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Myelodysplastic/Myeloproliferative Neoplasm, UnclassifiablePhase 2NCT00105001

Tacrolimus and Mycophenolate Mofetil With or Without Sirolimus in Preventing Acute Graft-Versus-Host Disease in Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

A Phase 2 study testing Fludarabine Phosphate, Total-Body Irradiation and Peripheral Blood Stem Cell Transplantation in people with Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable and Previously Treated Myelodysplastic Syndrome, run by Fred Hutchinson Cancer Center at 11 sites in 3 countries.

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 randomized phase II trial studies how well giving tacrolimus and mycophenolate mofetil (MMF) with or without sirolimus works in preventing acute graft-versus-host disease (GVHD) in patients undergoing donor stem cell transplant for hematologic cancer. Read more about this study

Who is it for?
Any age
What is being tested?
Fludarabine Phosphate, Total-Body Irradiation and Peripheral Blood Stem Cell Transplantation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
210 participants
Where
11 sitesin 3 countries
Study dates
Nov 2004to 8 May 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 Any age
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Ages > 50 years with hematologic malignancies treatable by unrelated hematopoietic cell transplant (HCT)
  • Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who through pre-existing medical conditions or prior therapy are considered to be at high risk for regimen related toxicity associated with a conventional transplant (> 40% risk of transplant related mortality [TRM]) (This criterion can include patients with a HCT-comorbidity index (CI) score of >= 1; transplants should be approved for these inclusion criteria by both the participating institutions' patient review committees such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC) and by the principal investigators at the collaborating centers)
  • Patients =< 50 years of age who have received previous high-dose transplantation do not require patient review committee approvals (All children < 12 years must be discussed with the FHCRC principal investigator (PI) [Brenda Sandmaier, MD 206 6674961] prior to registration)
  • Ages =< 50 years of age with chronic lymphocytic leukemia (CLL); these patients do not require patient review committee approvals
  • Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who refuse a conventional HCT (Transplants must be approved for these inclusion criteria by both the participating institutions' patient review committee such as PCC at the FHCRC and by the principal investigators at the collaborating centers)
  • The following diseases will be permitted although other diagnoses can be considered if approved by PCC or the participating institutions' patient review committees and the principal investigators:
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  • Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as Diffuse large B cell NHL not eligible for autologous hematopoietic stem cell transplant (HSCT), not eligible for conventional myeloablative HSCT, or after failed autologous HSCT
  • Mantle Cell NHL may be treated in first complete response (CR) (Diagnostic lumbar puncture [LP] required pretransplant)
  • Low grade NHL with < 6 month duration of CR between courses of conventional therapy
  • CLL must have either
  • Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine phosphate (FLU) (or another nucleoside analog, e.g. Cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog);
  • Failed FLU-CY-Rituximab (FCR) combination chemotherapy at any time point; or
  • Have "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR
  • Hodgkin Lymphoma must have received and failed frontline therapy
  • Multiple Myeloma must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted
  • Acute Myeloid Leukemia (AML) must have < 5% marrow blasts at the time of transplant
  • Acute Lymphocytic Leukemia (ALL) must have < 5% marrow blasts at the time of transplant
  • Chronic Myeloid Leukemia (CML) patients will be accepted if they are beyond chronic phase (CP)1 and if they have received previous myelosuppressive chemotherapy or HCT and have < 5% marrow blasts at time of transplant
  • Myelodysplasia (MDS)/Myeloproliferative Syndrome (MPS) patients must have received previous myelosuppressive chemotherapy or HCT and have < 5% marrow blasts at time of transplant
  • Waldenstrom's Macroglobulinemia must have failed 2 courses of therapy
  • DONOR: FHCRC matching allowed will be Grades 1.0 to 2.1: unrelated donors who are prospectively:
  • Matched for human leukocyte antigen (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
  • DONOR: 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; a positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
  • DONOR: 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
  • DONOR: Only filgrastim (G-CSF) mobilized peripheral blood mononuclear cell (PBMC) only will be permitted as a HSC source on this protocol

Who cannot join

  • Patients with rapidly progressive intermediate or high grade NHL
  • Patients with a diagnosis of chronic myelomonocytic leukemia (CMML)
  • Central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
  • Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, MDS, ALL or CML
  • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
  • Females who are pregnant or breast-feeding
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  • Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years
  • Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
  • Cardiac ejection fraction < 35%; ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease
  • Diffusion capacity of carbon monoxide (DLCO) < 40%, total lung capacity (TLC) < 40%, forced expiratory volume in one second (FEV1) < 40% and/or receiving supplementary continuous oxygen
  • The FHCRC PI of the study must approve of 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, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease
  • Karnofsky score < 60 or Lansky score < 50
  • Patient has poorly controlled hypertension and on multiple antihypertensives
  • Human immunodeficiency virus (HIV) positive patients
  • Active bacterial or fungal infections unresponsive to medical therapy
  • All patients receiving antifungal therapy voriconazole, posaconazole, or fluconazole and who are then randomized to ARM 3 must have rapamycin reduced according to the Standard Practice of Antifungal Therapy Guidelines
  • The addition of cytotoxic agents for cytoreduction with the exception of tyrosine kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the initiation of conditioning
  • DONOR: Donor (or centers) who will exclusively donate marrow
  • DONOR: Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of G-PBMC

Trial locations and contacts

11 sites in 3 countries.

11 sites in 3 countries

United States7 sites

  • Emory University/Winship Cancer Institute

    Atlanta, Georgia, 30322

  • Presbyterian - Saint Lukes Medical Center - Health One

    Denver, Colorado, 80218

  • Froedtert and the Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • Huntsman Cancer Institute/University of Utah

    Salt Lake City, Utah, 84112

  • LDS Hospital

    Salt Lake City, Utah, 84143

  • Veterans Administration Center-Seattle

    Seattle, Washington, 98108

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

    Seattle, Washington, 98109

Other trials in United States

Germany3 sites

  • Medizinische Univ Klinik Koln

    Cologne, 50924

  • Universitaet Leipzig

    Leipzig, D-04103

  • University of Tuebingen-Germany

    Tübingen, D-72076

Other trials in Germany

Denmark1 site

  • Rigshospitalet University Hospital

    Copenhagen, 2100

Other trials in Denmark

About this study

Official title: A Randomized Phase II Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute GVHD After Unrelated Donor G-CSF Mobilized Peripheral Blood Mononuclear Cell (G-PBMC) Transplantation Using Nonmyeloablative Conditioning for Patients With Hematologic Malignancies A Multi-Center Trial

This randomized phase II trial studies how well giving tacrolimus and mycophenolate mofetil (MMF) with or without sirolimus works in preventing acute graft-versus-host disease (GVHD) in patients undergoing donor stem cell transplant for hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body-irradiation 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). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving MMF and tacrolimus with or without sirolimus after transplant may stop this from happening.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine which of 3 GVHD prophylaxis regimens results in reduction of acute grades II-IV GVHD to =< 40%.

SECONDARY OBJECTIVES:

  1. Reduce the incidence of non-relapse mortality from infections and GVHD before day 200 to =< 15%.

II. Reduce the utilization of high-dose corticosteroids compared to protocols 1463, 1641, and 1668.

III. Compare survival and progression-free survival to that achieved under protocols 1463, 1641, and 1668.

OUTLINE:

CONDITIONING: All patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2 and undergo total-body irradiation on day 0.

TRANSPLANTATION: All patients undergo allogeneic peripheral blood stem cell transplantation on day 0.

IMMUNOSUPPRESSION: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive tacrolimus IV or orally (PO) every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.

ARM II: Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.

ARM III: Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.

After completion of study treatment, patients are followed up at 6 months and then every year thereafter.

Medical subject headings
Myeloproliferative Disorders, Leukemia, Lymphocytic, Chronic, B-Cell, Multiple Myeloma, Waldenstrom Macroglobulinemia, Leukemia, Myeloid, Accelerated Phase, Leukemia, Myelomonocytic, Acute, Leukemia, Promyelocytic, Acute, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative

What participants receive

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

Study groups in NCT00105001
Study groupRoleWhat they receive
Arm I (MMF and tacrolimus)Active comparatorPatients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD.
Receives: Drug: Fludarabine Phosphate; Radiation: Total-Body Irradiation; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Tacrolimus; Drug: Mycophenolate Mofetil
Arm II (MMF and tacrolimus alternate schedule)ExperimentalPatients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD.
Receives: Drug: Fludarabine Phosphate; Radiation: Total-Body Irradiation; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Tacrolimus; Drug: Mycophenolate Mofetil
Arm III (MMF, tacrolimus, and sirolimus)ExperimentalPatients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80.
Receives: Drug: Fludarabine Phosphate; Radiation: Total-Body Irradiation; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Drug: Sirolimus

What is being measured

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

  1. Number of Participants With Grades II-IV Acute GVHD

    Number of patients with grades II-IV acute GVHD

    aGVHD Stages

    Skin:

    1. a maculopapular eruption involving < 25% BSA
    2. a maculopapular eruption involving 25 - 50% BSA
    3. generalized erythroderma
    4. generalized erythroderma w/ bullous formation and often w/ desquamation

    Liver:

    1. bilirubin 2.0 - 3.0 mg/100 mL
    2. bilirubin 3 - 5.9 mg/100 mL
    3. bilirubin 6 - 14.9 mg/100 mL
    4. bilirubin > 15 mg/100 mL

    Gut:

    Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients w/ visible bloody diarrhea are at least stage 2 gut and grade 3 overall.

    aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death

    Measured: 150 days after transplant

Secondary outcomes (4)

  1. Number of Non-Relapse Mortalities

    Percentage of NRM as estimated by cumulative incidence methods with competing risks.

    Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198

    Measured: 200 days after transplant

  2. Number of Participants Utilizing High-Dose Corticosteroids

    Number of patients utilizing high-dose corticosteroids (as a surrogate marker for reduction of acute GVHD), estimated by cumulative incidence methods.

    Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198

    Measured: 150 days after transplant

  3. Number of Participants Surviving Overall

    Number of patients surviving, estimated by cumulative incidence methods

    Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198

    Measured: 1 Year post-transplant

  4. Number of Participants Surviving Without Progression

    Number of patients with progression-free survival, estimated by cumulative incidence methods

    Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref)" Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198

    Measured: 2 Years 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 posted4 Mar 2005 (estimated)
  2. Study startNov 2004
  3. Primary completionMay 2011
  4. Study completion8 May 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
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
210 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00105001
Sponsor's protocol ID
1938.00
Other IDs
NCI-2010-00268, 1938.00, P30CA015704, P01CA018029
Status last verified
Oct 2019
First submitted
3 Mar 2005
Last updated
30 Oct 2019
Data monitoring committee
Yes

Publications

  • Kornblit B, Maloney DG, Storer BE, Maris MB, Vindelov L, Hari P, Langston AA, Pulsipher MA, Bethge WA, Chauncey TR, Lange T, Petersen FB, Hubel K, Woolfrey AE, Flowers ME, Storb R, Sandmaier BM. A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation. Haematologica. 2014 Oct;99(10):1624-31. doi: 10.3324/haematol.2014.108340. Epub 2014 Aug 1.

    PubMed 25085357

  • 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

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Fludarabine Phosphate, Total-Body Irradiation and Peripheral Blood Stem Cell Transplantation in people with Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable and Previously Treated Myelodysplastic Syndrome, run by Fred Hutchinson Cancer Center at 11 sites in 3 countries.

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 26 inclusion and 20 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 30 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in United States, Germany, Denmark. 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 15 Sep 2015). 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?

Number of Participants With Grades II-IV Acute GVHD (time frame: 150 days after 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 NCT00105001, which also lists 2 linked publications.

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 30 Oct 2019.

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