Clinical trial NCT01660607: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2012-08-08
Enrollment: 68
Sex: ALL
Minimum age (years): 13
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study looks at giving specific types of immune cells, called regulatory T cells and conventional T cells, to patients with blood cancers who are receiving a stem cell transplant. These cells are added back to help the immune system recover and reduce complications after the transplant.

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

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

Primary outcomes:
measure: GvHD free Relapse free Survival (GRFS)
timeFrame: 12 months
Secondary outcomes:
measure: Dose-limiting toxicity (DLT)
timeFrame: 28 days
measure: Overall Survival (OS)
timeFrame: 1 year
measure: Incidence and Severity of Chronic GvHD
timeFrame: 2 years
measure: Incidence of Serious Infections
timeFrame: 24 months
measure: Concomitant Single-agent Immunosuppression
timeFrame: 2 years
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University School of Medicine Palo Alto, California, United States
state: California
Study officials:
affiliation: Stanford University
name: Everett Meyer
role: PRINCIPAL_INVESTIGATOR
References:
citation: Meyer EH, Laport G, Xie BJ, MacDonald K, Heydari K, Sahaf B, Tang SW, Baker J, Armstrong R, Tate K, Tadisco C, Arai S, Johnston L, Lowsky R, Muffly L, Rezvani AR, Shizuru J, Weng WK, Sheehan K, Miklos D, Negrin RS. Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients. JCI Insight. 2019 May 16;4(10):e127244. doi: 10.1172/jci.insight.127244. eCollection 2019 May 16.