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Adult Acute Lymphoblastic Leukemia in RemissionPhase 2NCT00036738

Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood 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

A Phase 2 study testing Cyclosporine, Dasatinib and Fludarabine Phosphate in people with Adult Acute Lymphoblastic Leukemia in Remission and Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, run by Fred Hutchinson Cancer Center at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This phase II trial is studying how well fludarabine phosphate and total-body irradiation followed by donor peripheral blood 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… Read more about this study

Who is it for?
Ages Up to 70 years
What is being tested?
Cyclosporine, Dasatinib and Fludarabine Phosphate
Could I receive a placebo?
No, everyone receives an active treatment
How many people
28 participants
Where
3 sitesUnited States
Study dates
13 Jul 2001to May 2018
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 70 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Patients =< 12 years of age must be approved by Fred Hutchinson Cancer Research Center (FHCRC) principal investigator (PI) in advance
  • Patients with a history of Ph+ ALL or CML-BC who, after receiving imatinib mesylate, (or either dasatinib or nilotinib) have < 15% blasts on morphologic marrow evaluation; patients with no detectable Ph+ ALL by morphologic or molecular assays (complete remission) will be accepted
  • An appropriately human leukocyte antigen (HLA) matched related or unrelated donor must be prospectively identified who will be available to donate filgrastim (G-CSF) mobilized stem cells
  • RELATED DONOR:
  • Related donor who is HLA genotypically identical at least at one haplotype and may be genotypically or phenotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1;
  • Donor must consent to G-CSR administration and leukapheresis;
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  • Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)
  • HLA-MATCHED UNRELATED DONOR:
  • FHCRC matching allowed will be grades 1.0 to 2.1; unrelated donors who are prospectively matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
  • A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion; donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT; if the PRA shows >10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results
  • Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed
  • Only G-CSF mobilized PBSC only will be permitted as a HSC source on this protocol

Who cannot join

  • Central nervous system (CNS) involvement with leukemia refractory to intrathecal chemotherapy; prior to HSCT (all patients must receive a diagnostic lumbar puncture (LP) with intrathecal (IT) chemotherapy as per standard practice)
  • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
  • Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • Females who are pregnant or breastfeeding
  • Patients who are human immunodeficiency virus (HIV)-positive
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  • Patients with poorly controlled hypertension despite multiple antihypertensives
  • Adults: Karnofsky score < 60
  • Pediatrics: Lansky play-performance score < 40
  • Patients with cardiac ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%); ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) < 30%
  • Total lung capacity (TLC) < 30%
  • Forced expiratory volume in one second (FEV1) < 30% and/or receiving supplementary continuous oxygen; the FHCRC PI of the study must approve enrollment of all patients with pulmonary nodules
  • Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease
  • Creatinine levels more than 2.2 X's the upper limit of normal (ULN) at the laboratory where the analysis was performed
  • Patients with active bacterial or fungal infections unresponsive to medical therapy
  • For patients receiving dasatinib or nilotinib, baseline corrected QT interval (QTc) (Fridericia's method) prolongation greater than 500 msec
  • RELATED DONORS:
  • Identical twin
  • Infection with HIV
  • Inability to achieve adequate venous access
  • Known allergy to G-CSF
  • Current serious system illness
  • Bone marrow (BM) donors
  • HLA-MATCHED UNRELATED DONORS:
  • BM donors
  • Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of PBSC

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Presbyterian - Saint Lukes Medical Center - Health One

    Denver, Colorado, 80218

  • VA Puget Sound Health Care System

    Seattle, Washington, 98101

  • Fred Hutch/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

Official title: Allogeneic Nonmyeloablative Hematopoietic Stem Cell Transplant for Patients With BCR-ABL Tyrosine Kinase Inhibitor Responsive Ph+ Acute Leukemia ? A Multi-center Trial

This phase II trial is studying how well fludarabine phosphate and total-body irradiation followed by donor peripheral blood 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. Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body irradiation (TBI) before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop 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 mycophenolate mofetil and cyclosporine after the transplant may stop this from happening.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine whether the rate of leukemia relapse can be decreased for patients with chronic myelogenous leukemia in blast crisis (CML-BC) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) responsive to imatinib mesylate (or either dasatinib or nilotinib for patients who have imatinib-resistant disease or who are intolerant of imatinib) followed by nonmyeloablative hematopoietic stem cell transplantation (HSCT) compared to historical controls given high-dose conventional allogeneic HSCT or chemotherapy.

II. To determine whether the rate of transplantation-related mortality (TRM) can be decreased for patients with CML-BC and Ph+ ALL responsive to imatinib mesylate (or dasatinib or nilotinib) followed by nonmyeloablative HSCT compared to historical controls given high-dose conventional allogeneic HSCT or chemotherapy.

SECONDARY OBJECTIVES:

  1. To evaluate whether donor lymphocyte infusion (DLI) can be safely used in patients with mixed or full donor chimerism as preemptive therapy to eliminate minimal residual disease.

OUTLINE:

INDUCTION THERAPY: Patients continue to receive imatinib mesylate orally (PO), dasatinib PO, or nilotinib PO once or twice daily until day -2 and resume on day 14 or when blood counts recover after peripheral blood stem cell (PBSC) transplantation.

NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine intravenously (IV) on days -4 to -2; and undergo TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBSC transplantation on day 0.

GRAFT-VERSUS-HOST-DISEASE (GVHD) PROPHYLAXIS: Patients receive mycophenolate mofetil (MMF) PO every 12 hours on days 0-27 (related donor recipients) or every 8 hours on days 0-96 with taper on day 40 (unrelated donor recipients). Patients also receive cyclosporine IV or PO every 12 hours on days -3 to 56, followed by taper on days 57-180 (related donor recipients) or on days -3 to 100, followed by taper on days 101-177 (unrelated donor recipients).

DONOR LYMPHOCYTE INFUSION: 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.

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

Patients are followed up periodically for 2 years and then annually thereafter for 5 years.

Medical subject headings
Blast Crisis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CyclosporineDrug

    Also called 27-400, Ciclosporin, CsA, Cyclosporin

    Given IV or PO

  • DasatinibDrug

    Also called BMS-354825, Sprycel

    Given PO

  • Fludarabine PhosphateDrug

    Also called 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara

    Given IV

  • Imatinib MesylateDrug

    Also called CGP 57148, CGP57148B, Gleevec, Glivec

    Given PO

  • Mycophenolate MofetilDrug

    Also called Cellcept, MMF

    Given PO

  • NilotinibDrug

    Also called AMN 107, Tasigna

    Given PO

  • Nonmyeloablative Allogeneic Hematopoietic Stem Cell TransplantationProcedure or surgery

    Also called Non-myeloablative allogeneic transplant, Nonmyeloablative Stem Cell Transplantation, NST

    Undergo nonmyeloablative allogeneic PBSC transplantation

  • Peripheral Blood Stem Cell TransplantationProcedure or surgery

    Also called PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support

    Undergo allogeneic PBSC transplantation

  • Therapeutic Allogeneic LymphocytesBiological

    Also called Allogeneic Lymphocytes

    Given IV

  • Total-Body IrradiationRadiation

    Also called Total Body Irradiation, Whole-Body Irradiation

    Undergo TBI

Study groups in NCT00036738
Study groupRoleWhat they receive
Treatment (allogeneic nonmyeloablative HSCT)ExperimentalSee Detailed Description
Receives: Drug: Cyclosporine; Drug: Dasatinib; Drug: Fludarabine Phosphate; Drug: Imatinib Mesylate; Drug: Mycophenolate Mofetil; Drug: Nilotinib; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Biological: Therapeutic Allogeneic Lymphocytes; Radiation: Total-Body Irradiation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Relapse Free Survival

    Number of patients with relapsed disease within 1 Year post-transplant. Relapse is defined as the detection of > 5% blasts after a documented complete remission.

    Measured: Assessed up to 1 year

Secondary outcomes (4)

  1. Leukemia-free Survival

    Number of patients surviving in CR up to five years post-transplant.

    Measured: Assessed up to 5 years

  2. Overall Survival

    Number of patients surviving up to five years post-transplant.

    Measured: Assessed up to 5 years

  3. Transplant-related Mortality

    Number of patients with TRM within 100 days post-transplant.

    Measured: At day 100

  4. Transplant-related Mortality

    Number of patients with TRM within one year post-transplant.

    Measured: At 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jan 2003 (estimated)
  2. Study start13 Jul 2001
  3. Primary completionJul 2014
  4. Study completionMay 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
28 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00036738
Sponsor's protocol ID
1581.00
Other IDs
NCI-2010-00131, 1581.00, P01CA078902, P30CA015704
Status last verified
Dec 2019
First submitted
13 May 2002
Last updated
29 Jan 2020
Data monitoring committee
Yes

Publications

  • Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.

    PubMed 32499241

  • Ram R, Storb R, Sandmaier BM, Maloney DG, Woolfrey A, Flowers ME, Maris MB, Laport GG, Chauncey TR, Lange T, Langston AA, Storer B, Georges GE. Non-myeloablative conditioning with allogeneic hematopoietic cell transplantation for the treatment of high-risk acute lymphoblastic leukemia. Haematologica. 2011 Aug;96(8):1113-20. doi: 10.3324/haematol.2011.040261. Epub 2011 Apr 20.

    PubMed 21508120

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