, 9, 12, 18, and 24 months and then annually for 5 years.

PROJECTED ACCRUAL: A total of 25 patients will be accrued for this study within 5 years.

Eligibility

Ages Eligible for Study:	up to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Diagnosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myelogenous leukemia in blast crisis
- Less than 15% blasts on morphologic bone marrow evaluation after receiving imatinib mesylate, dasatinib, or nilotinib
  - Patients with no detectable Ph+ ALL by morphologic or molecular assay (i.e., complete remission) after treatment with imatinib mesylate, dasatinib, or nilotinib are eligible
  - Patients who initially respond to imatinib mesylate, dasatinib, or nilotinib and then progress are ineligible for nonmyeloablative stem cell transplantation on this protocol
No CNS involvement with leukemia refractory to intrathecal chemotherapy
Availability of an HLA-matched related or unrelated peripheral blood stem cell donor
- Related donors HLA genotypically identical for at least 1 haplotype and may be genotypically or phenotypically identical for HLA-A, -B, -C, -DRB1, and -DQB1 alleles
  - No identical twin OR
- Unrelated donors meeting the following criteria:
  - Matched for HLA-A, -B, -C, -DRB1, and -DQB1 by high-resolution typing
  - Only a single allele disparity allowed for HLA-A, -B, or -C by high-resolution typing
- No bone marrow donors

PATIENT CHARACTERISTICS:

Age:

70 and under
Patients age 12 and under are allowed at the discretion of the protocol investigator

Performance status:

Karnofsky 60-100%
Lansky play performance score 40-100% (for pediatric patients)

Life expectancy:

Not specified

Hematopoietic:

See Disease Characteristics

Hepatic:

No fulminant liver failure
No cirrhosis of the liver with evidence of portal hypertension
No alcoholic hepatitis
No esophageal varices
No history of bleeding esophageal varices
No hepatic encephalopathy
No uncorrectable hepatic synthetic dysfunction, evidenced by prolongation of PT
No ascites related to portal hypertension
No bacterial or fungal liver abscess
No biliary obstruction
No chronic viral hepatitis (with bilirubin greater than 3 mg/dL)
No symptomatic biliary disease

Renal:

Creatinine ≤ 2 times upper limit of normal

Cardiovascular:

No poorly controlled hypertension despite multiple antihypertensives
No grade IV cardiac disease OR
Cardiac ejection fraction ≥ 35%* NOTE: *Required for patients > 50 years of age with a history of cardiac disease or prior anthracycline exposure
QTc prolongation ≤ 450 msec for patients receiving dasatinib or nilotinib

Pulmonary:

DLCO ≥ 30% predicted
Total lung capacity ≥ 30%
FEV1 ≥ 30%
No requirement for continuous supplementary oxygen

Other:

Not pregnant or nursing
Fertile patients must use effective barrier-method contraception during and for 1 year after study completion of study treatment
HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy:

See Disease Characteristics
No concurrent growth factors until after day 21 post-transplantation

Chemotherapy:

See Disease Characteristics

Endocrine therapy:

Not specified

Radiotherapy:

Not specified

Surgery:

Not specified

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00036738

Locations

United States, Colorado
Rocky Mountain Cancer Centers - Denver Midtown	Recruiting
Denver, Colorado, United States, 80218
Contact: Michael B. Maris, MD 303-388-4876
United States, Washington
Fred Hutchinson Cancer Research Center	Recruiting
Seattle, Washington, United States, 98109-1024
Contact: George Georges, MD 206-667-6886 ggeorges@fhcrc.org
Seattle Cancer Care Alliance	Recruiting
Seattle, Washington, United States, 98109-1023
Contact: Clinical Trials Office - Seattle Cancer Care Alliance 800-804-8824
Veterans Affairs Medical Center - Seattle	Recruiting
Seattle, Washington, United States, 98108
Contact: Thomas R. Chauncey, MD, PhD 206-764-2709

Sponsors and Collaborators

Fred Hutchinson Cancer Research Center

National Cancer Institute (NCI)

Investigators

Study Chair:

George Georges, MD

Fred Hutchinson Cancer Research Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Norasetthada L, Maris MB, Sandmaier BM, et al.: Feasibility and toxicity of nonmyeloablative hematopoietic cell transplantation (HCT) with or without imatinib for Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL). [Abstract] Blood 104 (11): A-5056, 2004.

Responsible Party:	Fred Hutchinson Cancer Research Center ( George Georges )
Study ID Numbers:	CDR0000069315, FHCRC-1581.00, NCI-H02-0087
Study First Received:	May 13, 2002
Last Updated:	July 7, 2009
ClinicalTrials.gov Identifier:	NCT00036738 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

childhood acute lymphoblastic leukemia in remission
childhood acute lymphoblastic leukemia
adult acute lymphoblastic leukemia

adult acute lymphoblastic leukemia in remission
Philadelphia chromosome positive chronic myelogenous leukemia
childhood chronic myelogenous leukemia

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Leukemia, Lymphoid
Vidarabine
Antimetabolites, Antineoplastic
Cyclosporine
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Mycophenolic Acid
Antibiotics, Antineoplastic
Protein Kinase Inhibitors
Cyclosporins
Leukemia

Therapeutic Uses
Antifungal Agents
Dasatinib
Mycophenolate mofetil
Dermatologic Agents
Immunoproliferative Disorders
Neoplasms by Histologic Type
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Hematologic Diseases
Myeloproliferative Disorders
Enzyme Inhibitors
Leukemia, Myeloid
Fludarabine monophosphate
Antiviral Agents

ClinicalTrials.gov processed this record on November 27, 2009