Combination Chemotherapy, Donor Stem Cell Transplant, Tacrolimus, Mycophenolate Mofetil, and Cyclophosphamide in Treating Patients With Hematologic Cancer

October 28, 2013 updated by: Northside Hospital, Inc.

A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients With Hematologic Malignancies

RATIONALE: Giving chemotherapy, such as fludarabine, busulfan, and cyclophosphamide, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a 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 cells from a donor can make an immune response against the body's normal cells. Giving high-dose cyclophosphamide together with tacrolimus and mycophenolate mofetil after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well combination chemotherapy works when given together with a donor stem cell transplant, followed by tacrolimus, mycophenolate mofetil, and high-dose cyclophosphamide, in treating patients with high-risk hematologic cancer.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

  • To estimate the incidence of graft rejection and severe graft-versus-host disease after myeloablative HLA-mismatched peripheral blood stem cell transplantation (PBSCT) from first-degree relatives in patients with high-risk hematologic malignancies.

Secondary

  • To estimate overall survival, relapse, non-relapse mortality, and event-free survival in these patients.
  • To characterize additional hematologic and non-hematologic toxicities of myeloablative haploidentical PBSCT.
  • To characterize donor hematopoietic chimerism in peripheral blood stem cells after PBSCT.

OUTLINE:

  • Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -2, busulfan IV over 3 hours on days -7 to -4, and cyclophosphamide IV over 1-2 hours on days -3 and -2.
  • Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo infusion of unmanipulated peripheral blood stem cells on day 0.
  • Post-transplant regimen: Patients receive high-dose cyclophosphamide IV over 1-2 hours on days 3 and 4, tacrolimus IV over 24 hours or orally twice daily on days 5-180, and oral mycophenolate mofetil 3 times daily on days 5-34 followed by a taper to day 90. Treatment continues in the absence of disease progression or clinically significant graft-vs-host disease.

After completion of PBSCT, patients are followed periodically for 1 year.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Georgia
      • Atlanta, Georgia, United States, 30342
        • Blood and Marrow Transplant Group of Georgia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Diagnosis of one of the following high-risk hematologic malignancies:

    • Chronic myelogenous leukemia meeting one of the following criteria:

      • Disease in chronic phase and resistant to available tyrosine kinase inhibitors
      • Disease in accelerated phase
      • Disease with blast crisis that has entered into a second chronic phase after induction chemotherapy

    • Acute myelogenous leukemia meeting the following criteria:

      • Marrow blasts < 5% but persistence of minimal residual disease by flow cytometry, cytogenetics, or FISH

      • Must meet one of the following criteria:

        • Disease in second or subsequent complete remission
        • Primary induction chemotherapy failure with disease subsequently entering complete remission
        • Disease in first complete remission with poor-risk cytogenetics or arising from preceding hematological disease

    • Myelodysplastic syndrome meeting at least one of the following criteria:

      • Treatment-related
      • Monosomy 7 or complex cytogenetics
      • International prognostic scoring system score ≥ 1.5
      • Chronic myelomonocytic leukemia

    • Acute lymphocytic leukemia or lymphoblastic lymphoma meeting the following criteria:

      • Marrow blasts < 5% but persistence of minimal residual disease by flow cytometry, cytogenetics, or FISH

      • Must meet one of the following criteria:

        • Disease in second or subsequent complete remission
        • Acute lymphocytic leukemia with poor-risk karyotype [e.g., t(9;22) or bcr-abl fusion, t(4;11), or other MLL translocation] and in first complete remission

    • Chronic lymphocytic leukemia or prolymphocytic leukemia meeting both of the following criteria:

      • Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy including purine analogs
      • In the opinion of the transplant physician, unlikely to benefit from reduced intensity transplantation due to the presence of one or more high-risk features (i.e., bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy)

    • Hodgkin or non-Hodgkin lymphoma (including low-grade, mantle cell, and intermediate-grade/diffuse disease) meeting the following criteria:

      • Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy or autologous transplantation
      • In the opinion of the transplant physician, unlikely to benefit from reduced intensity transplantation due to the presence of one or more high-risk features (i.e., bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy) NOTE: A new classification scheme for adult non-Hodgkin lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.
  • No available matched related or unrelated donor OR a matched related or unrelated donor will not be available in the time frame necessary to perform a transplant

  • Availability of a first-degree relative (parent, child, sibling) matched at 3/6-5/6 loci (HLA-A, -B, -DR)

    • Donor must be willing to donate mobilized peripheral blood stem cells
    • No positive HLA crossmatch in the host-vs-graft direction or high titer donor-specific antibodies

PATIENT CHARACTERISTICS:

  • Karnofsky performance status 70-100%
  • Bilirubin < 2 mg/dL (unless due to hemolysis, Gilbert syndrome, or primary malignancy)
  • Creatinine < 2 mg/dL OR creatinine clearance ≥ 40 mL/min
  • Not pregnant
  • Fertile patients must use effective contraception
  • LVEF (Left ventriculr ejection fraction) ≥ 45%
  • FEV_1 and forced vital capacity ≥ 50% predicted
  • No HIV positivity
  • No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment and follow-up

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No immunosuppressive agents ≤ 24 hours after completion of post-transplant cyclophosphamide (including steroids as antiemetics)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Myeloablative Haploidentical Transplant
All patients will receive treatment using Fludarabine, Busulfan and Cyclophosphamide prior to receiving a haploidentical transplant followed by post-transplant cyclosphosphamide.
Drug: busulfan
110 mg/m2 infused over 3 hours once daily on 4 consecutive days (Days -7, -6, -5, -4)
Drug: cyclophosphamide
14.5 mg/kg infused over 1-2 hours once daily on 2 consecutive days (days -3,-2).
Drug: fludarabine phosphate
30mg/m2 infused over 30 minutes once daily on three consecutive days (days -5, -4, -3)
Drug: mycophenolate mofetil
15 mg/kg po three times a daily with a maximum dose of 3gm/day starting D+5. To be discontinued on Day +35 in the absence of clinically significant GVHD.
Other Names:
  • CellCept
Drug: tacrolimus
0.03 mg/kg/day infuse over 24 hours starting on day +5 (adjusted to maintain trough level of 5-15 ng/ml). Switch to oral (twice daily divided dose) on day +21 or when able to tolerate PO. Discontinue on day +180 in the absence of clinically significant GVHD.
Other Names:
  • Prograf, FK-506
Procedure: allogeneic hematopoietic stem cell transplantation
Patients to received unmanipulated PBSCs on Day 0
Other Names:
  • Allo HSCT
Procedure: peripheral blood stem cell transplantation
patients to receive unmanipulated PBSCs on day 0
Other Names:
  • allogeneic hematopoietic stem cell transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Graft Rejection for Patients at Day 100
Time Frame: Day 100
Number of patients who experienced graft rejection by Day 100
Day 100
Number of Patients Who Experienced Severe Graft-versus-host Disease (GVHD)(Grade 3 or 4)
Time Frame: Day 100
Number of patients who experienced post-transplant complication (GVHD) as seen by clinical evidence
Day 100

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival at Day 100
Time Frame: Day 100
Overall survival is assessed, without regard to disease status, post-transplant, at Day 100.
Day 100
Non-relapse Mortality at 1 Year After Peripheral Blood Stem Cell Transplantation (PBSCT)
Time Frame: 1 year
Non-relapse mortality refers to whether a patient dies of causes related to something other than the primary disease.
1 year
Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 30 Post-transplantation
Time Frame: Day 30
Chimerism analysis of peripheral blood mononuclear cells using PCR (polymerase chain reaction) for STR/VNTR (short tandme repeat/variable number tandem repeat) will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.
Day 30
Non-relapse Mortality at Day 100 After Peripheral Blood Stem Cell Transplantation (PBSCT)
Time Frame: Day 100
Day 100
Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 60 Post-transplantation
Time Frame: Day 60
Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.
Day 60
Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 90 Post-transplantation
Time Frame: Day 90
Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.
Day 90
Overall Survival at 12 Months
Time Frame: 12 months
Overall survival, defined as a patient being alive after transplant, is without regard to disease status.
12 months
Disease Free Survival at 12 Months
Time Frame: 12 months
Disease free survival refers to patients with no evidence of disease after transplant, at the 12 month time point.
12 months
Disease Free Survival at Day 100
Time Frame: Day 100
Disease free survival refers to patients with no evidence of disease after transplant, at the Day 100 time point.
Day 100

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Northside Hospital, Inc.

Investigators

  • Principal Investigator: Scott R. Solomon, MD, Blood and Marrow Transplant Group of Georgia
  • Principal Investigator: H. Kent Holland, MD, Blood and Marrow Transplant Group of Georgia
  • Principal Investigator: Lawrence E. Morris, MD, Blood and Marrow Transplant Group of Georgia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2008

Primary Completion (Actual)

April 1, 2011

Study Completion (Actual)

April 1, 2012

Study Registration Dates

First Submitted

October 29, 2008

First Submitted That Met QC Criteria

October 29, 2008

First Posted (Estimate)

October 31, 2008

Study Record Updates

Last Update Posted (Estimate)

November 21, 2013

Last Update Submitted That Met QC Criteria

October 28, 2013

Last Verified

March 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000617648
  • BMTGG-NSH-864

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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