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.
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
- SECONDARY ID:
1R01HL114591-01
- 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
Drug | Synonyms | Arms |
---|
Conventional T cells (Tcon) and Regulatory T cells (Treg) | Purified regulatory T cells | Dose 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
Name | Type | Description | Interventions |
---|
Dose escalation | Experimental | For 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
August 20, 2021