Use of T-allo10 in Hematopoietic Stem Cell Transplantation (HSCT) for Blood Disorders

Study Overview
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Brief Summary
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A significant number of patients with hematologic malignancies need a hematopoietic stem cell transplant (HSCT) to be cured. Only about 50% of these patients have a fully matched donor, the remaining patients will require an HSCT from a mismatched related or unrelated donor. Almost 60% of these mismatched donor HSCTs will result in graft-versus-host disease (GvHD), which can cause significant morbidity and increased non-relapse mortality. GvHD is caused by the donor effector T cells present in the HSC graft that recognize and react against the mismatched patient's tissues. Researchers and physicians at Lucile Packard Children's Hospital, Stanford are working to prevent GvHD after HSCT with a new clinical trial. The objective of this clinical program is to develop a cell therapy to prevent GvHD and induce graft tolerance in patients receiving mismatched unmanipulated donor HSCT. The cell therapy consists of a cell preparation from the same donor of the HSCT (T-allo10) containing T regulatory type 1 (Tr1) cells able to suppress allogenic (host-specific) responses, thus decreasing the incidence of GvHD. This is the first trial of its kind in pediatric patients and is only available at Lucile Packard Children's Hospital, Stanford. The purpose of this phase 1 study is to determine the safety and tolerability of a cell therapy, T-allo10, to prevent GvHD in patients receiving mismatched related or mismatched unrelated unmanipulated donor HSCT for hematologic malignancies.

Detailed Description
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Patients ages 3-30 years, with hematologic malignancies undergoing mismatched related or unrelated donor transplant will receive conditioning chemotherapy with Total body radiation and cyclophosphamide, according to the standard procedure. The investigators plan to infuse the donor T-allo10 product one day before HSCT so that the Tr1 cells contained within the T-allo10 product will be able to prevent anti-host alloreactivity of the T cells present within the unmanipulated HSC graft. Indeed, Tr1 cells best exert their suppressive activity at the time of effector T cell activation, occurring when the T cells present in the HSC graft will be transferred to the patient ; therefore, the investigators expect that the early infusion of T-allo10 cells will optimally modulate anti-host alloreactivity of the donor T cells and prevent GvHD. Immunosuppression will also be administered at the time of HSCT. Up to 27 eligible patients will be given the T-allo10 product sequentially in 3 escalating dose cohorts to determine the maximum tolerated dose (or the highest dose tested if no maximum tolerated dose is reached). Each cohort will begin by evaluating 3 patients. The patients in each cohort will be staggered by 28 days and each succeeding patient will be enrolled no sooner than the 29 day after the preceding patient's infusion of T-allo10. If no patient in a cohort develops a dose limiting toxicity (DLT) following infusion of the investigational cellular product, the investigators will start enrolling patients at the next higher cell dose after completing the 28-day safety evaluation of the 3rd patient in the dose cohort. If one out of 3 patients in a cohort has a DLT, 3 additional patients will be evaluated at the same dose level. If one out of 6 patients experiences a DLT, dose escalation will occur. If 2 out of ≤ 6 patients experience a DLT, dose escalation will cease and that dose will be designated the maximally administered dose. Up to three (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose

Official Title
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Use of T-allo10 Cell Infusions Combined With Mismatched Related or Mismatched Unrelated Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies

Conditions
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AML - Acute Myeloid Leukemia, MDS (Myelodysplastic Syndrome), Mixed Phenotype Acute Leukemia, NHL - Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, ALL

Intervention / Treatment
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* Biological: T-allo10


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible diseases include: A. Acute Lymphoblastic Leukemia (B- or T-ALL) Complete Response (CR)1-ultra high risk features Unfavorable cytogenetics Hypodiploidy Induction failure Minimal Residual Disease (MRD) positive after consolidation CR-2: Any of the high risk features listed in CR1 B-ALL: any relapse considered eligible for transplant T- ALL CR-3-any B. Acute Myeloid Leukemia MRD >5% at day 22 induction 1 MRD >0.1% after induction 2 FLT/ITD with allelic ratio > 0.4 and MRD >0.1% at day 22 or 29 induction 1 Translocation (6:9), (8:6), (16:21), monosomy 7, monosomy 5, 5q M7 with KMT2A rearrangements, inv(16)(p13.3q24.3) [CBFA2T3-GLIS2] or t(11;12)(p15;p13) [NUP98-KDM5A] AML in 2nd or subsequent CR Therapy related or Secondary AML Refractory anemia with excess blasts (RAEB)2 C. Myelodysplastic syndrome D. Mixed Phenotype Acute Leukemia MRD>1% after consolidation E. Non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL) beyond first remission Age ≥3 to ≤45 years old. Subjects 1 and 2 (in Cohort 1) will be ≥ 12 years old Available mismatched related donor (mMRD) or mismatched unrelated donor (mMUD), Human leukocyte antigen (HLA) matched 8/10 or 9/10 Lansky (age <16) or Karnofsky (age ≥16) performance status ≥80% Able and willing to provide written, signed informed consent (assent as appropriate) Have adequate organ function defined as the following: Serum Creatinine <1.5 X upper limit of normal (ULN) or 24-hour creatinine clearance >50 ml/min Serum bilirubin ≤ 2 x ULN Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤10 x ULN Diffusion Capacity of the Lungs (DLCO) >60% predicted (in children, O2 saturation >92% on room air) Left ventricular ejection fraction >45% (in children, shortening fraction >26%) Male and female subjects of child bearing potential must agree to use an effective method of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression, and if the subject experiences any chronic GvHD. Exclusion Criteria: Prior bone marrow or peripheral blood HSCT within the last 6 (six) months HLA-matched related or unrelated donor available Any active, uncontrolled infection at the time of enrollment Pregnant or lactating females Any severe concurrent disease which, in the judgement of the investigator, would place the patient at increased risk during participation in the study Any subject with a history of significant renal, hepatic, pulmonary, or cardiac dysfunction or on treatment to support cardiac dysfunction HIV positive Non-cooperative behavior or non-compliance of the patient and/or of his/her family Received another investigational agent within 30 days of enrollment Patients with Down's syndrome

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Participants will receive 1 X 10^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant) | Biological: T-allo10<br>* The T-allo10 drug product consists of donor derived, host (patient) alloantigen hyporesponsive (anergic) CD4+ (cluster of differentiation 4) cells containing Type 1 regulatory T (Tr1) cells induced in vitro in the presence of IL-10 (interleukin-10), which are also defined as IL-10 anergized T cells. T-allo10 cell infusion is being developed to prevent acute Graft-versus-Host Disease (GvHD) and induce graft tolerance in patients with hematologic malignancies receiving mismatched related and unrelated unmanipulated hematopoietic stem cell transplant (HSCT).<br>|
| Experimental: Cohort 2<br>Participants will receive 3 X 10^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant) | Biological: T-allo10<br>* The T-allo10 drug product consists of donor derived, host (patient) alloantigen hyporesponsive (anergic) CD4+ (cluster of differentiation 4) cells containing Type 1 regulatory T (Tr1) cells induced in vitro in the presence of IL-10 (interleukin-10), which are also defined as IL-10 anergized T cells. T-allo10 cell infusion is being developed to prevent acute Graft-versus-Host Disease (GvHD) and induce graft tolerance in patients with hematologic malignancies receiving mismatched related and unrelated unmanipulated hematopoietic stem cell transplant (HSCT).<br>|
| Experimental: Cohort 3<br>Participants will receive 9 X 10^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant) | Biological: T-allo10<br>* The T-allo10 drug product consists of donor derived, host (patient) alloantigen hyporesponsive (anergic) CD4+ (cluster of differentiation 4) cells containing Type 1 regulatory T (Tr1) cells induced in vitro in the presence of IL-10 (interleukin-10), which are also defined as IL-10 anergized T cells. T-allo10 cell infusion is being developed to prevent acute Graft-versus-Host Disease (GvHD) and induce graft tolerance in patients with hematologic malignancies receiving mismatched related and unrelated unmanipulated hematopoietic stem cell transplant (HSCT).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events (TEAE) | Assessments of TEAE will include laboratory abnormalities, changes in vital signs, and changes in physical examination following infusion of T-allo10 cells in order to assess the tolerability of T-allo10. | Time of T-allo10 cell infusion until 28 days following the infusion. | 
| Severity of treatment emergent adverse events (TEAE) | Assessments of TEAE will include laboratory abnormalities, changes in vital signs, and changes in physical examination following infusion of T-allo10 cells in order to assess the safety of T-allo10. | Time of T-allo10 cell infusion until 28 days following the infusion. | 
| Safety of T-allo10 will be measured by the time to stem cell engraftment after Hematopoietic Stem Cell Transplant. | Stem cell engraftment is evaluated by clinical laboratory studies including absolute neutrophil count, hematopoiesis, chimerism analysis, and minimal residual disease (MRD) assay. | 42 days | 
| Feasibility defined by the successful manufacture of the T-allo10 product | Feasibility defined by the rate of successful manufacture of the T-allo10 product to satisfy the targeted dose level and meet the required release specifications. | By Day -9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of grade III and IV acute GvHD | The incidence of grade III and IV acute GvHD at Day +100 following infusion of Tallo10 cells, assessed using the Modified Keystone scale administered by an independent evaluator on study visits through Day +100 | Study visits through Day +100 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric, GvHD, Hematopoietic Stem Cell Transplantation, Stem Cells, Transplant, BMT - bone marrow transplant