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Accelerated Phase Chronic Myelogenous LeukemiaPhase 2NCT01427881

Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies

A Phase 2 study testing cyclophosphamide, cyclosporine and peripheral blood stem cell transplantation in people with Accelerated Phase Chronic Myelogenous Leukemia and Adult Acute Lymphoblastic Leukemia in Remission, run by Fred Hutchinson Cancer Center 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 phase II trial studies how well cyclophosphamide works in preventing chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplant in patients with hematological malignancies. Read more about this study

Who is it for?
Ages Up to 65 years
What is being tested?
cyclophosphamide, cyclosporine and peripheral blood stem cell transplantation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
43 participants
Where
1 siteUnited States
Study dates
Sep 2011to Jul 2015
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 Up to 65 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Acute lymphocytic leukemia (ALL) in morphologic first complete remission (CR1) with high risk features defined as, but not limited to: evidence of adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or mixed-lineage leukemia (MLL) rearrangements; presence of minimal residual disease; progenitor B-cell immunophenotype; high white blood cells (WBC) at diagnosis (> 30,000/ul in B-ALL; > 100,000/ul in T-ALL); or delayed attainment of CR (> 4 weeks) after induction therapy; additional clinical characteristics deemed to confer a high relapse risk may be discussed with and approved by the Principal Investigator (PI)
  • Acute myeloid leukemia (AML) in CR1 EXCEPT patients with low-risk features defined as:
  • Inv 16 or t(8;21) in the absence of c-kit mutations
  • Normal karyotype who are FLT3-ITD-negative and NPM1-positive in the absence of c-kit mutations
  • Patients with respective "low-risk" features are eligible, however, if (i) more than 1 cycle of induction therapy was required to achieve CR1 (ii) the patient had a preceding myelodysplastic syndrome (MDS) other than myelofibrosis, or (iii) secondary AML
  • Acute leukemia in 2nd or greater CR (CR >= 2)
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  • Refractory or relapsed AML with =< 10% bone marrow blasts and no circulating blasts or proven extramedullary disease
  • AML transformed from myelodysplastic syndrome (MDS) with < 10% bone marrow blasts
  • MDS with following high risk features:
  • High risk cytogenetics (including, but not limited to: 7q--, inv[3], t[3q], del[3q] or complex karyotype)
  • International Prognostic Scoring System (IPSS) intermediate (INT)-2 or greater
  • Treatment-related MDS
  • Any phase of MDS if patient is < 21 years of age
  • Chronic myelogenous leukemia (CML) beyond 1st chronic phase or resistant or intolerant to tyrosine kinase inhibitors (adults) or any phase (pediatric < 21 years)
  • Chronic myelomonocytic leukemia
  • Philadelphia-negative myeloproliferative disorder
  • Lymphoma: relapsed chemotherapy-sensitive (complete or partial response) Hodgkin or non-Hodgkin lymphoma
  • Multiple myeloma-stage III
  • The patient or legal representative must be able to understand and give written informed consent
  • DONORS: The donor must be a genotypically HLA-identical sibling, a phenotypically HLA-matched first-degree relative, or an unrelated donor who is molecularly matched with the patient at HLA-A, B, C, DRB1
  • DONORS: Donors must meet the selection criteria for administration of G-CSF (filgrastim) and apheresis defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened per the American Association of Blood Banks (AABB)
  • DONORS: Donors must be capable of giving informed consent

Who cannot join

  • Prior autologous or allogeneic stem cell transplant
  • Performance status > 2 (Eastern Cooperative Oncology Group [ECOG]) or < 50 (Lansky; for patients < 16 years old)
  • Uncontrolled infection; the protocol principal investigator (PI) will be final arbiter if there is uncertainty regarding whether a previous infection is under adequate control to allow enrollment in the study
  • Positive serology for human immunodeficiency virus (HIV)-1, 2 or human T cell lymphotropic virus (HTLV)-1, 2
  • Left ventricular ejection fraction < 45% or shortening fraction < 25%; no uncontrolled arrhythmias or symptomatic cardiac disease
  • Symptomatic pulmonary disease; forced expiratory volume in one second (FEV1), forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO) =< 50% of predicted (corrected for hemoglobin); if pulmonary function tests cannot be performed, an oxygen saturation < 92% on room air
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  • Calculated (Cockcroft-Gault or appropriate calculation for pediatric patients) serum creatinine clearance =< 60 mL/min; if the calculated CrCl is 50-60 mL/min, but a measured CrCl by 24 hour urine collection is > 60 mL/min, this measurement is acceptable
  • Total serum bilirubin more than twice upper normal limit
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3-fold higher than laboratory upper normal limits
  • Female patient must have negative serum pregnancy test (all women of child bearing-potential must have test performed)
  • DONORS: Potential donors who for psychological, physiological, or medical reasons cannot tolerate administration of G-CSF or apheresis
  • DONORS: Donors who are allergic to filgrastim or Escherichia (E.) coli-derived proteins
  • DONORS: Donor-related risks to recipients
  • DONORS: Positive anti-donor lymphocytotoxic crossmatch
  • DONORS: Donors who are positive for HIV

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

Official title: A Phase II Study to Evaluate the Efficacy of Posttransplant Cyclophosphamide for Prevention of Chronic Graft-versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation

This phase II trial studies how well cyclophosphamide works in preventing chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplant in patients with hematological malignancies. Giving chemotherapy and total-body irradiation before transplantation helps stop the growth of cancer cells and prevents the patient's immune system from rejecting the donor's stem cells. Healthy stem cells from a donor that are infused into the patient help the patient's bone marrow make blood cells; red blood cells, white blood cells, and platelets. Sometimes, however, the transplanted donor cells can cause an immune response against the body's normal cells, which is called graft-versus-host disease (GVHD). Giving cyclophosphamide after transplant may prevent this from happening or may make chronic GVHD less severe.

Read the detailed description

PRIMARY OBJECTIVES:

  1. The primary objective of this study is to assess outcomes when high-dose cyclophosphamide (CY) is administered on days 3 and 4 followed by cyclosporine (CSP) after human leukocyte antigen (HLA)-matched related or unrelated mobilized blood cell transplantation with total-body irradiation (TBI) or busulfan (BU)-based conditioning.

SECONDARY OBJECTIVES:

  1. The secondary objective of this study is to assess hematopoietic cell transplantation (HCT) outcomes when withdrawal of CSP is accelerated in patients without acute graft-versus-host disease (GVHD).

OUTLINE: Patients' conditioning regimens are determined by the Clinical Coordinator after consultation with the attending physician. Based on disease, patients receive either TBI or fludarabine and busulfan.

PREPARATIVE REGIMEN: Patients receive TBI twice daily (BID) on days -4 or -3 to -1. Some patients also receive fludarabine intravenously (IV) daily on days -5 to -2 and busulfan IV over 3 hours once daily (QD) or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo central nervous system (CNS) prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0 per standard practice.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.

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

After completion of study treatment, patients are followed up at day 180 and then annually for 5 years.

Medical subject headings
Leukemia, Myeloid, Accelerated Phase, Leukemia, Megakaryoblastic, Acute, Leukemia, Erythroblastic, Acute, Lymphoma, Extranodal NK-T-Cell, Lymphoma, Large-Cell, Anaplastic, Immunoblastic Lymphadenopathy, Blast Crisis, Burkitt Lymphoma

What participants receive

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

  • cyclophosphamideDrug

    Also called CPM, CTX, Cytoxan, Endoxan

    Given IV

  • cyclosporineDrug

    Also called ciclosporin, cyclosporin, cyclosporin A, CYSP

    Given IV

  • peripheral blood stem cell transplantationProcedure or surgery

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

    Undergo allogeneic PBSCT

  • total-body irradiationRadiation

    Also called TBI

    Undergo TBI

  • fludarabine phosphateDrug

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

    Given IV

  • busulfanDrug

    Also called BSF, BU, Misulfan, Mitosan

    Given IV

  • allogeneic hematopoietic stem cell transplantationProcedure or surgery

    Undergo allogeneic PBSCT

Study groups in NCT01427881
Study groupRoleWhat they receive
Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)ExperimentalPREPARATIVE REGIMEN: Patients receive TBI BID on days -4 or -3 to -1. Some patients also receive fludarabine IV daily on days -5 to -2 and busulfan IV over 3 hours QD or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo CNS prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 per standard practice. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.
Receives: Drug: cyclophosphamide; Drug: cyclosporine; Procedure: peripheral blood stem cell transplantation; Radiation: total-body irradiation; Drug: fludarabine phosphate; Drug: busulfan; Procedure: allogeneic hematopoietic stem cell transplantation

What is being measured

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

  1. Chronic GVHD Requiring Systemic Immunosuppressive Treatment

    Chronic GVHD will be defined by National Institutes of Health (NIH) criteria and requiring systemic treatment. A reduction in the cumulative incidence of GVHD from ~35% to ~15% at 1 year would represent a reasonable goal. A sample size of 42 patients provides 90% power to observe such a difference with one-side 5% type-1 error.

    Measured: At 1 year after transplantation

Secondary outcomes (9)

  1. Donor Engraftment

    Donor engraftment is defined as the count (percent) of patients with full donor chimerism. Full donor chimerism is defined as at least 95% donor CD3 cells in peripheral blood.

    Measured: At day 28

  2. Grades II-IV and III-IV Acute GVHD

    Grades II-IV and III-IV GVHD will be assessed with the use of cumulative incidence plots.

    Measured: Through day +100 post-transplant

  3. Duration of Systemic Immunosuppressive Treatment

    The need for additional immunosuppressive treatment with agents other than those used for prophylaxis, the reasons for their administration (acute GVHD, chronic GVHD, or other reasons) and the duration of its administration will be determined. Patients will be monitored to determine the duration of systemic immunosuppressive treatment. Primary and secondary treatment of acute GVHD and withdrawal of systemic immunosuppressive treatment will be assessed with the use of cumulative incidence plots.

    Measured: Up to 5 years

  4. Persistent or Recurrent Malignancy After HCT

    Recurrent or progressive malignancy will be assessed with the use of cumulative incidence plots. Recurrent malignancy will be defined by hematologic criteria. Recurrent malignancy will also be defined as any unplanned medical intervention designed to prevent progression of malignant disease in patients who have molecular, cytogenetic or flow-cytometric evidence of malignant cells after transplantation.

    Measured: At 2 years

  5. Non-relapse Mortality

    Defined as death in the absence of recurrent or progressive malignancy after HCT. Non-relapse morality will be assessed with the use of cumulative incidence plots. This secondary endpoint will be characterized and presented as a cumulative incidence.

    Measured: At 2 years

  6. Overall Survival

    Overall survival will be evaluated as Kaplan-Meier estimates.

    Measured: At 1 year post-transplant

  7. Disease-free Survival

    Disease-free survival will be evaluated as Kaplan-Meier estimates.

    Measured: At 1 year post-transplant

  8. Hematologic Recovery

    Descriptive statistics will be used to assess the median days of neutrophil and platelet recovery. The day of neutrophil recovery is defined as the first day of three consecutive lab values on different days, after the conditioning regimen-induced nadir of blood counts, that the absolute neutrophil count is > 500/uL. The day of platelet recovery is defined as the first day of three consecutive lab values on different days, after the conditioning regimen-induced nadir of blood counts, that the platelet count is >= 20,000/uL without platelet transfusion support in the seven days prior.

    Measured: Up to day +100

  9. Graft Failure

    Descriptive statistics will be used to assess the incidence of primary graft failure and secondary graft failure. Primary graft failure is defined as failure to achieve a sustained neutrophil count of >= 500/uL by >= 28 days post-transplant. Secondary graft failure is defined as the decline in neutrophil count to < 500/uL after achieving engraftment which is unrelated to infection or drug effect and is unresponsive to stimulation by growth factors.

    Measured: By greater than or equal to 28 days post-transplant

Timeline

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

  1. First posted2 Sep 2011 (estimated)
  2. Study startSep 2011
  3. Primary completionJun 2014
  4. Study completionJul 2015

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
43 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01427881
Sponsor's protocol ID
2541.00
Other IDs
NCI-2011-02459, P30CA015704
Status last verified
May 2017
First submitted
31 Aug 2011
Last updated
19 May 2017
Data monitoring committee
Yes

Publications

  • Mielcarek M, Furlong T, O'Donnell PV, Storer BE, McCune JS, Storb R, Carpenter PA, Flowers ME, Appelbaum FR, Martin PJ. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016 Mar 17;127(11):1502-8. doi: 10.1182/blood-2015-10-672071. Epub 2016 Jan 13.

    PubMed 26764356

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing cyclophosphamide, cyclosporine and peripheral blood stem cell transplantation in people with Accelerated Phase Chronic Myelogenous Leukemia and Adult Acute Lymphoblastic Leukemia in Remission, run by Fred Hutchinson Cancer Center 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 22 inclusion and 15 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 19 May 2017. 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 19 May 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?

Chronic GVHD Requiring Systemic Immunosuppressive Treatment (time frame: At 1 year after transplantation). 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 NCT01427881, which also lists 1 linked publication.

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 19 May 2017.

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