Clinical Trials /

Phase 1-2 MAHCT w/ TCell Depleted Graft w/ Simultaneous Infusion Conventional and Regulatory T Cell

NCT01660607

Description:

For patients with hematologic malignancies undergoing allogeneic myeloablative (MA) HCT with a T cell depleted graft, the infusion of naturally occurring regulatory T cells with conventional T cells (T cell add back) in pre-defined doses and ratios will reduce the incidence of acute graft vs host disease while augmenting the graft vs leukemia effect and improving immune reconstitution.

Related Conditions:
  • Acute Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1-2 MAHCT w/ TCell Depleted Graft w/ Simultaneous Infusion Conventional and Regulatory T Cell
  • Official Title: Phase 1-2 Trial for Patients With Advanced Hematologic Malignancies Undergoing Myeloablative Allogeneic HCT With a T-cell Depleted Graft With Infusion of Conventional T-cells and Regulatory T-cells

Clinical Trial IDs

  • ORG STUDY ID: IRB-21257
  • SECONDARY ID: SU-09142011-8407
  • SECONDARY ID: BMT236
  • NCT ID: NCT01660607

Conditions

  • Myeloid Leukemia, Chronic
  • Acute Myelogenous Leukemia
  • Myelodysplastic Syndromes (MDS)
  • Lymphoma, Non-Hodgkin
  • Acute Lymphoblastic Leukemia (ALL)
  • Myeloproliferative Syndrome
  • Acute Myeloid Leukemia
  • Acute Leukemia
  • Chronic Myelogenous Leukemia

Interventions

DrugSynonymsArms
Conventional T cells (Tcon) and Regulatory T cells (Treg)Purified regulatory T cellsDose escalation

Purpose

For patients with hematologic malignancies undergoing allogeneic myeloablative (MA) HCT with a T cell depleted graft, the infusion of naturally occurring regulatory T cells with conventional T cells (T cell add back) in pre-defined doses and ratios will reduce the incidence of acute graft vs host disease while augmenting the graft vs leukemia effect and improving immune reconstitution.

Detailed Description

      Primary Objectives:

        -  To determine the efficacy, safety and feasibility of administration of several dose
           combinations of conventional T cells (Tcon) and regulatory T cells (Treg) in patients
           undergoing allogeneic hematopoietic cell transplantation (HCT) with HLA matched donors
           (related or unrelated) using a T cell depleted graft [CD34+ hematopoietic progenitor
           cells ("CD34+ HSPC")], without immune suppression.

        -  To determine the maximum tolerated dose of infused regulatory and conventional T cells
           in the matched donor setting

        -  To determine 1 year event free survival (EFS) post HCT

      Secondary Objectives:

        -  To determine the 1 year OS in patients undergoing allogeneic HCT with matched donors.

        -  To measure the incidence and severity of acute and chronic graft vs host disease (GvHD)

        -  To measure incidence of serious infections
    

Trial Arms

NameTypeDescriptionInterventions
Dose escalationExperimentalFor the Phase I arm of the study the addition of planned numbers and ratios of Treg compared to Tcon will occur at defined time points after hematopoietic cell infusion. Each cohort will have 3 patients per group. The initial doses and ratios utilized will be 1 x 10^6/kg of T reg cells to 3x10^6/kg of Tcon cells at a 1:3 ratio. In order to progress to the next dose level, there must be no evidence of grade 3 or 4 acute GVHD.
  • Conventional T cells (Tcon) and Regulatory T cells (Treg)

Eligibility Criteria

        Recipient Inclusion Criteria

          1. Patients with the following diseases that are histopathologically confirmed are
             eligible

               -  Acute leukemia, primary refractory or beyond CR1, or minimal residual disease
                  (MRD) positivity.

               -  High risk acute myeloid leukemia in CR1 with any of the following features:

               -  Complex karyotype(≥3 clonal chromosomal abnormalities)

               -  Any of the following high risk chromosomal abnormalities:

                    -  Monosomal karyotype (-5, 5q-, -7, 7q-)

                    -  t(11q23), t(9;11), inv(3), t(3;3) t(6;9) t(9;22)

                    -  Normal karyotype with fms-like tyrosine kinase 3 (FLT3)-ITD mutation

               -  Other high risk features as determined by molecular studies, or clinical
                  presentation as assessed by the treating physician

               -  Chronic myelogenous leukemia (accelerated, blast or second chronic phase)

               -  Myelodysplastic syndromes

               -  Myeloproliferative syndromes

               -  Non-Hodgkin lymphoma with poor risk features not suitable for autologous HCT

          2. Age ≥18 yo and ≤ 60 yo for patients in Cohort 1 only. At the start of Cohort 2A and
             beyond, eligibility will be expanded to allow pediatric patients age ≥ 13 yo.

          3. Cardiac ejection fraction ≥ 45%

          4. Lung diffusion capacity ≥ 50%

          5. Calculated creatinine clearance ≥ 50 cc/min

          6. Serum glutamic-pyruvic transaminase( SGPT) and serum glutamic-oxaloacetic transaminase
             (SGOT) ≤ 3.0 x ULN (Upper limit of normal), unless elevated secondary to disease.

          7. Total bilirubin ≤ 2 x ULN (patients with Gilbert's syndrome may be included at the
             discretion of the PI or where hemolysis has been excluded

          8. Availability of a HLA matched donor (related or unrelated) defined by Class I (HLA-A
             and B) serologic typing (or higher resolution) and Class II (HLA DRB1) molecular
             typing. An HLA matched donor is defined for this study to be a sibling that is HLA
             matched 6/6; or an unrelated donor that is HLA matched 6/6 or 5/6. A sibling may be a
             "half sibling."

          9. Karnofsky performance status ≥70%

        Recipient Exclusion Criteria

          1. Seropositive for any of the following:

             HIV ab; hepatitis B sAg; hepatitis C ab

          2. Prior myeloablative therapy or hematopoietic cell transplant

          3. Candidate for autologous transplant

          4. HIV positive

          5. Active uncontrolled bacterial, viral or fungal infection, defined as currently taking
             antimicrobial therapy and progression of clinical symptoms.

          6. Uncontrolled central nervous system (CNS) disease involvement

          7. Pregnant or a lactating female

          8. Positive serum or urine beta human chorionic gonadotropin (HCG) test in females of
             childbearing potential within 3 weeks of registration

          9. Psychosocial circumstances that preclude the patient being able to go through
             transplant or participate responsibly in follow up care

        Donor Inclusion Criteria

          1. Age ≥13 yo and ≤ 75 years

          2. Karnofsky performance status of ≥ 70% defined by institutional standards

          3. Seronegative for HIV 1 RNA (polymerase chair reaction (PCR); HIV 1 and HIV 2 ab
             (antibody); HTLV 1 and HTLV 2 ab; PCR+ or sAg (surface antigen) hepatitis B ; or PCR+
             or sAg for hepatitis C; negative for the Treponema pallidum antibody Syphilis screen;
             and negative for HIV 1 and hepatitis C by nucleic acid testing (NAT) within 30 days of
             apheresis collection. In the case that T pallidum antibody tests are positive, donors
             must:

               -  Be evaluated and show no evidence of syphilis infection of any stage by physical
                  exam and history

               -  Have completed effective antibiotic therapy to treat syphilis

               -  Have a documented negative non treponemal test (such as RPR) or in the case of a
                  positive non treponemal test must be evaluated by an infectious disease expert to
                  evaluate for alternative causes of test positivity and confirm no evidence of
                  active syphilitic disease

          4. Must be 6/6 matched sibling donor as determined by HLA typing

          5. Female donors of child-bearing potential must have a negative serum or urine beta-HCG
             test within three weeks of mobilization

          6. Capable of undergoing leukapheresis, have adequate venous access, and be willing to
             undergo insertion of a central catheter should leukapheresis via peripheral vein be
             inadequate

          7. Agreeable to 2nd donation of Peripheral blood stem cell (PBPC) (or bone marrow
             harvest) in the event of graft failure

          8. The donor or legal guardian greater than 18 years of age, capable of signing an
             institutional review board (IRB-approved consent form.

        Donor Exclusion Criteria

          1. Evidence of active infection or viral hepatitis

          2. HIV positive

          3. Medical, physical, or psychological reason that would place the donor at increased
             risk for complications from growth factor or leukapheresis

          4. Lactating female
      
Maximum Eligible Age:60 Years
Minimum Eligible Age:13 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure:GvHD free Relapse free Survival (GRFS)
Time Frame:12 months
Safety Issue:
Description:GvHD-free is defined as no GvHD symptoms, and relapse free survival is defined as survival at 12 months without relapse.

Secondary Outcome Measures

Measure:Dose-limiting toxicity (DLT)
Time Frame:28 days
Safety Issue:
Description:Dose-limiting Toxicity (DLT) was assessed as: Absolute neutrophil count <500/µL, to 28 day Cytokine release syndrome/acute infusion reactions as CTCAE Grade 3 to 5 Grade 3 to 4 acute GvHD. GvHD was staged as follows: 1: Skin: rash <25%. Liver: bilirubin (BIL) 2-3mg/dL. Gut: diarrhea (DIA) 500-1000 mL/day 2: Skin: rash 25-50%. Liver: BIL 3-6mg/dL. Gut: DIA 1001-1500 mL/day 3: Skin: rash > 50%. Liver: BIL 6-15mg/dL. Gut: DIA >1501-2000 mL/day 4: Skin: generalized erythroderma. Liver: BIL >15mg/dL. Gut: DIA >2001 mL/day GvHD was graded as follows. 1: Skin Stage 1-2; No Liver stage; No Gut stage 2: Skin Stage 1-3 ; Liver Stage 1; +/- Gut Stage 1 3: Skin Stage 2-3, Liver Stage 2-4; +/- Gut Stage 2-3 4: Skin Stage 2-4; Liver Stage 2-4; +/- Gut Stage 2-4 The outcome is reported as the number of participants who received both Treg and Tcon cell infusions and had DLT events, per treatment level, a number without dispersion.
Measure:Overall Survival (OS)
Time Frame:1 year
Safety Issue:
Description:Overall Survival (OS) at 1 year was assessed as the number of participants per treatment level that received the hematopoietic cell transplant (HCT), and remained alive 12 months later, a number without dispersion.
Measure:Incidence and Severity of Chronic GvHD
Time Frame:2 years
Safety Issue:
Description:Incidence and severity of chronic GvHD wil be assessed in participants who received the hematopoietic cell transplant (HCT). Stage of chronic GvHD was assessed as follows. Stage 1: Skin: rash <25% of skin. Liver: bilirubin 2-3mg/dL. Gut: diarrhea 500-1000 mL/day Stage 2: Skin: rash 25-50% of skin. Liver: bilirubin 3-6mg/dL. Gut: diarrhea 1001-1500 mL/day Stage 3: Skin: rash > 50% of skin. Liver: bilirubin 6-15mg/dL. Gut: diarrhea >1501-2000 mL/day Stage 4: Skin: generalized erythroderma. Liver: bilirubin >15mg/dL. Gut: diarrhea >2001 mL/day Grade of chronic GvHD was determined as follows. Grade 1: Skin Stage 1-2; No Liver stage; No Gut stage Grade 2: Skin Stage 1-3 ; Liver Stage 1; +/- Gut Stage 1 Grade 3: Skin Stage 2-3, Liver Stage 2-4; +/- Gut Stage 2 to 3 Grade 4: Skin Stage 2-4; Liver Stage 2-4; +/- Gut Stage 2 to 4 The outcome is reported as the number of participants by cGvHD grade and treatment level, a number without dispersion.
Measure:Incidence of Serious Infections
Time Frame:24 months
Safety Issue:
Description:The outcome is reported as the number of serious infections per treatment level, in participants who received the hematopoietic cell transplant (HCT), a number without dispersion.
Measure:Concomitant Single-agent Immunosuppression
Time Frame:2 years
Safety Issue:
Description:During Phase 2, stage 1, concomitant single-agent immunosuppression will be assessed as in participants receiving fresh Treg cells. The outcome is reported as number of such participants who received single-agent immunosuppression, by treatment level, a number without dispersion.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Everett Meyer

Last Updated

June 12, 2019