Ex-Vivo Expanded Donor Regulatory T Cells for Prevention of Acute Graft-versus-Host Disease
This phase I trial studies donor regulatory T lymphocytes in preventing acute graft-versus-host disease (GVHD) in patients undergoing donor stem cell transplant. GVHD is a disease caused when cells from a donated stem cell graft attack the normal tissue of the transplant patient. Regulatory T lymphocytes are a type of immune cell that blocks the actions of some other types of lymphocytes, to keep the immune system from becoming over-active. Regulatory T lymphocytes may be a better treatment for preventing acute graft-versus-host disease caused by a donor stem cell transplant.
Inclusion Criteria
- Signed informed consent
- Hematologic malignancies - Acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), multiple myeloma (MM) - in complete remission (CR) * Complete remission is defined per morphologic, cytogenetic, fluorescence in situ hybridization (FISH), molecular, and radiographic imaging studies appropriate for each condition listed
- AML, ALL * Normal values for absolute neutrophil count (> 1000/microL) and platelet count (> 100,000/microL) * Absence of extramedullary leukemia * Less than 5 percent blast cells present in the bone marrow
- MDS * Bone marrow with =< 5 percent myeloblasts with normal maturation of all cell lines * Peripheral blood demonstrates hemoglobin >= 11 g/dL, platelets >= 100 x 10^9/L, neutrophils >= 1 x 10^9/L, and no circulating blasts
- CLL * Absence of constitutional symptoms attributable to CLL * No lymph nodes > 1.5 cm in diameter on computed tomography * No hepatomegaly or splenomegaly by computed tomography * Absolute neutrophil count > 1500/microL * Platelet count > 100,000/microL * No clonal lymphocytes in the peripheral blood by immunophenotyping * Bone marrow with no evidence of clonal CLL (by flow cytometry and/or immunohistochemistry)
- NHL * No clinical evidence of disease or disease-related symptoms * Typically fludeoxyglucose (FDG)-avid lymphomas: a post-treatment residual mass of any size is permitted as long as it is positron emission tomography (PET) negative * Variably FDG-avid lymphoma/FDG avidity unknown: all lymph nodes normal size by computed tomography (CT) * Spleen and liver non-palpable and without nodules * If pretreatment bone marrow biopsy was positive, repeat bone marrow biopsy must be negative; if morphologically indeterminate, immunohistochemistry should be negative
- HL * No clinical evidence of disease or disease-related symptoms * A post-treatment residual mass of any size is permitted as long as it is PET negative * Spleen and liver must be non-palpable and without nodules * If a pre-treatment bone marrow biopsy was positive, an adequate bone marrow biopsy from the same site must be cleared of infiltrate; if this is indeterminate by morphology, immunohistochemistry should be negative
- MM * Absence of monoclonal protein in serum and urine by immunofixation with no current evidence of soft tissue plasmacytoma * Bone marrow aspirate and biopsy must demonstrate less than 5 percent clonal plasma cells * In patients who lack measurable M proteins in the serum and urine being monitored using the free light chain (FLC) levels, the definition of complete response (CR) requires a normalization of the FLC ratio in addition to the above criteria
- MDS – may have achieved CR through either hypomethylating agent therapy, induction chemotherapy, or other therapy
- MDS – low/intermediate-1 International Prognostic Scoring System (IPSS) risk category patients are eligible only if they have failed prior therapy or are transfusion-dependent
- Peripheral blood white blood cells (WBC) greater than 2,000 per microliter (required for collection of dendritic cell precursors)
- Left ventricular ejection fraction (LVEF) >= 45% by multi gated acquisition (MUGA) scan or echocardiogram
- Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted values on pulmonary function tests
- Transaminases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) < 3 times upper limit of normal values
- Creatinine clearance >= 50 cc/min
- Infectious disease criteria: * No active infection; infection controlled with antimicrobial therapy is not excluded * Human immunodeficiency virus (HIV) negative by enzyme-linked immunosorbent assay (ELISA) or reverse transcription-polymerase chain reaction (RT-PCR) (if ELISA is positive and RT-PCR is negative, the ELISA is considered false positive) * Hepatitis B and C negative by serology or RT-PCR * Must complete full screening panel: ** HIV 1, 2 serology and RT-PCR ** Human T-lymphotropic virus (HTLV) 1,2 serology ** Rapid plasma reagin (RPR) serology ** Epstein–Barr virus (EBV) serology ** Cytomegalovirus (CMV) serology ** Herpes simplex virus (HSV) serology ** Varicella zoster virus (VZV) serology
- Karnofsky performance status score >= 60%
- Agreement to utilize effective contraceptive methods during the study (for one year)
- DONOR: Eligible donors will include siblings age >= 18 matched with the recipient at human leukocyte antigen (HLA)-A, B, C, and DRB1 * Donor selection and stem cell product transplantation will be in compliance with 21 Code of Federal Regulation (CFR) 1271
Exclusion Criteria
- Antithymocyte globulin (ATG) as part of the conditioning regimen
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01795573.
PRIMARY OBJECTIVE:
I. To evaluate the safety of sirolimus based immune suppression and ex-vivo expanded donor regulatory T cells for the prevention of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation.
SECONDARY OBJECTIVE:
I. Monitor regulatory T cells (Treg) repopulation, longevity, and antigen-specific suppressive function after hematopoietic cell transplantation (HCT) in vivo.
OUTLINE:
CONDITIONING REGIMEN: Patients receive standard fludarabine phosphate and busulfan or fludarabine phosphate and melphalan.
LYMPHOCYTE AND DONOR STEM CELL INFUSION: Patients receive donor regulatory T lymphocytes IV on day -2 and undergo allogeneic hematopoietic stem cell transplant on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or orally (PO) starting on day 0 with taper at day 50 and sirolimus PO daily starting on day -2 and continuing until 1 year in the absence of acute GVHD.
After completion of study treatment, patients are followed up for 1 year.
Trial PhasePhase I
Trial Typeprevention
Lead OrganizationMoffitt Cancer Center
Principal InvestigatorJoseph Pidala
- Primary ID17263
- Secondary IDsNCI-2014-01426, MCC-17263
- ClinicalTrials.gov IDNCT01795573