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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

Primary Purpose

Lymphoma, Leukemia, Myeloproliferative Disorders

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Rituximab
Fludarabine
Etoposide
Doxorubicin
Vincristine
Cyclophosphamide
Peripheral blood stem cell (PBSC) transplantation
T cell donor lymphocyte infusion (DLI) with unmanipulated donor T cells
Prednisone
Allogeneic hematopoietic stem cell transplant (HSCT)
Filgrastim
T-Rapa cell Donor Lymphocyte Infusion (DLI)
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoma focused on measuring Leukemia, Lymphoma, Multiple Myeloma, Bone Marrow Transplantation, Immune Therapy

Eligibility Criteria

11 Years - 90 Years (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

INCLUSION CRITERIA: PATIENT RECIPIENT 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 National Cancer Institute (NCI) or Hackensack (There will be no central pathology review). Chronic Lymphocytic Leukemia - Disease Status: a) Relapse post-fludarabine, b) Non-Complete Response (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 stem cell transplant (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 natural killer (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 first CR or any later CR Chronic Epstein Barr Virus (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 stem cell transplant (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) Refractory Anemia with Excess Blasts (RAEB), b) Refractory Anemia with Excess Blasts in Transformation (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 (CML) - 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. Patient age of 16 to 75 years. Consenting first degree relative matched at 6/6 HLA antigens (A, B, and DR). Patient or legal guardian must be able to give informed consent. All previous intravenous therapy administered outside of the National Institutes of Health (NIH) Clinical Center 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. Eastern Cooperative Oncology Group (ECOG) performance status equal to 0 or 1. Life expectancy of at least 3 months. Patients with acute leukemia must have chemotherapy sensitive disease, as defined by at least a 50% reduction in circulating absolute blast count due to the most proximal regimen. Left ventricular ejection fraction greater than or equal to 45%, preferably by 2-dimension (2-D) echo, or by multi-gated acquisition scan (MUGA). However, patients with left ventricular ejection fraction (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. Corrected diffusing capacity or transfer of the lung for carbon monoxide (DLCO) greater than 50% of expected value. Creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than or equal to 50 ml/min. Serum total bilirubin less than 2.5 mg/dl; serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal 2.5 times upper limit of normal. Values above these levels may be accepted, at the discretion of the principal investigator (PI) or study chairman, if such elevations are thought to be due to liver involvement by malignancy or graft versus host disease (GVHD). Adequate central venous access potential. Potential patients referred for the study may not be eligible for the experimental protocol therapy due to reasons such as uncertainty about donor human leukocyte antigen (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 principal investigator (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 cluster of differentiation 4 (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 criteria detailed above. Attempts will be made to standardize such pretransplant chemotherapy (by administration of etoposide, prednisolone, oncovin, cyclophosphamide, hydroxydaunorubicin, fludarabine, rituximab (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 First-degree relative with genotypic identity at 6/6 HLA loci (HLA- A, B, and DR). 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. Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis. Donors must be human immunodeficiency virus (HIV) negative. 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 lead associate investigator (LAI). Lactating donors must substitute formula feeding for her infant during period of filgrastim administration (to prevent any filgrastim effect on infant). EXCLUSION CRITERIA: PATIENT Active infection that is not responding to antimicrobial therapy. Active central nervous system (CNS) involvement by malignancy. HIV infection (treatment may result in progression of HIV and other viral infections). 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. 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. 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. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent. EXCLUSION CRITERIA: DONOR History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent. 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. 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. Donors must not be pregnant (unknown effect of filgrastim on fetus). Donors of childbearing potential must use an effective method of contraception. Anemia (Hemoglobin (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 National Institutes of Health (NIH) or Hackensack Blood Bank.

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike
  • Hackensack University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm IVD cohort 1 (Th2 DLI)

Arm IVD cohort 2 (conventional DLI)

Arm IVD cohort 3 (multiple Th2 DLI)

Arm IVA (12-day expanded Th2 DLI)

Arm IVB (6-day expanded Th2 DLI)

Arm IVC (6-day expanded Th2 DLI and High-Dose Sirolimus)

Arm Description

Patients receive low intensity fludarabine phosphate intravenous (IV) and cyclophosphamide IV on days -6 to -3. Patients undergo donor lymphocyte infusion (DLI) with sirolimus generated donor T-helper 2 (Th2) cells on day 14 (single T-Rapa cell DLI in patients with cluster of differentiation 4 (CD4) count between 100 and 200 inclusive)

Patients receive low intensity fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3. Patients undergo DLI with unmanipulated donor T-cells on day 14 (single T- cell DLI in patients with low CD4 count between 100 and 200 inclusive)

Patients with nonlymphoma diagnosis or rapidly progressive lymphoma undergo DLI with multiple infusions of sirolimus generated donor Th2 cells beginning on day 14 (multiple T-Rapa cell DLI in patients with CD4 count lower than 100 or ALC lower than 300)

Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine by mouth twice a day (PO BID) on days -4 to 100, and standard dose sirolimus PO on days -2 to 14. Patients undergo mobilized allogeneic peripheral blood stem cells (PBSC) on day 0. Patients undergo DLI with 12-day expanded sirolimus-generated donor Th2 cells on day 14.

Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine PO BID on days -4 to 100, and standard dose sirolimus PO on days -2 to 14. Patients undergo mobilized allogeneic PBSC or bone marrow transplant on day 0. Patients undergo DLI with 6-day expanded sirolimus-generated donor Th2 cells on day 14.

Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine PO BID on days -7 to 100 and high dose sirolimus PO on days -4 to 7, Patients undergo mobilized allogeneic PBSC on day 0. Patients undergo DLI with 6-day expanded sirolimus-generated donor Th2 cells on day 14.

Outcomes

Primary Outcome Measures

Percentage of Patients to Receive T Cell Infusion
T cells administered by intravenous infusion after patient received transplant.
Percentage of Patients With ≥ Grade 2 Acute Graft Versus Host Disease (GVHD)
GVHD of the skin, liver and gut were graded on a scale of 1, 2, 3, and 4 (e.g. the grades are not added together) using the National Institutes of Health Consensus Criteria. Grade 1 is minimal GVHD, Grade 2 is moderate GVHD, Grade 3 is severe GVHD and Grade 4 is very severe GVHD. Grade 4 is a worse outcome than Grade 1.

Secondary Outcome Measures

Detection of of Post-transplantation Cluster of Differentiation 4 (CD4)+ and CD8+ T-cell Production of T Helper 1 -2 (Th1-Th2)-Type Cytokines
Detection of cytokine secretion was done by enzyme-linked immunosorbent assay.
Percentage of Patients With Opportunistic Infection
Participants are susceptible to opportunistic infections such as bacterial, fungal, viral, protozoan infections and more due to immune suppression from chemotherapy drugs used to treat their disease.
Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0)
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Full Information

First Posted
June 19, 2006
Last Updated
December 28, 2018
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00074490
Brief Title
Donor Stem Cell Transplant With No or Low-Intensity Chemotherapy Using Sirolimus and Treated Immune Cells to Treat Blood and Lymph Cancers
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Terminated
Why Stopped
Premature closure due to inability to accrue to ARM IVD, cohorts 1 and 2
Study Start Date
January 1, 2004 (Actual)
Primary Completion Date
July 20, 2017 (Actual)
Study Completion Date
August 16, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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 (T helper 2 (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: Hematologic Neoplasms, Myeloproliferative Disorders Intervention: Biological; therapeutic allogeneic lymphocytes Drug: Sirolimus Study Type: Interventional Study Design: Primary Purpose: Treatment Phase: Phase II
Detailed Description
Background In protocol 99-C-0143, we evaluated a new approach to allogeneic hematopoietic stem cell transplant (HSCT) that involved intensive host T cell ablation and graft augmentation with in vitro generated donor T helper 2 (Th2) cells. Rapid full donor engraftment occurred with this regimen; however, grade II to IV acute graft versus host disease (GVHD) was not significantly reduced in Th2 cell recipients. In an attempt to improve clinical results using Th2 cell graft engineering, this second-generation Th2 cell clinical trial was developed that incorporates the following interventions: (1) In an attempt to reduce transplant-related toxicity, this protocol now uses a very low-intensity host preparative chemotherapy; (2) In an attempt to reduce GVHD, this study will utilize Th2 cells expanded in the presence of the immune modulation agent, rapamycin (sirolimus), as murine Th2 cells grown in rapamycin reduce GVHD more effectively than control Th2 cells; (3) To further reduce GVHD, subjects will receive a short-course of sirolimus therapy in addition to standard cyclosporine GVHD prophylaxis; and (4) Using this novel low-intensity transplant platform, compare in a preliminary manner the post-transplant outcome of patients receiving pre-emptive donor lymphocyte infusion (DLI) using either Th2 cells or unmanipulated donor T cells. Objectives In the setting of human leukocyte antigen (HLA)-matched sibling allogeneic HSCT using GVHD prophylaxis of cyclosporine and short-course sirolimus, compare in a preliminary manner the safety, feasibility, alloengraftment, clinical anti-tumor effects, and GVHD rate of low-intensity Preparative Chemotherapy with pre-emptive DLI using either Th2 cells or unmanipulated T cells at day 14 post-HSCT. Eligibility Subjects that are 16 to 75 years of age that have a suitable 6/6 HLA-matched sibling donor are potentially eligible. Subjects with a diagnosis of acute or chronic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome are potentially eligible. Adequate kidney, cardiac, and pulmonary function are required. Design Patients age 18 or older with lymphoma (all types) or chronic lymphocytic leukemia will be randomized just prior to the transplant regimen to receive DLI with either donor Th2 cells (cohort 1) or unmanipulated T cells (cohort 2); n=10 patients will be accrued to each arm provided that stopping rules pertaining to excessive GVHD or graft rejection are not met. For these randomized patients, the preparative regimen will consist of low-intensity fludarabine (120 mg/m(2)) plus cyclophosphamide (1200 mg/m(2)) and GVHD prophylaxis will consist of short-course, high-dose sirolimus followed by maintenance cyclosporine. Cohorts 1 and 2 will be compared in a preliminary manner with respect to their post-transplant outcome, in particular: (a) conversion of mixed chimerism to predominant donor chimerism; (b) rate and severity of classical acute and late acute GVHD at the day 100 and day 180 post-transplant time points; and (c) time to induction of leukemia/lymphoma remission (if entering transplant with disease) or time to relapse (if entering transplant in remission). Patients with non-lymphoma diagnoses, patients with lymphoma that are under the age of 18 and lymphoma patients that are projected to be unable to complete the protocol-defined therapy through day 180 post-transplant will not be randomized but will be treated on cohort 3 (n=40), which will evaluate transplantation without the Flu/Cy preparative regimen and with pre-emptive Th2 cell DLI. The primary objective of cohort 3 is to evaluate whether transplantation without a preparative regimen will reduce the rate of acute GVHD associated with Th2 cell DLI from 41% (the rate observed with the fludarabine/cyclophosphamide (Flu/Cy) preparative regimen) to a rate of 15% (6 cases out of 40).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma, Leukemia, Myeloproliferative Disorders, Multiple Myleoma, Myelodysplastic Syndrome
Keywords
Leukemia, Lymphoma, Multiple Myeloma, Bone Marrow Transplantation, Immune Therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
442 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm IVD cohort 1 (Th2 DLI)
Arm Type
Experimental
Arm Description
Patients receive low intensity fludarabine phosphate intravenous (IV) and cyclophosphamide IV on days -6 to -3. Patients undergo donor lymphocyte infusion (DLI) with sirolimus generated donor T-helper 2 (Th2) cells on day 14 (single T-Rapa cell DLI in patients with cluster of differentiation 4 (CD4) count between 100 and 200 inclusive)
Arm Title
Arm IVD cohort 2 (conventional DLI)
Arm Type
Experimental
Arm Description
Patients receive low intensity fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3. Patients undergo DLI with unmanipulated donor T-cells on day 14 (single T- cell DLI in patients with low CD4 count between 100 and 200 inclusive)
Arm Title
Arm IVD cohort 3 (multiple Th2 DLI)
Arm Type
Experimental
Arm Description
Patients with nonlymphoma diagnosis or rapidly progressive lymphoma undergo DLI with multiple infusions of sirolimus generated donor Th2 cells beginning on day 14 (multiple T-Rapa cell DLI in patients with CD4 count lower than 100 or ALC lower than 300)
Arm Title
Arm IVA (12-day expanded Th2 DLI)
Arm Type
Experimental
Arm Description
Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine by mouth twice a day (PO BID) on days -4 to 100, and standard dose sirolimus PO on days -2 to 14. Patients undergo mobilized allogeneic peripheral blood stem cells (PBSC) on day 0. Patients undergo DLI with 12-day expanded sirolimus-generated donor Th2 cells on day 14.
Arm Title
Arm IVB (6-day expanded Th2 DLI)
Arm Type
Experimental
Arm Description
Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine PO BID on days -4 to 100, and standard dose sirolimus PO on days -2 to 14. Patients undergo mobilized allogeneic PBSC or bone marrow transplant on day 0. Patients undergo DLI with 6-day expanded sirolimus-generated donor Th2 cells on day 14.
Arm Title
Arm IVC (6-day expanded Th2 DLI and High-Dose Sirolimus)
Arm Type
Experimental
Arm Description
Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine PO BID on days -7 to 100 and high dose sirolimus PO on days -4 to 7, Patients undergo mobilized allogeneic PBSC on day 0. Patients undergo DLI with 6-day expanded sirolimus-generated donor Th2 cells on day 14.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan
Intervention Description
Rituximab: 375 mg/m(2)/day intravenous (IV), day 1 (for cluster of differentiation 20 (CD20+) patients).
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
Toposar
Intervention Description
Etoposide: 50 mg/m(2)/day continuous intravenous (CIV), days 1-4.
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Doxil
Intervention Description
Doxorubicin:10 mg/m(2)/day continuous intravenous (CIV), days 1-4.
Intervention Type
Drug
Intervention Name(s)
Vincristine
Other Intervention Name(s)
Leurocristine
Intervention Description
Vincristine: 0.4 mg/m(2)/day continuous intravenous (CIV), days 1-4.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.
Intervention Type
Procedure
Intervention Name(s)
Peripheral blood stem cell (PBSC) transplantation
Intervention Description
PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.
Intervention Type
Genetic
Intervention Name(s)
T cell donor lymphocyte infusion (DLI) with unmanipulated donor T cells
Intervention Description
The dose of the T cells will attempt to be held constant for each study recipient (target dose 2.5 x 10(7) T cells/kg; minimum dose will be 1 x 10(7) T cells/kg).
Intervention Type
Drug
Intervention Name(s)
Prednisone
Other Intervention Name(s)
Deltasone
Intervention Description
Prednisone: 60 mg/m(2)/day by mouth (PO), days 1-5.
Intervention Type
Procedure
Intervention Name(s)
Allogeneic hematopoietic stem cell transplant (HSCT)
Intervention Description
Allogeneic Hematopoietic Stem Cell Transplant.
Intervention Type
Drug
Intervention Name(s)
Filgrastim
Other Intervention Name(s)
Neupogen
Intervention Description
Filgrastim: 5 mcg/kg/day subcutaneous (SC), day 6 (require absolute neutrophil count (ANC) > 1000, two values; or ANC > 5000 cells/ul on one occasion).
Intervention Type
Genetic
Intervention Name(s)
T-Rapa cell Donor Lymphocyte Infusion (DLI)
Intervention Description
The dose of T helper 2 (Th2) cells or unmanipulated donor T cells will attempt to be held constant for each study recipient (target dose 2.5 x 10(7) Th2/kg; minimum dose will be 1 x 10(7) Th2/kg).
Primary Outcome Measure Information:
Title
Percentage of Patients to Receive T Cell Infusion
Description
T cells administered by intravenous infusion after patient received transplant.
Time Frame
first 100 days post-transplant
Title
Percentage of Patients With ≥ Grade 2 Acute Graft Versus Host Disease (GVHD)
Description
GVHD of the skin, liver and gut were graded on a scale of 1, 2, 3, and 4 (e.g. the grades are not added together) using the National Institutes of Health Consensus Criteria. Grade 1 is minimal GVHD, Grade 2 is moderate GVHD, Grade 3 is severe GVHD and Grade 4 is very severe GVHD. Grade 4 is a worse outcome than Grade 1.
Time Frame
first 100 days post-transplant
Secondary Outcome Measure Information:
Title
Detection of of Post-transplantation Cluster of Differentiation 4 (CD4)+ and CD8+ T-cell Production of T Helper 1 -2 (Th1-Th2)-Type Cytokines
Description
Detection of cytokine secretion was done by enzyme-linked immunosorbent assay.
Time Frame
First 100 days post-transplant
Title
Percentage of Patients With Opportunistic Infection
Description
Participants are susceptible to opportunistic infections such as bacterial, fungal, viral, protozoan infections and more due to immune suppression from chemotherapy drugs used to treat their disease.
Time Frame
First 100 days post-transplant
Title
Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0)
Description
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time Frame
Date treatment consent signed to date off study, approximately 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
11 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
INCLUSION CRITERIA: PATIENT RECIPIENT 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 National Cancer Institute (NCI) or Hackensack (There will be no central pathology review). Chronic Lymphocytic Leukemia - Disease Status: a) Relapse post-fludarabine, b) Non-Complete Response (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 stem cell transplant (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 natural killer (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 first CR or any later CR Chronic Epstein Barr Virus (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 stem cell transplant (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) Refractory Anemia with Excess Blasts (RAEB), b) Refractory Anemia with Excess Blasts in Transformation (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 (CML) - 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. Patient age of 16 to 75 years. Consenting first degree relative matched at 6/6 HLA antigens (A, B, and DR). Patient or legal guardian must be able to give informed consent. All previous intravenous therapy administered outside of the National Institutes of Health (NIH) Clinical Center 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. Eastern Cooperative Oncology Group (ECOG) performance status equal to 0 or 1. Life expectancy of at least 3 months. Patients with acute leukemia must have chemotherapy sensitive disease, as defined by at least a 50% reduction in circulating absolute blast count due to the most proximal regimen. Left ventricular ejection fraction greater than or equal to 45%, preferably by 2-dimension (2-D) echo, or by multi-gated acquisition scan (MUGA). However, patients with left ventricular ejection fraction (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. Corrected diffusing capacity or transfer of the lung for carbon monoxide (DLCO) greater than 50% of expected value. Creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than or equal to 50 ml/min. Serum total bilirubin less than 2.5 mg/dl; serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal 2.5 times upper limit of normal. Values above these levels may be accepted, at the discretion of the principal investigator (PI) or study chairman, if such elevations are thought to be due to liver involvement by malignancy or graft versus host disease (GVHD). Adequate central venous access potential. Potential patients referred for the study may not be eligible for the experimental protocol therapy due to reasons such as uncertainty about donor human leukocyte antigen (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 principal investigator (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 cluster of differentiation 4 (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 criteria detailed above. Attempts will be made to standardize such pretransplant chemotherapy (by administration of etoposide, prednisolone, oncovin, cyclophosphamide, hydroxydaunorubicin, fludarabine, rituximab (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 First-degree relative with genotypic identity at 6/6 HLA loci (HLA- A, B, and DR). 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. Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis. Donors must be human immunodeficiency virus (HIV) negative. 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 lead associate investigator (LAI). Lactating donors must substitute formula feeding for her infant during period of filgrastim administration (to prevent any filgrastim effect on infant). EXCLUSION CRITERIA: PATIENT Active infection that is not responding to antimicrobial therapy. Active central nervous system (CNS) involvement by malignancy. HIV infection (treatment may result in progression of HIV and other viral infections). 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. 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. 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. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent. EXCLUSION CRITERIA: DONOR History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent. 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. 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. Donors must not be pregnant (unknown effect of filgrastim on fetus). Donors of childbearing potential must use an effective method of contraception. Anemia (Hemoglobin (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 National Institutes of Health (NIH) or Hackensack Blood Bank.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven Z Pavletic, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
8114836
Citation
Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827-38. doi: 10.1056/NEJM199403243301206. No abstract available.
Results Reference
background
PubMed Identifier
20661232
Citation
Jamshed S, Fowler DH, Neelapu SS, Dean RM, Steinberg SM, Odom J, Bryant K, Hakim F, Bishop MR. EPOCH-F: a novel salvage regimen for multiple myeloma before reduced-intensity allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011 May;46(5):676-81. doi: 10.1038/bmt.2010.173. Epub 2010 Jul 26.
Results Reference
background
PubMed Identifier
23426943
Citation
Fowler DH, Mossoba ME, Steinberg SM, Halverson DC, Stroncek D, Khuu HM, Hakim FT, Castiello L, Sabatino M, Leitman SF, Mariotti J, Gea-Banacloche JC, Sportes C, Hardy NM, Hickstein DD, Pavletic SZ, Rowley S, Goy A, Donato M, Korngold R, Pecora A, Levine BL, June CH, Gress RE, Bishop MR. Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. Blood. 2013 Apr 11;121(15):2864-74. doi: 10.1182/blood-2012-08-446872. Epub 2013 Feb 20.
Results Reference
result
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2004-C-0055.html
Description
NIH Clinical Center Detailed Web Page

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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

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