Infusion of Conventional and Regulatory T-Cells for the Treatment of Patients with Hematologic Malignancies Undergoing Reduced Intensity Donor Stem Cell Transplant
This phase I trial studies the side effects and best dose of conventional T cells and regulatory T cells and to see how well they work in treating patients with hematologic malignancies that are undergoing T cell-depleted donor stem cell transplant. Giving chemotherapy and total body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells (conventional T cells) from a donor can make an immune response against the body's normal cells called graft-versus-host disease (GVHD). Removing the conventional T cells from the donor cells before transplant may stop this from happening, but may also increase the risk of infections and cancer relapse. Regulatory T cells are a type of T cell that inhibits the activity of the conventional T cells so the conventional T cells that are given to are less likely to cause severe GVHD. Giving an infusion of the donor's conventional and regulatory T cells may reduce the risk of GVHD and relapse of the cancer.
Inclusion Criteria
- RECIPIENT INCLUSION CRITERIA: Acute myeloid, lymphoid, or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi) or beyond first complete remission (CR1) without the presence of minimal residual disease
- RECIPIENT INCLUSION CRITERIA: Acute myeloid, lymphoid, or mixed phenotype leukemia that is either: * Not in morphologic CR with bone marrow infiltration by leukemic blasts of =< 10 percent, or * In morphologic CR with evidence of minimal residual disease positivity by either multiparametric flow cytometric analysis or by a nucleic acid-based technique
- RECIPIENT INCLUSION CRITERIA: Primary refractory acute myeloid, lymphoid, or mixed phenotype leukemia
- RECIPIENT INCLUSION CRITERIA: Chronic myelogenous leukemia (accelerated, blast or second chronic phase)
- RECIPIENT INCLUSION CRITERIA: Myelodysplastic syndromes
- RECIPIENT INCLUSION CRITERIA: Myelofibrosis that is transplant-eligible
- RECIPIENT INCLUSION CRITERIA: Myeloproliferative syndromes
- RECIPIENT INCLUSION CRITERIA: Match to the subject as follows: * For Arm A1 (CLOSED): ** Availability of a 8/8 or 7/8 HLA-matched donor (related or unrelated) defined by Class I (HLA–A, -B, -C) serologic typing (or higher resolution) and Class II (HLA-DRB1) molecular typing ** If the donor is a 7/8 HLA-match, the mismatch can be a permissive or non-permissive allelic mismatch as assessed by an independent HLA and transplantation expert * For Arm A2: ** Availability of a 8/8 HLA-matched donor (related or unrelated) defined by Class I (HLA-A, -B, -C) serologic typing (or higher resolution) and Class II (HLA-DRB1) molecular typing * For Arm B (CLOSED): ** Availability of a haploidentical donor who is a >= 4/8 but < 7/8 match at HLA-A, -B, -C, and –DRB1 (typed using deoxyribonucleic acid [DNA]-based high-resolution methods), with at most one mismatch per locus * For Arm C: ** Availability of a 7/8 HLA-matched (related or unrelated) defined by Class I (HLA-A, -B, -C) serologic typing (or higher resolution) and Class II (HLA-DRB1 or HLA-DQB1) molecular typing
- RECIPIENT INCLUSION CRITERIA: Age >= 18 and =< 75 years old at the time of enrollment
- RECIPIENT INCLUSION CRITERIA: Left ventricular ejection fraction (LVEF) >= 45%
- RECIPIENT INCLUSION CRITERIA: Diffusing capacity of the lungs for carbon monoxide (DLCO) >= 50 percent
- RECIPIENT INCLUSION CRITERIA: Calculated creatinine clearance >= 50 mL/min or creatinine < 2.0 mg/dL
- RECIPIENT INCLUSION CRITERIA: serum glutamic-pyruvic transferase (SGPT) and serum glutamic-oxaloacetic transaminase (SGOT) =< 5 x upper limit of normal (ULN), unless elevated secondary to disease
- RECIPIENT INCLUSION CRITERIA: Total bilirubin =< 3 x ULN (subjects with Gilbert’s syndrome may be included at the discretion of the principal investigator [PI] or where hemolysis has been excluded)
- RECIPIENT INCLUSION CRITERIA: Negative serum or urine beta-human chorionic gonadotropin (HCG) test in females of childbearing potential within 3 weeks of registration
- RECIPIENT INCLUSION CRITERIA: Karnofsky performance status >= 70%
- DONOR INCLUSION CRITERIA: Age >= 18 and =< 75 years of age
- DONOR INCLUSION CRITERIA: Karnofsky performance status of >= 70% defined by institutional standards or cleared by the National Marrow Donor Program (NMDP) for NMDP donors
- DONOR INCLUSION CRITERIA: Medical history and physical examination (PE) confirm good health status as defined by institutional standards or the NMDP for NMDP donors
- DONOR INCLUSION CRITERIA: Seronegative for HIV 1 ribonucleic acid (RNA) polymerase chain 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 negative 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
- DONOR INCLUSION CRITERIA: In the case that Treponema (T). pallidum antibody testing is positive, donors must: * Be evaluated and show no evidence of syphilis infection of any stage by physical exam and history, or * Have completed effective antibiotic therapy to treat syphilis, or * Have a documented negative non-treponemal test (such as rapid plasma reagin [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
- DONOR INCLUSION CRITERIA: Match to the subject as follows: * Arm A1 (CLOSED): ** Must be a related or unrelated, 8/8 or 7/8-HLA match to recipient at HLA-A, -B, -C, –DRB1. If 7/8 HLA-matched, can be with permissive or non-permissive allelic HLA mismatch as assessed by an independent HLA and transplantation expert * Arm A2: ** Must be a related or unrelated, 8/8-HLA match to recipient at HLA-A, -B, -C, and -DRB1 * Arm B (CLOSED): ** Must be a haploidentical donor who is ≥ 4/8 but ≤ 7/8 match at HLA-A, -B, -C, and –DRB1, with at most one mismatch per locus * Arm C: ** Must be a related or unrelated 7/8 HLA-matched to recipient at HLA-A, -B, -C, -DRB1 or -DQB1
- DONOR INCLUSION CRITERIA: Must be willing to donate peripheral blood stem cells (PBSC) for up to 2 consecutive days
- DONOR INCLUSION CRITERIA: Female donors of child-bearing potential must have a negative serum or urine beta HCG test within 3 weeks of mobilization
- DONOR INCLUSION CRITERIA: 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
- DONOR INCLUSION CRITERIA: Agreeable to 2nd donation of PBSC (or bone marrow harvest) in the event of graft failure or mobilization failure
- DONOR INCLUSION CRITERIA: The donor or legal guardian greater than 18 years of age, capable of signing an institutional review board (IRB) approved consent form
- DONOR INCLUSION CRITERIA: Meets all other criteria for donation as specified by standard NMDP guidelines (NMDP donors) or institutional standards (non NMDP donors)
- DONOR INCLUSION CRITERIA: Donors not meeting federal eligibility criterion, may nonetheless be included if either apply as follows per 21 Code of Federal Regulations (CFR) § 1271.65: * The donor is a first-degree or second-degree blood relative of the recipient, or * Documented urgent medical need (DUMN), meaning no comparable human cell product is available and the recipient is likely to suffer death or serious morbidity without the human cell product, as attested by the investigator or sub-investigator
Exclusion Criteria
- RECIPIENT EXCLUSION CRITERIA: Seropositive for any of the following: * Human immunodeficiency virus (HIV) antibodies * Hepatitis B surface antigen (sAg) * Hepatitis C antibodies (If hepatitis C virus antibody [HCV ab] positive; may still be enrolled if HCV nucleic acid test [NAT] testing is negative)
- RECIPIENT EXCLUSION CRITERIA: Subjects deemed candidates for fully myeloablative preparative conditioning regimens
- RECIPIENT EXCLUSION CRITERIA: Candidate for autologous transplant
- RECIPIENT EXCLUSION CRITERIA: HIV-positive
- RECIPIENT EXCLUSION CRITERIA: Active uncontrolled bacterial, viral or fungal infection, defined as currently taking antimicrobial therapy and progression of clinical symptoms
- RECIPIENT EXCLUSION CRITERIA: Uncontrolled central nervous system (CNS) disease involvement
- RECIPIENT EXCLUSION CRITERIA: Pregnant or a lactating female
- RECIPIENT EXCLUSION CRITERIA: Positive serum or urine beta-HCG test in females of childbearing potential within 3 weeks of registration
- RECIPIENT EXCLUSION CRITERIA: Psychosocial circumstances that preclude the subject being able to go through transplant or participate responsibly in follow-up care
- RECIPIENT EXCLUSION CRITERIA: Known allergy or hypersensitivity to, or intolerance of, tacrolimus
- RECIPIENT EXCLUSION CRITERIA: Positive anti-donor HLA antibodies against a mismatched allele in the selected donor determined by either: * A positive crossmatch of any titer; or * The presence of anti-donor HLA antibody to any HLA locus
- RECIPIENT EXCLUSION CRITERIA: Any uncontrolled autoimmune disease requiring active immunosuppressive treatment
- RECIPIENT EXCLUSION CRITERIA: Concurrent malignancies or active disease within 1 year, except non-melanomatous skin cancers that have been curatively resected
- DONOR EXCLUSION CRITERIA: Evidence of active infection
- DONOR EXCLUSION CRITERIA: Seropositive for HIV-1 or-2, HTLV-1 or -2
- DONOR EXCLUSION CRITERIA: Medical, physical, or psychological reason that would place the donor at increased risk for complications from growth factor or leukapheresis
- DONOR EXCLUSION CRITERIA: Pregnant or breastfeeding female
Additional locations may be listed on ClinicalTrials.gov for NCT05088356.
Locations matching your search criteria
United States
California
Palo Alto
PRIMARY OBJECTIVE:
I. Determine the safety, and feasibility of administration of several dose combinations of conventional T-cells (Tcon) and regulatory T-cells (Treg) in subjects undergoing allogeneic hematopoietic cell transplantation (HCT) with:
Ia. 8/8 human leukocyte antigen (HLA) matched related or unrelated donors, or;
Ib. 7/8 HLA-mismatched related or unrelated donors, or;
Ic. Haploidentical donors with reduced intensity conditioning preparative regimen, using an engineered CD34 selected graft and defined dose of T cells and regulatory T cells (CD34+ hematopoietic progenitor cells [“CD34+ HSPC”]).
SECONDARY OBJECTIVES:
I. To determine the graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) post-HCT.
II. To determine the overall survival (OS) post-HCT.
III. To measure the incidence and severity of acute and chronic GVHD.
EXPLORATORY OBJECTIVES:
I. To measure incidence of serious infections.
II. To measure the incidence and timing of engraftment.
III. To measure T cell immunity reconstitution parameters.
OUTLINE: This is a dose-escalation study of Treg and Tcon. Patients are assigned to 1 of 4 arms.
ARM A1 (CLOSED): Patients receive melphalan intravenously (IV) on day -7 and fludarabine IV on days -7, -6, -5, and -4, and undergo total-body irradiation (TBI) on days -3 and -2. Patients then receive CD34+ HSPCs and Treg IV on day 0, followed by Tcon IV on day 2 or 3 per discretion of the treating physician. Patients also undergo blood sample collection throughout the trial and bone marrow biopsy and aspiration or positron emission tomography (PET)/computed tomography (CT) scans during follow up as clinically indicated.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) 12-24 hours after Tcon infusion and continuing until day 100 in the absence of unacceptable toxicity.
ARM A2: Patients receive thiotepa on days -7 and -6, fludarabine IV on days -7, -6, -5, and -4, and undergo TBI on days -3 and -2. Patients then receive CD34+ HSPCs and Treg IV on day 0, followed by Tcon IV on day 2 or 3 per discretion of the treating physician. Patients also undergo blood sample collection throughout the trial and bone marrow biopsy and aspiration or PET/CT scans during follow up as clinically indicated.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning 12-24 hours after Tcon infusion and continuing until day 100 in the absence of unacceptable toxicity.
ARM B (CLOSED): Patients receive melphalan IV on day -7 and fludarabine IV on days -7, -6, -5, and -4 and undergo TBI on days -3 and -2. Patients then receive CD34+ HSPCs and Treg IV on day 0, followed by Tcon IV on day 2 or 3 per discretion of the treating physician. Patients receive cyclophosphamide IV 50-72 hours after Tcon infusion on days 5 and 6 or days 6 and 7. Patients also undergo blood sample collection throughout the trial and bone marrow biopsy and aspiration or PET/CT scans during follow up as clinically indicated.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on days 7 or 8 and continuing until day 100 in the absence of unacceptable toxicity.
ARM C: Patients receive thiotepa on days -7 and -6, fludarabine IV on days -7, -6, -5, and -4, and undergo TBI on days -3 and -2. Patients then receive CD34+ HSPCs and Treg IV on day 0, followed by Tcon IV on day 2 or 3 per discretion of the treating physician. Patients also undergo blood sample collection throughout the trial and bone marrow biopsy and aspiration or PET/CT scans during follow up as clinically indicated.
GVHD PROPHYLAXIS: Patients receive tacrolimus and mycophenolate mofetil IV or PO beginning 12-24 hours after Tcon infusion and continuing until day 100 in the absence of unacceptable toxicity.
After completion of study treatment, patients are followed up at days 180 and 365, and then at 2 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationStanford Cancer Institute Palo Alto
Principal InvestigatorEverett Meyer
- Primary IDBMT372
- Secondary IDsNCI-2021-12228, 60439
- ClinicalTrials.gov IDNCT05088356