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Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00520130
First Posted: August 23, 2007
Last Update Posted: August 24, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Steven Pavletic, M.D., National Institutes of Health Clinical Center (CC)
  Purpose

Background:

Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without a human leukocyte-antigen (HLA) tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patients immune system attacks the transplanted donor cells.

This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic.

Objectives:

To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system.

To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant.

Eligibility:

People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling.

Design:

All patients receive chemotherapy before transplant to treat the cancer and suppress immune function.

All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant.

Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows:

  • Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continues for 6 months following SCT.
  • Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months.

Patients receive the donors stem cells and immune cells 2 days after completing the conditioning regimen.

Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status.

A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.


Condition Intervention Phase
Myelodysplastic Syndrome Hodgkin's Lymphoma Non-Hodgkin's Disease Acute Leukemia Multiple Myeloma Biological: Rituximab Drug: Cyclosporine Drug: Allogenic stem cell transplant (ASCT) Drug: Conditioning Chemotherapy Drug: TMS Drug: FLAG Drug: EPOCH-F Biological: Alemtuzumab Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Targeted Immune-Depleting Chemotherapy and Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation Using 8/8 and 7/8 HLA-matched Unrelated Donors and Utilizing Two Graft-versus-Host Disease Prophylaxis Regimens for the Treatment of Leukemias, Lymphomas, and Pre-malignant Blood Disorders

Resource links provided by NLM:


Further study details as provided by Steven Pavletic, M.D., National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Percentage of Participants With Grade II-IV Acute Graft Versus Host Disease (GVHD) [ Time Frame: 6 months ]
    Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria.

  • Percentage of Participants With Chronic Graft Versus Host Disease (cGVHD) [ Time Frame: 2 years post transplant ]
    Chronic GVHD is assessed by the 2005 Chronic GVHD Consensus Project. First the individual organ scoring is done, and then based on that the Global score is determined (mild-moderate-severe). See Citation: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11:945-56., for grading criteria.

  • Recovery of Naïve Cluster of Differentiation 4 (CD4) T Cells [ Time Frame: Recipient recovery at 6, 12 and 24 months post transplant ]
    The percentage of C-C motif chemokine receptor 7 (CCR7)+CD45RA+ naïve T cells within the CD4 T cell populations was determined by flow cytometry.

  • Recovery of Naïve Cluster of Differentiation 8 (CD8) T Cells [ Time Frame: Recipient recovery at 6, 12 and 24 months post transplant ]
    The percentage of CCR7+CD45RA+ naïve T cells within the CD4 and CD8 T cell populations was determined by flow cytometry.

  • Changes in Cluster of Differentiation 4 (CD4) T Cell Receptor Vbeta Repertoire [ Time Frame: Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant ]
    Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lower numbers are consistent with a more normal highly diverse repertoire, and high numbers represent a highly skewed, oligoclonal repertoire. The assay is described in Memon SA et al, J Immunol Methods, 2012, 375: 84-92. The repertoire diversity of the CD4 and CD8 T cells of the donor infusion is shown for comparison.

  • Changes in CD8 T Cell Receptor Vbeta Repertoire [ Time Frame: Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant ]
    Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lower numbers are consistent with a more normal highly diverse repertoire, and high numbers represent a highly skewed, oligoclonal repertoire. The assay is described in Memon SA et al, J Immunol Methods, 2012, 375: 84-92. The repertoire diversity of the CD4 and CD8 T cells of the donor infusion is shown for comparison.


Secondary Outcome Measures:
  • Percentage of Participants With Grade III-IV Acute Graft Versus Host Disease (GVHD) [ Time Frame: 6 months ]
    Acute GVHD is assessed by the 1994 Consensus Conference on acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria.

  • Toxicities [ Time Frame: 103 months and 22 days ]
    Here are the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

  • Days to Engraftment of Neutrophils [ Time Frame: 2 years ]
    Days to engraftment is defined as neutrophil recovery: designated by the first of 3 consecutive days with an absolute neutrophil count (ANC) above 500/mm(3).

  • Days to Engraftment of Platelets [ Time Frame: 2 years ]
    Platelet recovery: designated by the first of 7 days where the platelet count remains above 20,000/mm(3) without transfusion support

  • Days to Engraftment of Lymphocytes [ Time Frame: 2 years ]
    Lymphocyte recovery: designated by the first of 3 consecutive days with absolute lymphocyte count (ALC) above 500/mm(3).

  • Overall Survival [ Time Frame: Patients were followed for an average of up to 5 years. ]
    Time between the first day of transplant to the day of death.

  • Early Treatment Related Mortality [ Time Frame: Less than or equal to 28 days after transplantation ]
    Any death occurring within 28 days after transplantation in a patient in continuous remission.

  • Percentage of Participants With Late Treatment Related Mortality [ Time Frame: Greater than 28 days after transplantation ]
    Any death occurring 28 days or more after transplantation in a patient in continuous remission.

  • Decline in Homeostatic Cytokine Interleukin 7 (IL-7) Post-Transplant [ Time Frame: Day 0, 1 week and 2 weeks ]
    During depletion of lymphocytes during transplant conditioning, levels of homeostatic cytokines increase in the blood. These then decline with the expansion of new donor-derived cells. The rapidity of decline may predict acute graft versus host disease (AGVHD). Decline in cytokine IL-7 will be assessed by the enzyme-linked immunosorbent assay (ELISA).

  • Immune Reconstitution of Normal Killer (NK) Cells [ Time Frame: 2 weeks, and 1, 3, 6, 12, and 24 months post transplant ]
    Cluster of differentiation 3 (CD3) - cluster of differentiation 56 (CD56) + Natural Killer (NK) cells within the lymphocyte population were determined by flow cytometry. The absolute numbers of cells/µl were calculated from the absolute lymphocyte count.

  • Immune Reconstitution of Cluster of Differentiation 4 (CD4) T Cell Populations [ Time Frame: 2 weeks, and 1, 3, 6, 12 and 24 months post transplant ]
    Cluster of Differentiation 3 (CD3)+CD4+ and CD3+Cluster of Differentiation 8 (CD8)+ T cells within the lymphocyte population were determined by flow cytometry. The absolute numbers of cells/µl were calculated from the absolute lymphocyte count.

  • Immune Reconstitution of Cluster of Differentiation 8 (CD8) T Cell Populations [ Time Frame: 2 weeks, 1, 3, 6, 12 and 24 months post transplant ]
    Cluster of differentiation 3 (CD3)+cluster of differentiation 4 (CD4)+ and CD3+CD8+ T cells within the lymphocyte population were determined by flow cytometry. The absolute numbers of cells/µl were calculated from the absolute lymphocyte count.


Enrollment: 92
Actual Study Start Date: October 30, 2007
Estimated Study Completion Date: March 2018
Primary Completion Date: October 14, 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A - Tacrolimus, methotrexate, sirolimus (TMS) Arm
TMS Arm
Biological: Rituximab
Rituximab: 375 mg/m(2) intravenous (IV), day 1 for patients with cluster of differentiation 20 (CD20)-positive disease.
Other Name: Rituxan
Drug: Allogenic stem cell transplant (ASCT)
Allogenic stem cell transplant
Drug: Conditioning Chemotherapy

Fludarabine:30 mg/m(2) per day IV infusion over 30 minutes, daily. On days -6, -5, -4, and -3.

Cyclophosphamide:1200 mg/m(2) per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m(2) per day IV infusion, Daily on days 6, -5,-4, and -3

Drug: TMS
Tacrolimus: starting day -3 before transplant, given initially at 0.02 mg/kg/day CIV. Continue IV and then switch to an equivalent oral dose (when patient taking po) titrated for a goal level of 5 to 10 ng/ml; Sirolimus: given as an initial loading dose of 12 mg p.o. on day -3 pre-transplant, 4 mg starting day -2 pre-transplant and titrated for levels 3-12 ng/ml; Methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11 post-transplant. Tacrolimus and sirolimus will be tapered at day +63, day +119 and day +180 post-transplant as tolerated.
Other Name: Prograf
Drug: FLAG
Fludarabine:25 mg/m(2) per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m(2) IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day subcutaneous (SC) beginning 24 hours PRIOR to initiation of chemotherapy
Other Name: Fludarabine+high-dose cytarabine+G-CSF (Filgrastim))
Drug: EPOCH-F
Fludarabine:25 mg/m(2) per day IV infusion over 30 minutes, daily on days 1-4 Etoposide :50 mg/m(2) per day continuous IV infusion over 24 hours on days 1-4 Doxorubicin:10 mg/m(2)/day CIV, days 1-4 Vincristine:0.4 mg/m(2) per day continuous IV infusion over 24 hours daily on days 1-4 Cyclophosphamide:750 mg/m(2) IV infusion over 30 minutes on day 5
Experimental: B - Cyclosporine (AC) Arm
AC Arm
Biological: Rituximab
Rituximab: 375 mg/m(2) intravenous (IV), day 1 for patients with cluster of differentiation 20 (CD20)-positive disease.
Other Name: Rituxan
Drug: Cyclosporine
Cyclosporine: IV over 2 hours or orally every 12 hours on days -1 to 100, followed by a taper if graft versus host disease (GVHD) does not develop.
Other Name: Neoral
Drug: Allogenic stem cell transplant (ASCT)
Allogenic stem cell transplant
Drug: Conditioning Chemotherapy

Fludarabine:30 mg/m(2) per day IV infusion over 30 minutes, daily. On days -6, -5, -4, and -3.

Cyclophosphamide:1200 mg/m(2) per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m(2) per day IV infusion, Daily on days 6, -5,-4, and -3

Drug: FLAG
Fludarabine:25 mg/m(2) per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m(2) IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day subcutaneous (SC) beginning 24 hours PRIOR to initiation of chemotherapy
Other Name: Fludarabine+high-dose cytarabine+G-CSF (Filgrastim))
Drug: EPOCH-F
Fludarabine:25 mg/m(2) per day IV infusion over 30 minutes, daily on days 1-4 Etoposide :50 mg/m(2) per day continuous IV infusion over 24 hours on days 1-4 Doxorubicin:10 mg/m(2)/day CIV, days 1-4 Vincristine:0.4 mg/m(2) per day continuous IV infusion over 24 hours daily on days 1-4 Cyclophosphamide:750 mg/m(2) IV infusion over 30 minutes on day 5
Biological: Alemtuzumab
Alemtuzumab:20 mg/day IV over 8 h on days 8 to 4 pre-transplant.
Other Name: Campath

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 74 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • ELIGIBILITY CRITERIA RECIPIENT ON STANDARD CARE THERAPY:
  • The patient is 18-74 years of age.
  • The patient has a potentially suitable 8/8 donor if they are between the ages of 69-74 years of age or a potentially suitable 8/8 or 7/8 unrelated donor(s) in the National Marrow Registry or Other Available Registry if they are between the ages of 18-74.
  • The patient currently does not meet the protocol s eligibility/enrollment criteria for any reason.
  • There is a high likelihood that the patient, in the opinion of the principal investigator (PI) or lead associate investigator (LAI), will meet the protocols eligibility/enrollment criteria to proceed to transplant after standard therapy is completed.
  • The patient or legal guardian is able to give informed consent.

EXCLUSION CRITERIA RECIPIENT ON STANDARD CARE THERAPY:

  • Human immunodeficiency virus (HIV) infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.
  • Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00520130


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Steven Z Pavletic, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:

Responsible Party: Steven Pavletic, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00520130     History of Changes
Other Study ID Numbers: 070195
07-C-0195
First Submitted: August 21, 2007
First Posted: August 23, 2007
Results First Submitted: November 17, 2016
Results First Posted: August 24, 2017
Last Update Posted: August 24, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Steven Pavletic, M.D., National Institutes of Health Clinical Center (CC):
Unrelated Donors
Reduced Intensity Stem Cell Transplant
Leukemia
Lymphoma
Allogeneic Stem Cell Transplant
Myelodysplastic Syndrome
Multiple Myeloma

Additional relevant MeSH terms:
Lymphoma
Leukemia
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Precancerous Conditions
Fludarabine
Fludarabine phosphate
Alemtuzumab
Rituximab
Cytarabine
Sirolimus
Tacrolimus
Cyclosporins