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Accelerated Phase Chronic Myelogenous LeukemiaNCT00856388

Fludarabine Phosphate, Melphalan, Total-Body Irradiation, Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Bone Marrow Failure Disorders

A study testing fludarabine phosphate, melphalan and total-body irradiation in people with Accelerated Phase Chronic Myelogenous Leukemia and Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, run by Roswell Park Cancer Institute at 1 site 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 clinical trial is studying how well giving fludarabine phosphate and melphalan together with total-body irradiation followed by donor stem cell transplant works in treating patients with hematologic cancer or bone marrow failure disorders. Read more about this study

Who is it for?
Ages 3 to 75 years
What is being tested?
fludarabine phosphate, melphalan and total-body irradiation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
62 participants
Where
1 siteUnited States
Study dates
14 Jan 2009to 13 Mar 2019
Phase
Interventional

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 3 to 75 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Diagnosis of a histology documented hematologic malignancy or marrow disorder
  • Bone marrow failure disorders and other non-malignant hematologic or immunologic disorders:
  • Acquired bone marrow failure disorders include aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH):
  • Primary allogeneic hematopoietic stem cell transplantation (HSCT) is appropriate for selected patients with severe aplastic anemia; however, patients with aplastic anemia must have failed at least one cycle of standard immunosuppressive therapy with calcineurin inhibitor plus anti-thymocyte globulin (ATG) if a fully-matched donor is not available
  • Patients with PNH must have a history of thrombosis related to PNH
  • Hereditary bone marrow failure disorders include Fanconi anemia or related chromosomal breakage syndrome dyskeratosis congenita, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, Kostmann syndrome, congenital amegakaryocytic thrombocytopenia:
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  • Fanconi anemia or related chromosomal breakage syndrome: positive chromosome breakage analysis using diepoxybutane (DEB) or mitomycin C if applicable
  • Dyskeratosis: diagnosis is supported by using either telomerase reverse transcriptase (TERC) gene mutation in autosomal dominant Dyskeratosis Congenita or Xlinked DKC1 gene mutation
  • Other non-malignant hematologic or immunologic disorders that require transplantation
  • Quantitative or qualitative congenital platelet disorders (including but not limited to congenital amegakaryocytopenia, absent-radii syndrome, Glanzmann's thrombasthenia)
  • Quantitative or qualitative congenital neutrophil disorders (including but not limited to chronic granulomatous disease, congenital neutropenia)
  • Congenital primary immunodeficiencies (including but not limited to Severe Combined Immunodeficiency Syndrome, Wiskott-Aldrick syndrome, CD40 ligand deficiency, T-cell deficiencies)
  • Acute leukemias:
  • Subjects must be ineligible for conventional myeloablative transplantation;
  • Resistant or recurrent disease after at least one standard combination chemotherapy regime or first remission patients at high risk of relapse OR First remission patients at high risk of relapse:
  • Acute myeloid leukemia (AML)- antecedent myelodysplastic syndrome, secondary AML, high risk cytogenetic abnormalities or normal cytogenetics with high-risk molecular features (e.g. Flt3-ITD mutation, mixed-lineage leukemia [MLL], wildtype NPM1);
  • Acute lymphocytic leukemia (ALL)- high or standard risk ALL
  • Chronic Myeloid Leukemia (CML):
  • Chronic phase (intolerant or unresponsive to imatinib and/or other tyrosine kinase inhibitors), second chronic phase or accelerated phase who are ineligible for conventional myeloablative transplantation
  • Myeloproliferative and myelodysplastic syndromes (MDS):
  • Myelofibrosis (with/without splenectomy) with intermediate to high risk features
  • Advanced polycythemia vera not responding to standard therapy
  • MDS with an international prostate symptom score (IPSS) score of Int-2 or higher
  • MDS with lower IPSS scores Int-1 or less with severe clinical features such as severe neutropenia or thrombocytopenia or high risk chromosome abnormalities such as monosomy 7
  • Secondary massively parallel signature sequencing (MPSS) with any IPSS scores
  • Chronic myelomoncytic leukemia
  • Lymphoproliferative disease:
  • Chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin lymphoma (NHL) (recurrent or persistent) fludarabine refractory or with less than 6 months duration of complete response (CR) between courses of conventional therapy
  • Multiple myeloma, progressive disease after autologous stem cell transplant or as planned tandem (allogeneic transplant after prior autologous stem cell transplant)
  • Waldenstroms macroglobulinemia (failed one standard regimen)
  • High grade NHL and diffuse large B-cell lymphoma (DLBCL)
  • Not eligible for conventional myeloablative HSCT OR failed autologous HSCT
  • First remission lymphoblastic lymphoma, or small, non-cleaved cell lymphoma or mantle cell lymphoma
  • Hodgkin disease:
  • Relapsed or refractory after front-line therapy
  • Failed or were not eligible for autologous transplantation
  • Failed prior autotransplant
  • Age >= 3 and =< 75 years for blood and bone marrow transplants and age >= 3, < 60 for cord blood transplants
  • No serious uncontrolled psychiatric illness
  • No concomitant active malignancy other than non-melanoma skin cancer
  • Non-pregnant and non-nursing women (women or men with reproductive potential should agree to use an effective means of birth control)
  • Patients may have received prior autologous bone marrow transplant (BMT) or prior myeloablative allogeneic BMT (at least 60 days have elapsed)
  • At least 2 weeks since prior chemotherapy, radiation treatment and/or surgery
  • Informed consent
  • DONOR: Permissible HLA matching: Related donors- single antigen mismatch at HLA A, B or DRB 1; unrelated donors- a single antigen mismatch at HLA A, B, or C, +/- additional single allele level mismatch at A, B, C or DRB1; cord blood >= 4 out of 6 antigen match at HLA A, B, DRB1)
  • DONOR: Compatibility at the four most informative HLA loci: A, B, C and DRB1 are important for reducing the risk of GVHD and successful transplant outcomes; the A, B, C and DRB1 loci comprise 8 possible alleles (a haplotype being inherited from each parent); one additional locus, HLA-DQ, is also typed to ascertain haplotypes and assist in the search for a compatible donor; however mismatching at DQ has not been shown to be associated with adverse outcomes; high resolution molecular typing (at the allele level) is now the standard of care for unrelated donor searches and allows greater refinement of the search strategy
  • DONOR: Matched related donor: a single antigen mismatch at A, B, or the DR transplant from a family member is associated with a higher risk of GVHD but similar overall survival when compared to full identity at these 3 regions; related donor/recipient pairs must be matched at 5 of 6 HLA antigens (A, B, DRBl)
  • DONOR: Unrelated donor: when evaluating patients for unrelated donor transplant, a higher degree of matching is preferred due to minimize the risk of GVHD; the A, B, C, DRB1 and DQ loci, comprising 10 possible alleles, will be typed routinely for all unrelated transplants; given the higher risk of TRM in mismatched transplants, RIT is often the best way to mitigate the risk; evolving data from the National Marrow Donor Program now makes it possible to estimate the risks of donor-recipient HLA mismatch at the allele or antigen level; the higher risk from HLA-mismatching must be carefully assessed with respect to the clinical urgency and the patient's risk by the transplant physician; antigen level mismatches at DQ are inconsequential to transplant outcomes and are ignored with respect to donor selection for the purposes of this protocol, with matching requirements confined to the 8 loci involving HLA A, B, C and DRB1; for the purpose of this protocol, a single antigen mismatch at HLA A, B, or C, with or without additional single allele level mismatch may participate in this protocol for voluntary unrelated donors (blood or marrow); patients must be at least antigen-level matched at DRB1
  • DONOR: If a patient has no suitable family donor matched for 5 of 6 HLA antigens (A, B, DRB1) and no suitable unrelated donor is identified or for reasons of urgency, the patient can be considered a candidate for cord blood transplant, provided a cord blood donor is identified with a >= 4 out of 6 antigen match at HLA A, B, DRB1 antigens; the cord blood product must provide a minimum of 2 x 10^7 nucleated cells/kg, test negative for HIV and Hepatitis A, Band C, and sterility assays have no growth; the cord blood products are located through the National Marrow Donor Program, the American Registry, or the Bone Marrow Donor Worldwide or other established registries, and may be stored in the N.Y Placental Cord Blood Bank, the St. Louis Cord Blood Bank, or any of the established, registered International blood and marrow banks
  • DONOR: Donor must be healthy and have nonreactive test results for all infectious disease assays as required by state and federal regulations; donors who screen seropositive for hepatitis and/or syphilis must be cleared by infectious disease consultation
  • DONOR: The donor must have no uncontrolled cardiopulmonary, renal, endocrine, hepatic or psychiatric disease to render donation unsafe
  • DONOR: The donor must be able to give informed consent for peripheral blood stem cell collection or bone marrow collection
  • DONOR: Syngeneic donors are not eligible
  • DONOR: Donors who have poor peripheral venous access, may require central venous line placement for stem cell apheresis

Who cannot join

  • Uncontrolled central nervous system (CNS) disease (for hematologic malignancies)
  • Karnofsky (adult) or Lansky (for =< 16 years) performance status =< 50%
  • Diffusing capacity of the lung for carbon monoxide (DLCO) less than 40% predicted, corrected for hemoglobin (Hb) and/or alveolar ventilation
  • Cardiac: left ventricular ejection fraction less than 40%
  • Bilirubin >= 3 x upper limit of normal
  • Liver alkaline phosphatase >= 3 x upper limit of normal
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  • Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvate transaminase (SGPT) >= 3 x upper limit of normal
  • Child's class B and C liver failure
  • Calculated creatinine clearance < 40 cc/min by the modified Cockcroft-Gault formula for adults or the Schwartz formula for pediatrics
  • Patients who have received maximally allowed doses (given in 2 Gy fractions, or equivalent) of previous radiation therapy to various organs as follows:
  • Mediastinum 40 Gy
  • Heart (any volume) 36 Gy
  • Whole lungs 12 Gy
  • Small bowel (any volume) 46 Gy
  • Kidneys 12 Gy
  • Whole liver 20 Gy
  • Spinal cord (any volume) 36 Gy
  • Whole brain 30 Gy Enrollment of patients who previously receive higher than allowed dose of radiation to a small volume of lungs, liver, and brain will be determine by the discretion of the radiation oncologist on the study
  • Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or other condition which, in the opinion of treating physician, would make this protocol unreasonably hazardous for the patient
  • Human immunodeficiency virus (HIV) positive
  • Patients who in the opinion of the treating physician are unlikely to comply with the restrictions of allogeneic stem cell transplantation based on formal psychosocial screening
  • Females of childbearing potential with a positive pregnancy test

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Roswell Park Cancer Institute

    Buffalo, New York, 14263

Other trials in United States

About this study

Official title: A Pilot Trial Of Reduced Intensity Allogeneic Stem Cell Transplantation With Fludarabine, Melphalan, And Low Dose Total Body Irradiation

This clinical trial is studying how well giving fludarabine phosphate and melphalan together with total-body irradiation followed by donor stem cell transplant works in treating patients with hematologic cancer or bone marrow failure disorders. Giving low doses of chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells or abnormal 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 cells and help destroy any remaining cancer or abnormal cells (graft-versus-tumor effect)

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the transplant related mortality (TRM) of this reduced intensity transplantation (RIT) combination in a patient population that is usually not eligible for a full myeloablative allogeneic transplant.

SECONDARY OBJECTIVES:

  1. To evaluate engraftment, safety, clinical response, evidence of graft-versus-malignancy effect/graft-versus-host disease (GVHD) and overall outcomes of treatment with our RIT regimen across a variety of hematological conditions.

OUTLINE: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -2 and melphalan* IV over 30 minutes on day -2. Patients then undergo total-body irradiation on day -1 and allogeneic stem cell transplantation on day 0.

Note: *Patients with chromosomal breakage syndromes, such as Fanconi anemia or dyskeratosis congenita, receive anti-thymocyte globulin IV over 4 hours on day -4 to -2 instead of melphalan.

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

Being tested
fludarabine phosphate, melphalan, total-body irradiation, allogeneic hematopoietic stem cell transplantation, anti-thymocyte globulin
Medical subject headings
Leukemia, Myeloid, Accelerated Phase, Congenital Abnormalities, Lymphoma, Extranodal NK-T-Cell, Lymphoma, Large-Cell, Anaplastic, Immunoblastic Lymphadenopathy, Anemia, Aplastic, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative, Lymphoma, Large B-Cell, Diffuse

What participants receive

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

  • fludarabine phosphateDrug

    Also called 2-F-ara-AMP, Beneflur, Fludara

    Given IV

  • melphalanDrug

    Also called Alkeran, CB-3025, L-PAM, L-phenylalanine mustard

    Given IV

  • total-body irradiationRadiation

    Also called TBI

    Undergo total-body irradiation

  • allogeneic hematopoietic stem cell transplantationProcedure or surgery

    Undergo allogeneic stem cell transplantation

  • anti-thymocyte globulinBiological

    Also called ATG, ATGAM, lymphocyte immune globulin, Thymoglobulin

    Given IV

Study groups in NCT00856388
Study groupRoleWhat they receive
Treatment (Reduced intensity allogeneic stem cell transplant)ExperimentalPatients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan* IV over 30 minutes on day -2. Patients then undergo total-body irradiation on day -1 and allogeneic stem cell transplantation on day 0. Note: *Patients with chromosomal breakage syndromes, such as Fanconi anemia or dyskeratosis congenita, receive anti-thymocyte globulin IV over 4 hours on day -4 to -2 instead of melphalan.
Receives: Drug: fludarabine phosphate; Drug: melphalan; Radiation: total-body irradiation; Procedure: allogeneic hematopoietic stem cell transplantation; Biological: anti-thymocyte globulin

What is being measured

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

  1. Day 100 TRM

    Day 100 Treatment Related Mortality An exact 95% confidence interval will be provided.

    Measured: First 100 days

Secondary outcomes (7)

  1. Median Time to ANC Engraftment

    Median Time to ANC Engraftment

    Summarized using standard descriptive statistics along with corresponding 95% confidence intervals.

    Measured: Days 30

  2. Median Time to Platelet Engraftment

    Median Time to Platelet Engraftment

    Summarized using standard descriptive statistics along with corresponding 95% confidence intervals.

    Measured: Day 100

  3. Rate of Complete Donor Chimerism - Blood

    Rate of Complete Donor Chimerism - Blood

    Summarized using standard descriptive statistics.

    Measured: Day 30

  4. Rate of Complete Donor Chimerism - Blood

    Rate of Complete Donor Chimerism - Blood

    Summarized using standard descriptive statistics.

    Measured: Day 100

  5. Acute GVHD Grade III-IV

    Acute GVHD grade III-IV

    Summarized using standard descriptive statistics along with corresponding 95% confidence intervals.

    Measured: Up to day 100

  6. 1 yr Extenstive Chronic GVHD

    1 yr Extensive Chronic GVHD

    Summarized using standard descriptive statistics along with corresponding 95% confidence intervals.

    Measured: Up to 4.5 years

  7. 3 yr Overall Survival

    3 yr Overall Survival estimated using the Kaplan-Meier method.

    Measured: Up to 4.5 years

Timeline

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

  1. First posted5 Mar 2009 (estimated)
  2. Study start14 Jan 2009
  3. Primary completion9 Aug 2012
  4. Study completion13 Mar 2019

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 N/A
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
62 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00856388
Sponsor's protocol ID
I 118807
Other IDs
NCI-2009-01508
Status last verified
Oct 2019
First submitted
4 Mar 2009
Last updated
13 Nov 2019
Data monitoring committee
Yes

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