Phase 1-2 MAHCT w/ TCell Depleted Graft w/ Simultaneous Infusion Conventional and Regulatory T Cell
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1/Phase 2 |
Detailed Description
Primary Objectives:
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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.
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To determine the maximum tolerated dose of infused regulatory and conventional T cells in the matched donor setting
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To determine 1 year event free survival (EFS) post HCT
Secondary Objectives:
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To determine the 1 year OS in patients undergoing allogeneic HCT with matched donors.
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To measure the incidence and severity of acute and chronic graft vs host disease (GvHD)
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To measure incidence of serious infections
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Dose escalation 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. |
Biological: Conventional T cells (Tcon) and Regulatory T cells (Treg)
A baseline cell dose of conventional T cells of 1x10^6/kg will be used with escalation to the maximum tolerated dose up to 1x10^7/kg
Other Names:
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Outcome Measures
Primary Outcome Measures
- GvHD free Relapse free Survival (GRFS) [12 months]
GvHD-free is defined as no GvHD symptoms, and relapse free survival is defined as survival at 12 months without relapse.
Secondary Outcome Measures
- Dose-limiting toxicity (DLT) [28 days]
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.
- Overall Survival (OS) [1 year]
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.
- Incidence and Severity of Chronic GvHD [2 years]
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.
- Incidence of Serious Infections [24 months]
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.
- Concomitant Single-agent Immunosuppression [2 years]
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.
Eligibility Criteria
Criteria
Recipient Inclusion Criteria
- Patients with the following diseases that are histopathologically confirmed are eligible
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Acute leukemia, primary refractory or beyond CR1, or minimal residual disease (MRD) positivity.
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High risk acute myeloid leukemia in CR1 with any of the following features:
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Complex karyotype(≥3 clonal chromosomal abnormalities)
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Any of the following high risk chromosomal abnormalities:
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Monosomal karyotype (-5, 5q-, -7, 7q-)
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t(11q23), t(9;11), inv(3), t(3;3) t(6;9) t(9;22)
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Normal karyotype with fms-like tyrosine kinase 3 (FLT3)-ITD mutation
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Other high risk features as determined by molecular studies, or clinical presentation as assessed by the treating physician
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Chronic myelogenous leukemia (accelerated, blast or second chronic phase)
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Myelodysplastic syndromes
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Myeloproliferative syndromes
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Non-Hodgkin lymphoma with poor risk features not suitable for autologous HCT
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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.
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Cardiac ejection fraction ≥ 45%
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Lung diffusion capacity ≥ 50%
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Calculated creatinine clearance ≥ 50 cc/min
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Serum glutamic-pyruvic transaminase( SGPT) and serum glutamic-oxaloacetic transaminase (SGOT) ≤ 3.0 x ULN (Upper limit of normal), unless elevated secondary to disease.
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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
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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."
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Karnofsky performance status ≥70%
Recipient Exclusion Criteria
- Seropositive for any of the following:
HIV ab; hepatitis B sAg; hepatitis C ab
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Prior myeloablative therapy or hematopoietic cell transplant
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Candidate for autologous transplant
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HIV positive
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Active uncontrolled bacterial, viral or fungal infection, defined as currently taking antimicrobial therapy and progression of clinical symptoms.
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Uncontrolled central nervous system (CNS) disease involvement
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Pregnant or a lactating female
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Positive serum or urine beta human chorionic gonadotropin (HCG) test in females of childbearing potential within 3 weeks of registration
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Psychosocial circumstances that preclude the patient being able to go through transplant or participate responsibly in follow up care
Donor Inclusion Criteria
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Age ≥13 yo and ≤ 75 years
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Karnofsky performance status of ≥ 70% defined by institutional standards
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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:
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Be evaluated and show no evidence of syphilis infection of any stage by physical exam and history
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Have completed effective antibiotic therapy to treat syphilis
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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
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Must be 6/6 matched sibling donor as determined by HLA typing
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Female donors of child-bearing potential must have a negative serum or urine beta-HCG test within three weeks of mobilization
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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
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Agreeable to 2nd donation of Peripheral blood stem cell (PBPC) (or bone marrow harvest) in the event of graft failure
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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
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Evidence of active infection or viral hepatitis
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HIV positive
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Medical, physical, or psychological reason that would place the donor at increased risk for complications from growth factor or leukapheresis
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Lactating female
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Stanford University School of Medicine Palo Alto, California, United States | Palo Alto | California | United States | 94305 |
Sponsors and Collaborators
- Everett Meyer
- National Institutes of Health (NIH)
Investigators
- Principal Investigator: Everett Meyer, Stanford University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB-21257
- SU-09142011-8407
- BMT236
- 1R01HL114591-01