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Accelerated Phase Chronic Myelogenous LeukemiaPhase 2NCT01529827

Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

A Phase 2 study testing fludarabine phosphate, melphalan and total-body irradiation in people with Accelerated Phase Chronic Myelogenous Leukemia and Adult Acute Lymphoblastic Leukemia in Remission, 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
Search all trials

Trial summary

This phase II trial studies how well giving fludarabine phosphate, melphalan, and low-dose total-body irradiation (TBI) followed by donor peripheral blood stem cell transplant (PBSCT) works in treating patients with hematologic malignancies. 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
94 participants
Where
1 siteUnited States
Study dates
28 Feb 2012to 29 Aug 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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:
  • Acquired bone marrow failure disorders include aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH) * Primary allogeneic 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 available * Patients with PNH should not be eligible for a myeloablative HSCT
  • Hereditary bone marrow failure disorders include Diamond-Blackfan Anemia, Shwachman-Diamond Syndrome, Kostmann Syndrome, congenital Amegakaryocytic Thrombocytopenia; Fanconi Anemia or related chromosomal breakage syndrome, Dyskeratosis Congenital are excluded from this study die to their poor deoxyribonucleic acid (DNA) repair capacity * Fanconi anemia or related chromosomal breakage syndrome: positive chromosome breakage analysis using diepoxybutane (DEB) or mitomycin C if applicable * Dyskeratosis Congenita: diagnosis is supported by using either telomerase RNA component (TERC) gene mutation in autosomal dominant Dyskeratosis Congenita or X-linked 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 immunodeficiency syndrome, Wiskott-Aldrich syndrome, CD40 ligand deficiency, T-cell deficiencies)
  • ACUTE LEUKEMIAS:
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  • Subjects must be ineligible for or unable to receive a conventional myeloablative transplantation
  • Resistant or recurrent disease after at least one standard combination chemotherapy 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 mutations (e.g., fms-like tyrosine kinase3-internal tandem duplication [Flt3-ITD] mutation) * 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 SYNDROME (MDS):
  • Myelofibrosis (with/without splenectomy) with intermediate to high risk features
  • Advanced polycythemia vera nor responding to standard therapy
  • MDS with lower International Prognostic Scoring System (IPSS) score of intermediate (Int)-2 or higher
  • MDS with lower IPSS score Int-1 or less with severe clinical features such as severe neutropenia or thrombocytopenia or high risk chromosome abnormalities such as monosomy 7
  • Secondary MDS with any IPSS scores
  • Chronic myelomonocytic 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 or complete remission (CR) between courses of conventional therapy
  • Multiple myeloma (progressive disease after autologous stem cell transplant, tandem allogeneic transplant after prior autologous stem cell transplant)
  • Waldenstrom's 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 LYMPHOMA:
  • Received and failed front-line therapy
  • Failed or were not eligible for autologous transplantation DONOR: Permissible human leukocyte antigen (HLA) matching: related donors
  • single antigen mismatch at HLA A, B, or DRB1; unrelated donors
  • a single antigen mismatch at HLA A, B, or C, +/- additional single allele level mismatch at A, B, V or DRB1
  • Minimum goal for peripheral blood stem cells (PBSC) dose is 2 x 10^6 CD34+ cells/kg of recipient weight; minimum goal for the marrow dose is 1 x 10^8 nucleated cells/kg of recipient weight
  • No serious uncontrolled psychiatric illness
  • No concomitant active malignancy that would be expected to require chemotherapy within 3 years of transplant (other than non-melanoma skin cancer)
  • Non-pregnant and non-nursing woman; (women or men with reproductive potential should agree to use an effective means of birth control)
  • Patients who have failed a prior autologous or allogeneic transplant are eligible; however, at least 90 days must have elapsed between the start of this reduced intensity conditioning regimen and the last transplant if patient had a prior autologous or myeloablative allogeneic bone marrow transplant (BMT)
  • At least 2 weeks since prior chemotherapy, radiation treatment and/or surgery
  • Informed consent
  • 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, DRB1)
  • DONOR: Unrelated Donor:
  • When evaluating patients for unrelated donor transplant, the higher degree of matching, the lower risk of GvHD; the A, B, C, DRB1 and DQB1 loci, comprising 10 possible antigen (with alleles), will be typed for all unrelated transplants; given the higher risk of TRM in mismatched transplants, RIT is often the best way to mitigate the risk; data from the National Marrow Donor Program makes it possible to estimate the risk of donor-recipient HLA mismatch at the allele or antigen level; the higher risk from HLA-mismatching must be balanced against the clinical urgency and the patient's risk by the transplant team; at this time, antigen level mismatches at DQB1 do not affect outcomes and will not be used for matching purposes for donor selection; thus, the matching required will be at the HLA A, B, C and DRB1 (8 loci); for this protocol, a single antigen mismatch at the HLA A, B, C, with or without additional single allele level mismatch may participate in this protocol for voluntary unrelated donors (blood or marrow) DONOR: Donor must be healthy and have non-reactive test results for all infectious disease assays as required by state and federal regulations; donors who screen seropositive for hepatitis an/or syphilis must be cleared by infectious disease consultation DONOR: Donor must have no uncontrolled cardiopulmonary, renal, endocrine, hepatic or psychiatric disease to render donation unsafe DONOR: The donor (or parent in minor) must 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) < 40% predicted, corrected for hemoglobin and/or alveolar ventilation
  • Left ventricular ejection fraction < 40% - Bilirubin >= 3 X upper limit of normal
  • Liver alkaline phosphatase >= 3 x upper limit of normal
  • Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvate transaminase (SGPT) >= 3 x upper limit of normal
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  • Child's class B and C liver failure
  • Calculated creatinine clearance < 40 cc/min by the modified Cockroft-Gault formula for adults or the Schwartz formula for pediatrics
  • Patients who have received maximally allowed doses (given in 2 Gy fractionations, or equivalent) of previous radiation therapy to various organs as follows: * Mediastinum: adult -40, pediatric (=<18 yrs) - 21 * Heart: adult 36, pediatric - 26 * Whole lung(s): adult - 12, pediatric - 10 * Small bowel: adult - 46, pediatric - 40 * Kidneys: adult - 12, pediatric - 10 * Whole liver: adult - 20, pediatric - 20 * Spinal cord: adult - 36, pediatric - 36 * Whole Brain: adult 30, pediatric - 30
  • Patients who previously have received a higher than allowed dose of radiation to a small lung, liver, and brain volume, will be evaluated by the radiation oncologist to determine if the patient is eligible for 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
  • Female 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 Phase II Trial of Reduced Intensity Allogeneic Stem Cell Transplantation With Fludarabine, Melphalan and Low Dose Total Body Irradiation

This phase II trial studies how well giving fludarabine phosphate, melphalan, and low-dose total-body irradiation (TBI) followed by donor peripheral blood stem cell transplant (PBSCT) works in treating patients with hematologic malignancies. Giving chemotherapy drugs such as fludarabine phosphate and melphalan, and low-dose TBI before a donor PBSCT helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from the donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cell from a donor can make an immune response against the body's normal cells. Giving tacrolimus, mycophenolate mofetil (MMF), and methotrexate after transplant may stop this from happening

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the transplant related mortality (TRM) of this reduced-intensity transplantation (RIT) combination, fludarabine (fludarabine phosphate), melphalan, and TBI in a patient population usually not eligible for a full a myeloablative allogeneic hematopoietic stem cell transplantation (HSCT).

SECONDARY OBJECTIVES:

  1. To evaluate clinical response, progression free survival (PFS) at one year, engraftment rate, and graft-versus-host disease (GvHD) incidence with the proposed RIT regimen across a variety of hematological conditions.

II. Correlative studies will include chimerism analysis by molecular analysis and evaluation of immune reconstitution by cytomegalovirus (CMV) dextramer analysis using flow cytometry.

OUTLINE: PREPARATIVE REGIMEN:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -2 and melphalan IV over 30 minutes on day -2. Patients undergo low-dose TBI twice daily (BID) on day -1.

TRANSPLANTATION:

Patients undergo allogeneic PBSCT on day 0.

GvHD PROPHYLAXIS:

Patients receive tacrolimus IV or orally (PO) BID on days -1 to 100 with taper over 4-6 months, MMF PO or IV every 6-8 hours on days -1 to 60, and methotrexate IV over 15-30 minutes on days 1, 3, and 6. After completion of study treatment, patients are followed up periodically.

Being tested
fludarabine phosphate, melphalan, total-body irradiation, tacrolimus, mycophenolate mofetil
Medical subject headings
Leukemia, Myeloid, Accelerated Phase, Congenital Abnormalities, Lymphoma, Extranodal NK-T-Cell, Lymphoma, Large-Cell, Anaplastic, Immunoblastic Lymphadenopathy, Anemia, Aplastic, Burkitt Lymphoma, 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 TBI

  • tacrolimusDrug

    Also called FK 506, Prograf

    Given IV or PO

  • mycophenolate mofetilDrug

    Also called Cellcept, MMF

    Given IV or PO

  • methotrexateDrug

    Also called amethopterin, Folex, methylaminopterin, Mexate

    Given IV

  • laboratory biomarker analysisOther

    Correlative studies

  • allogeneic hematopoietic stem cell transplantationProcedure or surgery

    Undergo allogeneic PBSCT

  • peripheral blood stem cell transplantationProcedure or surgery

    Also called PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell

    Undergo PBSCT

Study groups in NCT01529827
Study groupRoleWhat they receive
Treatment (reduced intensity allogeneic PBSCT)ExperimentalPREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan IV over 30 minutes on day -2. Patients undergo low-dose TBI BID on day -1. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. GvHD PROPHYLAXIS: Patients receive tacrolimus IV or PO BID on days -1 to 100 with taper over 4-6 months, MMF PO or IV every 6-8 hours on days -1 to 60, and methotrexate IV over 15 to 30 minutes on days 1, 3, and 6.
Receives: Drug: fludarabine phosphate; Drug: melphalan; Radiation: total-body irradiation; Drug: tacrolimus; Drug: mycophenolate mofetil; Drug: methotrexate; Other: laboratory biomarker analysis; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation

What is being measured

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

  1. Transplant Related Mortality (TRM)

    Day 100 transplant related mortality (TRM). An exact 95% confidence interval will be provided.

    Measured: In the first 100 days from day 0 of transplant

Secondary outcomes (3)

  1. Clinical Response

    Patients will be followed according to response criteria as referenced in BMT SOP "Standards of Therapy" last updated 2008. Clinical Response = CR + PR.

    Complete Response Requires all of the following:

    • Serum and urine negative for monoclonal proteins by immunofixation
    • Normal free light chain ratio
    • Plasma cells in marrow < 5%

    Partial Response (PR) Requires any of the following:

    • ≥ 50% reduction in current serum monoclonal protein levels > 0.5 g/dL or urine light chain levels > 100 mg/day with a visible peak or free light chain levels > 10mg/dL

    Progressive Disease (PD) Requires any of the following:

    • If progressing from CR, any detectable monoclonal protein or abnormal free light chain ratio (light chain must double)
    • If progressive from PR or SD, ≥ 50% increase in the serum M protein to > 0.5 g/dL,or ≥ 50% increase in urine M protein to > 200mg/day with visible peak present.
    • Free light chain increase of ≥ 50% to

    Measured: In the first 100 days from day 0 of transplant

  2. Progression Free Survival (PFS) at One Year

    Assessed using Kaplan Meier and Proportional Hazards

    Measured: day of transplant until progression up to 5 years

  3. Median Time to Neutrophil Engraftment

    Median time to recovery of absolute neutrophil count >=500/uL for 3 consecutive days. Summarized using standard descriptive statistics along with corresponding 95% confidence intervals.

    Measured: Day 100

Timeline

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

  1. First posted9 Feb 2012 (estimated)
  2. Study start28 Feb 2012
  3. Primary completion28 May 2015
  4. Study completion29 Aug 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 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
94 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01529827
Sponsor's protocol ID
I 177110
Other IDs
NCI-2011-03563
Status last verified
Sep 2019
First submitted
6 Feb 2012
Last updated
24 Sep 2019
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing fludarabine phosphate, melphalan and total-body irradiation in people with Accelerated Phase Chronic Myelogenous Leukemia and Adult Acute Lymphoblastic Leukemia in Remission, run by Roswell Park Cancer Institute at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 44 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Transplant Related Mortality (TRM) (time frame: In the first 100 days from day 0 of transplant). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01529827.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Sep 2019; AzTrials last refreshed its copy on 26 Oct 2026.

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