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: October 11, 2014
Last verified: September 2014
  Purpose

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

...


Condition Intervention Phase
Hematologic Neoplasms
Neural Tube Defects
Myeloproliferative Disorders
Drug: Rituximab
Drug: Fludarabine
Drug: Cyclosporine
Drug: Etoposide
Drug: Doxorubicin
Drug: Vincristine
Drug: Cyclophosphamide
Biological: T-Rapa cell DLI
Procedure: T cell DLI
Drug: Prednisone
Procedure: Allogeneic HSCT
Drug: Filgrastim
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 510
Study Start Date: December 2003
Estimated Study Completion Date: December 2021
Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: IVDco 1
Transplant + GVHD prophylaxis + preparative chemotherapy regimen + single T-Rapa cell DLI in patients with CD4 count between 50 and 200 inclusive
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).
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: IVD co 2
Transplant + GVHD prophylaxis + preparative chemotherapy regimen + single T- cell DLI in patients with low CD4 count between 50 and 200 inclusive
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
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: IVD co 3
Transplant + GVHD prophylaxis + multiple T-Rapa cell DLI in patients with CD4 count lower than 50
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: 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).
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)

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   11 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • 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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00074490

Contacts
Contact: Daniel H Fowler, M.D. (301) 402-8641 dhfowler@helix.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States
Sponsors and Collaborators
Investigators
Principal Investigator: Daniel H Fowler, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT00074490     History of Changes
Obsolete Identifiers: NCT00077480
Other Study ID Numbers: 040055, 04-C-0055
Study First Received: June 19, 2006
Last Updated: October 11, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Leukemia
Lymphoma
Multiple Myeloma
Bone Marrow Transplantation
Immune Therapy

Additional relevant MeSH terms:
Hematologic Neoplasms
Myeloproliferative Disorders
Neural Tube Defects
Spinal Dysraphism
Bone Marrow Diseases
Congenital Abnormalities
Hematologic Diseases
Neoplasms
Neoplasms by Site
Nervous System Diseases
Nervous System Malformations
Cyclophosphamide
Cyclosporine
Cyclosporins
Doxorubicin
Etoposide
Fludarabine
Fludarabine phosphate
Liposomal doxorubicin
Prednisone
Rituximab
Sirolimus
Vincristine
Alkylating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimetabolites

ClinicalTrials.gov processed this record on October 20, 2014