Ex-vivo Expanded Donor Regulatory T Cells for Prevention of Acute Graft-Versus-Host Disease

Phase 1

Completed

• Conditions: Graft Versus Host Disease
• Interventions: Biological: Cultured Treg cells

• Registration Number: NCT01795573
• Lead Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Brief Summary

Clinical trial of allospecific regulatory t cells (Tregs) for prevention of acute graft-versus-host disease (GVHD) in human leukocyte antigen (HLA) identical sibling transplants.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2013-02-18
• Study First Submitted QC: 2013-02-18
• Study First Posted: 2013-02-20
• Study Start: 2014-10-29
• Primary Completion: 2020-08-14
• Study Completion: 2020-08-14
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-02
• Last Update Posted: 2022-11-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 38

Inclusion Criteria

• Signed informed consent

• Diagnoses:

  a. 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, 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 FDG-avid lymphomas: a post-treatment residual mass of any size is permitted as long as it is PET negative; Variably FDG-avid lymphoma/FDG avidity unknown: all lymph nodes normal size by 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 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 FLC levels, the definition of CR requires a normalization of the free light chain (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 IPSS risk category patients are eligible only if they have failed prior therapy or are transfusion-dependent

• Peripheral blood white blood count (WBC) greater than 2,000 per microliter (required for collection of dendritic cell precursors)

• Adequate vital organ function: Left ventricular ejection fraction (LVEF) ≥ 45% by multigated acquisition (MUGA) scan or echocardiogram; Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and diffusing lung capacity oxygenation (DLCO) ≥ 50% of predicted values on pulmonary function tests; Transaminases (AST, ALT) < 3 times upper limit of normal values; Creatinine clearance ≥ 50cc/min

• Infectious disease criteria:

  • No active infection; infection controlled with antimicrobial therapy is not excluded
  • HIV negative by 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 cell lymphotropic virus types 1/2 (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

• Performance status: Karnofsky Performance Status Score ≥ 60%.

• Agreement to utilize effective contraceptive methods during the study (for one year)

• Eligible donors will include siblings age ≥ 18 matched with the recipient at HLA-A, B, C, and DRB1

Exclusion Criteria

• Antithymocyte globulin (ATG) as part of the conditioning regimen

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cultured Treg cells	Cultured Treg cells	Co-culturing of recipient dendritic cells and donor Treg cells given prior to allogeneic stem cell transplant

Primary Outcome Measures

Name	Time	Method
Maximally Tolerated dose (MTD)	Up to 1 year	MTD of donor Treg in combination with standard dose SIR/TAC immune suppression. The occurrence of dose-limiting toxicity in \>= 33% serves as the boundary for the MTD of donor Treg.

Secondary Outcome Measures

Name	Time	Method
Non-relapse Mortality	Up to 1 year	Defined as mortality while underlying malignancy is in remission.
Overall Survival (OS)	Up to 1 year	Defined as time from transplantation (day 0 as day of stem cell infusion per standard nomenclature) to death from any cause.
Acute GVHD incidence	Up to day 100	Clinical evidence of acute GVHD will be recorded per standard grading scheme. GVHD grade will be reported weekly from day 0-100 both for site-specific involvement, as well as an overall composite score.
Relapse Free Survival	Up to 1 year	Defined as time from transplantation (day 0 as day of stem cell infusion per standard nomenclature) to relapse or death from any cause.

Trial Locations

Locations (1)

H Lee Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States