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Donor Stem Cell Transplant With No or Low-Intensity Chemotherapy Using Sirolimus and Treated Immune Cells to Treat Blood and Lymph Cancers

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00074490
First received: June 19, 2006
Last updated: November 7, 2014
Last verified: September 2014

June 19, 2006
November 7, 2014
December 2003
December 2021   (final data collection date for primary outcome measure)
  • Safety and feasibility [ Time Frame: first 100 days post-transplant ] [ Designated as safety issue: Yes ]
  • Graft-versus-host disease rate [ Time Frame: first 100 days post-transplant ] [ Designated as safety issue: Yes ]
Not Provided
Complete list of historical versions of study NCT00074490 on ClinicalTrials.gov Archive Site
  • Pattern of post-transplantation CD4+ and CD8+ T-cell production of Th1-Th2-type cytokines [ Time Frame: First 100 days post-transplant ] [ Designated as safety issue: No ]
  • Incidence of opportunistic infection [ Time Frame: 2 years post-transplant ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
Not Provided
 
Donor Stem Cell Transplant With No or Low-Intensity Chemotherapy Using Sirolimus and Treated Immune Cells to Treat Blood and Lymph Cancers
Allogeneic HSCT Without Preparative Chemotherapy or With Low-Intensity Preparative Chemotherapy Using Sirolimus and Sirolimus-Generated Donor Th2 Cells for Therapy of Refractory Leukemia, Lymphoma, Myeloma, or Myelodysplastic Syndrome

Background:

Patients with cancers of the blood and immune system often benefit from transplants of stem cells from a genetically well-matched sibling. However, severe problems may follow these transplants because of the high-dose chemotherapy and radiation that accompany the procedure. Also, donated immune cells sometimes attack healthy tissues in a reaction called graft-versus-host disease (GVHD), damaging organs such as the liver, intestines and skin. To reduce toxicity of high-dose preparative chemotherapy, this study performs allogeneic transplant after low doses of chemotherapy. In an attempt to improve anti-tumor effects without increasing GVHD, this study uses donor immune cells (Th2 cells) grown in the laboratory; some patients will receive standard donor immune cells (not grown in laboratory). All patients will receive immune modulating drugs sirolimus and cyclosporine to prevent GVHD.

Objective:

To determine the safety, treatment effects and rate of GVHD in patients receiving transplants that use low-intensity chemotherapy, sirolimus plus cyclosporine, and transplant booster with either Th2 cells or standard immune cells.

Eligibility:

Patients 16 to 75 years of age with acute or chronic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome.

Patients must have a suitable genetically matched sibling donor and adequate kidney, heart and lung function.

Design: The protocol has three treatment groups: cohort 1, Th2 booster at two weeks post-transplant; cohort 2, standard T cell booster at two weeks post-transplant; cohort 3, multiple infusion of Th2 cells.

Condition< TAB> Hematologic Neoplasms, Myeloproliferative Disorders

Intervention< TAB> Biological; therapeutic allogeneic lymphocytes

< TAB> < TAB> Drug: Sirolimus

Study Type:< TAB> Interventional

Study Design:< TAB> Primary Purpose: Treatment

Phase:< TAB> < TAB> Phase II

...

Background:

Patients with cancers of the blood and immune system often benefit from transplants of stem cells from a genetically well-matched sibling. However, severe problems may follow these transplants because of the high-dose chemotherapy and radiation that accompany the procedure. Also, donated immune cells sometimes attack healthy tissues in a reaction called graft-versus-host disease (GVHD), damaging organs such as the liver, intestines and skin. To reduce toxicity of high-dose preparative chemotherapy, this study performs allogeneic transplant after low doses of chemotherapy. In an attempt to improve anti-tumor effects without increasing GVHD, this study uses donor immune cells (Th2 cells) grown in the laboratory; some patients will receive standard donor immune cells (not grown in laboratory). All patients will receive immune modulating drugs sirolimus and cyclosporine to prevent GVHD.

Objective:

To determine the safety, treatment effects and rate of GVHD in patients receiving transplants that use low-intensity chemotherapy, sirolimus plus cyclosporine, and transplant booster with either Th2 cells or standard immune cells.

Eligibility:

Patients 16 to 75 years of age with acute or chronic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome.

Patients must have a suitable genetically matched sibling donor and adequate kidney, heart and lung function.

Design: The protocol has three treatment groups: cohort 1, Th2 booster at two weeks post-transplant; cohort 2, standard T cell booster at two weeks post-transplant; cohort 3, multiple infusion of Th2 cells.

Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Hematologic Neoplasms
  • Neural Tube Defects
  • Myeloproliferative Disorders
  • Drug: Rituximab
    Rituximab:375 mg/m2/day IV, day 1 (for CD20+ patients)
  • Drug: Fludarabine
    Fludarabine:25 mg/m2/day IV, days 1-4
  • Drug: Cyclosporine
    Cyclosporine:2 mg/kg/dose every 12 hours on day +7
  • Drug: Etoposide
    Etoposide: 50 mg/m2/day CIV, days 1-4
  • Drug: Doxorubicin
    Doxorubicin:10 mg/m2/day CIV, days 1-4
  • Drug: Vincristine
    Vincristine:0.4 mg/m2/day CIV, days 1-4
  • Drug: Cyclophosphamide
    Cyclophosphamide, 750 mg/m2/day IV, day 5
  • Biological: T-Rapa cell DLI
    The dose of Th2 cells or unmanipulated donor T cells will attempt to be held constant for each study recipient (target dose 2.5 x 107 Th2/kg; minimum dose will be 1 x 107 Th2/kg).
  • Procedure: T cell DLI
    Th2 Cell Transplantation
  • Drug: Prednisone
    Prednisone:60 mg/m2/day PO, days 1-5
  • Procedure: Allogeneic HSCT
    Allogeneic Hematopoietic Stem Cell Transplant
  • Drug: Filgrastim
    Filgrastim:5 mcg/kg/day SC, day 6 (require ANC & gt; 1000, two values; or ANC & gt; 5000 cells/ul on one occasion)
  • Experimental: IVDco 1
    Transplant + GVHD prophylaxis + preparative chemotherapy regimen + single T-Rapa cell DLI in patients with CD4 count between 50 and 200 inclusive
    Interventions:
    • Drug: Rituximab
    • Drug: Fludarabine
    • Drug: Cyclosporine
    • Drug: Etoposide
    • Drug: Doxorubicin
    • Drug: Vincristine
    • Drug: Cyclophosphamide
    • Biological: T-Rapa cell DLI
    • Drug: Prednisone
    • Procedure: Allogeneic HSCT
    • Drug: Filgrastim
  • Experimental: IVD co 2
    Transplant + GVHD prophylaxis + preparative chemotherapy regimen + single T- cell DLI in patients with low CD4 count between 50 and 200 inclusive
    Interventions:
    • Drug: Rituximab
    • Drug: Fludarabine
    • Drug: Cyclosporine
    • Drug: Etoposide
    • Drug: Doxorubicin
    • Drug: Vincristine
    • Drug: Cyclophosphamide
    • Procedure: T cell DLI
    • Drug: Prednisone
    • Procedure: Allogeneic HSCT
    • Drug: Filgrastim
  • Experimental: IVD co 3
    Transplant + GVHD prophylaxis + multiple T-Rapa cell DLI in patients with CD4 count lower than 50
    Interventions:
    • Drug: Rituximab
    • Drug: Fludarabine
    • Drug: Cyclosporine
    • Drug: Etoposide
    • Drug: Doxorubicin
    • Drug: Cyclophosphamide
    • Biological: T-Rapa cell DLI
    • Drug: Prednisone
    • Procedure: Allogeneic HSCT
    • Drug: Filgrastim

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
510
December 2021
December 2021   (final data collection date for primary outcome measure)
  • INCLUSION CRITERIA: PATIENT RECIPIENT

    1. Patients with hematologic malignancies, myelodysplasia, or myeloproliferative disorders, as summarized in the following table. The diagnosis must be histologically confirmed by the Laboratory of Pathology of NCI or Hackensack (There will be no central pathology review).
    2. Chronic Lymphocytic Leukemia - Disease Status: a) Relapse post-fludarabine, b) Non-CR after salvage regimen.

      Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma) - Disease Status: a) Primary treatment failure, b) Relapse after autologous SCT, c) Non-CR after salvage regimen

      Special Cases of High-Risk Lymphoma, including but not limited to : (1) plasma dendritic cell type, 2) Hepato-splenic T cell type, 3) gamma delta pinniculitic T cell type, 4) Muco-cutaneous NK cell type and 5) stage III-IV nasal NK cell type- Disease Status: a) Primary treatment failure, b) Relapse after autologous, c) Non-CR after salvage regimen, d) In forist CR or any later CR

      Chronic EBV-associated lymphoproliferative disease a) At any point after diagnosis, including up-front therapy

      Multiple Myeloma - Disease Status: a) Primary treatment failure, b) Relapse after autologous SCT, c) Non-CR after salvage regimen.

      Acute Myelogenous Leukemia - Disease Status: a) CR number 1 and high-risk [excludes t(8;21), t(15;17), or inv(16)], b) CR number 2 or greater).

      Acute Lymphocytic Leukemia - Disease Status: a) CR number 1 plus high-risk [t(9;22) or bcr-abl(+); t(4;11), 1(1;19), t(8;14)], b) In CR number2 or greater.

      Myelodysplastic Syndrome - Disease Status: a) RAEB, b) RAEB-T (requires marrow and blood blasts less than 10% after induction chemotherapy).

      Myeloproliferative disorders - Disease Status: a) Idiopathic myelofibrosis, b) Polycythemia vera, c) Essential thrombocytosis, d) Chronic myelomonocytic leukemia.

      Chronic Myelogenous Leukemia - Disease Status: a) Chronic phase CML, refractory to imatinib treatment b) Accelerated phase CML. b) Accelerated phase CML

      Patients with myeloproliferative disorders must be end-stage, which is primarily defined as disease severity refractory to splenectomy.

    3. Patient age of 16 to 75 years.
    4. Consenting first degree relative matched at 6/6 HLA antigens (A, B, and DR).
    5. Patient or legal guardian must be able to give informed consent.
    6. All previous therapy must be completed at least 2 weeks prior to study entry, with recovery to less than or equal to non-hematologic grade 2 toxicity of previous therapy.
    7. ECOG performance status equal to 0 or 1.
    8. Life expectancy of at least 3 months.
    9. Acute leukemia must be in hematologic remission (less than 10% blood or marrow blasts).
    10. Left ventricular ejection fraction greater than or equal to 45%, preferably by 2-D echo, or by MUGA. However, patients with LVEF of between 35% and 44% may also be eligible provided that such patients are cleared by a Cardiology Consultation that must include a cardiac stress test.
    11. Corrected DLCO greater than 50% of expected value.
    12. Creatinine less than or equal to1.5 mg/dl and creatinine clearance greater than or equal to 50 ml/min.
    13. Serum total bilirubin less than 2.5 mg/dl; serum ALT and AST equal 2.5 times upper limit of normal. Values above these levels may be accepted, at the discretion of the PI or study chairman, if such elevations are thought to be due to liver involvement by malignancy.
    14. Adequate central venous access potential.
    15. Potential patients referred for the study may not be eligible for the experimental protocol therapy due to reasons such as uncertainty about donor HLA typing or need to control malignant disease, infection, or metabolic abnormality such as hypercalcemia on a emergent basis. Should a referred patient present to us in such a scenario, the patient will be referred back to their primary hematologist-oncologist for treatment. However, if referral back to the referring physician is not in the best interest of the patient according to the clinical judgement of the PI, then the patient may receive standard treatment for the malignant disease or complicating conditions (infection, metabolic problems under the current study. In other cases, a patient may have reasonable control of malignancy but does not meet the CD4 cell cut-off of 50 cells per microliter required for cohort 3 therapy; in such cases, standard care chemotherapy regimens may be administered for the specific goal of reducing the CD4 count (that is, immune depleting regimens such as the pentostatin plus cyclophosphamide combination, administered similar to the manner that we have developed on protocol 08-C- 0088). If it becomes apparent that the patient will not be able to proceed to experimental therapy, then he/she must come off study. Recipient-Subjects receiving a standard therapy, and availability of receiving the same treatment elsewhere, outside of a research protocol. Because such standard care therapy is not experimental, it is not necessary to complete the eligibility criteria prior to receiving such standard care; however, prior to initiation of the experimental therapy, the patient must meet each of the eligibility crieteria detailed above. Attempts will be made to standardize such pretransplant

chemotherapy (by administration of EPOCH-FR chemotherapy, which is detailed later in this protocol); however, other regimens using approved agents will be allowed if such regimens are thought to be in the best interest of the patient.

INCLUSION CRITERIA: DONOR

  1. First-degree relative with genotypic identity at 6/6 HLA loci (HLA- A, B, and DR).
  2. Age 11 to 90 years and able to give consent or assent. For donors < 18 years old, the legal guardian must be able to provide informed consent.
  3. Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis.
  4. Donors must be HIV negative.
  5. Donors with a history of hepatitis B or hepatitis C infection may be eligible. However, eligibility determination of such patients will require a hepatology consultation. The risk/benefit of the transplant and the possibility of transmitting hepatitis will be discussed with the patient and eligibility will then be determined by the principal investigator and LAI.
  6. Lactating donors must substitute formula feeding for her infant during period of filgrastim administration (to prevent any filgrastim effect on infant).

EXCLUSION CRITERIA: PATIENT

  1. Active infection that is not responding to antimicrobial therapy.
  2. Active CNS involvement by malignancy.
  3. HIV infection (treatment may result in progression of HIV and other viral infections).
  4. Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For patients with concomitant positive hepatitis B surface antigen, patient will require a hepatology consultation. The risk/benefit profile of transplant and hepatitis B will be discussed with the patient and eligibility determined by the principal investigator and Lead Associate Investigator.
  5. Hepatitis C infection. Patient may have hepatitis C infection. However, each patient will require a hepatology consultation. The risk/benefit profile of transplant and hepatitis C will be discussed with the patient and eligibility determined by the principal investigator and Lead Associate Investigator.
  6. 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.
  7. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.

EXCLUSION CRITERIA: DONOR

  1. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
  2. History of hypertension that is not controlled by medication, stroke, autoimmune disease, or severe heart disease (donors with symptomatic angina will be excluded). Donors with a history of coronary artery bypass grafting or angioplasty who are symptom free will receive a cardiology evaluation and be considered on a case-by-case basis.
  3. History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy may be considered for stem cell donation on a case-by-case basis. In addition, donors with localized cancer such as prostate cancer that are on a watch-and-wait management due to the low-risk of disease progression may also be considered for stem cell donation on a case-by-case basis. The risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time of transplantation will be discussed with the patient.
  4. Donors must not be pregnant (unknown effect of filgrastim on fetus). Donors of childbearing potential must use an effective method of contraception.
  5. Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per microliter). However, potential donors with Hb levels less than 11 gm/dl that is due to iron deficiency will be eligible as long as the donor is initiated on iron replacement therapy and the case is individually approved by NIH or Hackensack Blood Bank.
Both
11 Years to 90 Years
Yes
Contact: Daniel H Fowler, M.D. (301) 435-8641 dhfowler@helix.nih.gov
United States
 
NCT00074490
040055, 04-C-0055
Not Provided
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Daniel H Fowler, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP