Study Stopped
Premature closure due to inability to accrue to ARM IVD, cohorts 1 and 2
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
2 other identifiers
interventional
442
1 country
2
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
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2 lymphoma
Started Jan 2004
Longer than P75 for phase_2 lymphoma
2 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Posted
Study publicly available on registry
December 15, 2003
CompletedStudy Start
First participant enrolled
January 1, 2004
CompletedFirst Submitted
Initial submission to the registry
June 19, 2006
CompletedPrimary Completion
Last participant's last visit for primary outcome
July 20, 2017
CompletedStudy Completion
Last participant's last visit for all outcomes
August 16, 2017
CompletedResults Posted
Study results publicly available
December 31, 2018
CompletedDecember 31, 2018
December 1, 2018
13.6 years
June 19, 2006
October 22, 2018
December 28, 2018
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Percentage of Patients to Receive T Cell Infusion
T cells administered by intravenous infusion after patient received transplant.
first 100 days post-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.
first 100 days post-transplant
Secondary Outcomes (3)
Detection of of Post-transplantation Cluster of Differentiation 4 (CD4)+ and CD8+ T-cell Production of T Helper 1 -2 (Th1-Th2)-Type Cytokines
First 100 days post-transplant
Percentage of Patients With Opportunistic Infection
First 100 days post-transplant
Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0)
Date treatment consent signed to date off study, approximately 5 years
Study Arms (6)
Arm IVD cohort 1 (Th2 DLI)
EXPERIMENTALPatients 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 IVD cohort 2 (conventional DLI)
EXPERIMENTALPatients 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 IVD cohort 3 (multiple Th2 DLI)
EXPERIMENTALPatients 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 IVA (12-day expanded Th2 DLI)
EXPERIMENTALPatients 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 IVB (6-day expanded Th2 DLI)
EXPERIMENTALPatients 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 IVC (6-day expanded Th2 DLI and High-Dose Sirolimus)
EXPERIMENTALPatients 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.
Interventions
Rituximab: 375 mg/m(2)/day intravenous (IV), day 1 (for cluster of differentiation 20 (CD20+) patients).
Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.
Etoposide: 50 mg/m(2)/day continuous intravenous (CIV), days 1-4.
Doxorubicin:10 mg/m(2)/day continuous intravenous (CIV), days 1-4.
Vincristine: 0.4 mg/m(2)/day continuous intravenous (CIV), days 1-4.
Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.
PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.
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).
Prednisone: 60 mg/m(2)/day by mouth (PO), days 1-5.
Allogeneic Hematopoietic Stem Cell Transplant.
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).
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).
Eligibility Criteria
You may qualify if:
- 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.
- +16 more criteria
You may not qualify if:
- 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.
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (2)
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892, United States
Hackensack University Medical Center
Hackensack, New Jersey, 07601, United States
Related Publications (3)
Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827-38. doi: 10.1056/NEJM199403243301206. No abstract available.
PMID: 8114836BACKGROUNDJamshed 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.
PMID: 20661232BACKGROUNDFowler 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.
PMID: 23426943RESULT
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Limitations and Caveats
118 subjects were enrolled on this study on cohorts no longer represented in the protocol due to amendments. Of the 118, 50% were participants and 50% were donors. These participants are not represented in the data being reported.
Results Point of Contact
- Title
- Dr. Steven Pavletic
- Organization
- National Cancer Institute
Study Officials
- PRINCIPAL INVESTIGATOR
Steven Z Pavletic, M.D.
National Cancer Institute (NCI)
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
June 19, 2006
First Posted
December 15, 2003
Study Start
January 1, 2004
Primary Completion
July 20, 2017
Study Completion
August 16, 2017
Last Updated
December 31, 2018
Results First Posted
December 31, 2018
Record last verified: 2018-12
Data Sharing
- IPD Sharing
- Will not share