Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells

A Feasibility Trial of Post-Transplant Infusion of Allogeneic Regulatory T Cells and Allogeneic Conventional T Cells in Patients With Hematologic Malignancies Undergoing Allogeneic Myeloablative Hematopoietic Cell Transplantation From Haploidentical-Related Donors

Patients with hematologic malignancies will receive myeloablative chemotherapy followed by stem cell rescue with bone marrow or hematopoietic peripheral blood stem cells collected by apheresis from a filgrastim- (G-CSF)-mobilized haploidentical related-donor, ie, hematopoietic peripheral blood stem cell transplant (HSCT).

Study Overview

• Status: Terminated
• Conditions: Chronic Lymphocytic Leukemia (CLL); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndrome (MDS); Acute Myelogenous Leukemia (AML); Leukemia, Acute; Chronic Myelogenous Leukemia (CML); Non-Hodgkin Lymphoma (NHL)
• Intervention / Treatment: Drug: Regulatory T-cells; Drug: Conventional T-cells; Drug: Melphalan; Drug: Thiotepa; Device: Fludarabine; Drug: Anti-thymocyte globulin, rabbit; Drug: CliniMACS CD34 Reagent System

Detailed Description

This is dose-escalation study intended to evaluate the use of classification determinant 15-positive (CD15+), CD4+, CD127dim, and FoxP3+ regulatory T-cells (T-reg cells) supplemented by conventional T-cells (T-con cells), to enhance the efficacy of allogeneic (CliniMACS CD34+ selected) hematopoietic stem cell transplantation (allo-HSCT), in the setting of leukemia, lymphoma, and myelodysplastic syndrome (MDS). This study investigates amelioration of the impaired immune recovery and address the significant relapse incidence in the haploidentical HSCT setting.

Pre-transplant myeloablative conditioning will be melphalan; thiotepa; fludarabine and rabbit antithymocyte globulin (rATG).

Stem cell rescue will be with CD34+ selected cells. The rescue infusion will be supplemented with infusions of regulatory T-cells (T-reg) and conventional T-cells (T-con) from the same donor collection, on Treatment Days 14 and 16 respectively. CD34+ cell infusion day is Treatment Day 0.

T-reg cells are those cells enriched by immunomagnetic selection of CD25+ cells, and further purified by flow cytometric cell sorting for the CD15+, CD4+, CD127dim, FoxP3+ cell population. These cells are an enriched but naturally-occurring T-cell population.

T-con cells are unseparated/unfractionated cells, ie, as collected by the peripheral blood stem cells apheresis procedure.

Post-transplant follow-up is for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

RECIPIENT

• Histopathologically-confirmed:
• Acute leukemia (in first remission with poor risk factors and molecular prognosis)
• Acute myelogenous leukemia (AML) with -5,-7, t (6;9), tri8, -11
• Acute lymphoblastic leukemia (ALL) with Ph+ t (9;22), t (4;22), (q34;q11)
• Acute leukemia with refractory disease or > Complete Remission (CR) 1
• Chronic myelogenous leukemia (CML) (accelerated, blast or second chronic phase)
• Myelodysplastic syndrome (in high and high intermediate risk categories)
• Non-Hodgkin's lymphoma (NHL) with poor risk features and not suitable for autologous transplantation
• Refractory Chronic lymphocytic leukemia (CLL)
• At least 21 days from the end of most recent prior therapy to start of the transplant conditioning regimen
• Must be < 60 years old at time of registration.
• Karnofsky Performance Status (KPS) > 70%

Must have related donor who is:

• Genotypically human leukocyte antigen (HLA) -A, B,C and DR beta 1 (DRB1), DQ loci haploidentical to the recipient (but differing for 2 to 3 HLA alleles on the unshared haplotype in the graft-versus-host disease (GvHD) direction)
• No HLA-matched sibling or matched-unrelated donor is identified.
• Adequate cardiac and pulmonary function (left ventricular ejection fraction (LVEF) > 45%, diffusing capacity of the lungs for carbon monoxide (DLCO) >50% corrected for hemoglobin)
• Serum creatinine < 1.5 mg/dL OR Creatinine clearance > 50 mL/min for those above serum creatinine at least 1.5 mg/dL
• Serum bilirubin < 2.0 mg/dL
• Alanine transaminase (ALT) < 2x upper normal limit (ULN) (unless secondary to disease)
• No prior myeloablative therapy or hematopoietic cell transplantation

DONOR:

• Age ≤ 70 years
• Weight ≥ 25 kg.
• Medical history and physical examination confirm good health status as defined by institutional standards
• Seronegative for HIV Ag within 30 days of apheresis collection for:
• Hepatitis B surface antigen (sAg) or polymerase chain reaction (PCR) +
• Hepatitis C ab or PCR+
• Genotypically haploidentical as determined by HLA typing
• Female donors (child-bearing potential) must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within 3 weeks of mobilization
• Capable of undergoing leukapheresis
• Has adequate venous access
• Willing to undergo insertion of a central catheter if leukapheresis via peripheral vein is inadequate
• Capable of agreeing to second donation of peripheral blood progenitor cell (PBPC) (or a bone marrow harvest) should the patient fail to demonstrate sustained engraftment following the transplant
• Institutional review board (IRB)-approved consent form signed by donor or legal guardian > 18 years of age

Donor Selection in the priority order:

• Recipient's biological mother preferred, if available
• Other available haploidentical donors will be selected based upon the presence of natural killer (NK) alloreactivity between donor and recipient by high-resolution HLA typing of the C locus. An NK-alloreactive donor will be preferentially chosen. Recipients lacking a killer immunoglobulin-like receptor (KIR)-ligand present in the donor along with the corresponding KIR defines "NK alloreactivity".
• If more than one NK-alloreactive donor is available, preference is to cytomegalovirus (CMV)-seronegative donor

Exclusion Criteria

RECIPIENT:

• Suitable candidate for autologous transplantation or allogeneic transplantation with an available matched-related or matched-unrelated donor
• Seropositive for:
• HIV ab
• Hepatitis B sAg or PCR+
• Hepatitis C ab or PCR+
• History of invasive Aspergillosis
• Any active, uncontrolled bacterial, viral or fungal infection
• Uncontrolled central nervous system (CNS) disease involvement
• Lactating female

DONOR:

• Evidence of active infection or viral hepatitis
• Factors of increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy
• Lactating female
• HIV-positive

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: T-reg Cell Infusion after Allogeneic Stem Cell Transplant

Drug: Regulatory T-cells; To ameliorate the impaired immune recovery and address the significant relapse incidence in the haploidentical setting. Cells will be selected by a tandem selection process and infused on day +14. These are the enriched but naturally-occurring regulatory T cells. Possible dose cohorts and levels are: Cohort 1; T-reg: 1 x 10e5/kg; T-con: 3 x10e5/kg Cohort 2; T-reg: 3 x 10e5/kg; T-con: 1 x 10e6/kg Cohort 3; T-reg: 1 x 10e6/kg; T-con: 3 x 10e6/kg Cohort 4; T-reg: 3 x 10e6/kg; T-con: 1 x 10e7/kg; Other Names: T-reg cells; Drug: Conventional T-cells; These are conventional (unselected) donor T-cells. Cell dosage of the infusion will be based on the CD3+ cell content and infused on day +16.; Other Names: T-con cells; Drug: Melphalan; Anti-cancer chemotherapy drug administered IV at 140 mg/m² on Day -8 prior to HSCT (a component of the conditioning regiment prior to infusion of cells); Other Names: L-PAM; L-Sarcolysin; Phenylalanine Mustard; Drug: Thiotepa; Anti-cancer chemotherapy drug administered IV at 10 mg/kg on Day -7 prior to HSCT (a component of the conditioning regiment prior to infusion of cells); Other Names: TESPA; TSPA; thiophosphamide; Device: Fludarabine; Anti-cancer chemotherapy drug administered IV at 160mg/m² on Days -6; -5; -4; and -3 prior to HSCT (a component of the conditioning regiment prior to infusion of cells; Other Names: Fludara; Fludarabine phosphate; FAMP; Fludarabine 5'-monophosphate; Drug: Anti-thymocyte globulin, rabbit; Rabbit-derived antibodies against human T-cells used as transplant rejection prophylaxis. Administered at 6 mg/kg IV on Days -6; -5; -4; and -3 prior to HSCT; Other Names: Thymoglobulin; rATG; Drug: CliniMACS CD34 Reagent System; An in vitro medical device system that uses antibodies conjugated to magnetic beads to select and enrich for CD34+ blood stem cells from the allogeneic donor apheresis product prior to HSCT, while removing other cells that can cause GvHD. CD34+ cell dosage will be based on the participant's body weight.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum-tolerated Dose (MTD) of Regulatory and Conventional T-cells	The maximum-tolerated dose (MTD) was to be determined based on the safety and feasibility observed for a pre-determined set of cellular dose level combinations of regulatory T-cells (T-reg) and conventional T-cells (T-con).	30 days after HSCT infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute Graft-versus-Host-Disease (aGvHD)	The primary outcome was incidence of grade 3 or 4 acute graft-vs-host-disease (aGvHD), reported as the number of participants developing grade 3 or 4 aGvHD.	1 year
Overall Survival (OS), 1 Year	Assessed as subjects remaining alive 12 months after CD34+ cell infusion (ie, excludes death due to any cause)	1 year
Median Overall Survival (OS)	Reported as the median overall survival (OS) in months from infusion of the hematopoietic stem cells (HSCT)	25 months
To Measure the Incidence and Severity of Acute and Chronic GvHD	Population of participants that received HSCT and T-reg plus T-con, and developed actue, chronic, or any graft vs host disease (GvHD)	1 year
Serious Infections	Serious infections are reported as the number of participants experienced serious infections.	1 year

Collaborators and Investigators

• Sponsor: Everett Meyer
• Collaborators: Doris Duke Charitable Foundation
• Investigators: Principal Investigator: Everett H Meyer, MD, PhD, Stanford University

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: January 11, 2010
• First Submitted That Met QC Criteria: January 14, 2010
• First Posted (Estimate): January 15, 2010

Study Record Updates

• Last Update Posted (Actual): June 27, 2018
• Last Update Submitted That Met QC Criteria: June 1, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Precancerous Conditions; Leukemia, Lymphoid; Leukemia, B-Cell; Lymphoma; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Melphalan; Fludarabine; Fludarabine phosphate; Thiotepa; Thymoglobulin; Antilymphocyte Serum; Vidarabine
• Other Study ID Numbers: IRB-15919; BMT204 (Other Identifier: OnCore); SU-03312009-2059 (Other Identifier: Stanford University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No