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

Primary Purpose

AML - Acute Myeloid Leukemia, MDS (Myelodysplastic Syndrome), Mixed Phenotype Acute Leukemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
T-allo10
Sponsored by
Roncarolo, Maria Grazia, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for AML - Acute Myeloid Leukemia focused on measuring Pediatric, GvHD, Hematopoietic Stem Cell Transplantation, Stem Cells, Transplant, BMT - bone marrow transplant

Eligibility Criteria

3 Years - 45 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Eligible diseases include:

    A. Acute Lymphoblastic Leukemia (B- or T-ALL)

    1. Complete Response (CR)1-ultra high risk features

      • Unfavorable cytogenetics
      • Hypodiploidy
      • Induction failure
      • Minimal Residual Disease (MRD) positive after consolidation

    2. CR-2:

      • Any of the high risk features listed in CR1
      • B-ALL: any relapse considered eligible for transplant
      • T- ALL
    3. CR-3-any

    B. Acute Myeloid Leukemia

    1. MRD >5% at day 22 induction 1
    2. MRD >0.1% after induction 2
    3. FLT/ITD with allelic ratio > 0.4 and MRD >0.1% at day 22 or 29 induction 1
    4. Translocation (6:9), (8:6), (16:21), monosomy 7, monosomy 5, 5q
    5. M7 with KMT2A rearrangements, inv(16)(p13.3q24.3) [CBFA2T3-GLIS2] or t(11;12)(p15;p13) [NUP98-KDM5A]
    6. AML in 2nd or subsequent CR
    7. Therapy related or Secondary AML
    8. 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

  2. Age ≥3 to ≤45 years old. Subjects 1 and 2 (in Cohort 1) will be ≥ 12 years old
  3. Available mismatched related donor (mMRD) or mismatched unrelated donor (mMUD), Human leukocyte antigen (HLA) matched 8/10 or 9/10
  4. Lansky (age <16) or Karnofsky (age ≥16) performance status ≥80%
  5. Able and willing to provide written, signed informed consent (assent as appropriate)

  6. 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%)
  7. 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:

  1. Prior bone marrow or peripheral blood HSCT within the last 6 (six) months
  2. HLA-matched related or unrelated donor available
  3. Any active, uncontrolled infection at the time of enrollment
  4. Pregnant or lactating females
  5. Any severe concurrent disease which, in the judgement of the investigator, would place the patient at increased risk during participation in the study
  6. Any subject with a history of significant renal, hepatic, pulmonary, or cardiac dysfunction or on treatment to support cardiac dysfunction
  7. HIV positive
  8. Non-cooperative behavior or non-compliance of the patient and/or of his/her family
  9. Received another investigational agent within 30 days of enrollment
  10. Patients with Down's syndrome

Sites / Locations

  • Lucile Packard Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Arm Description

Participants will receive 1 X 10^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant)

Participants will receive 3 X 10^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant)

Participants will receive 9 X 10^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant)

Outcomes

Primary Outcome Measures

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.
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.
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.
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.

Secondary Outcome Measures

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

Full Information

First Posted
April 11, 2017
Last Updated
April 7, 2023
Sponsor
Roncarolo, Maria Grazia, MD
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03198234
Brief Title
Use of T-allo10 in Hematopoietic Stem Cell Transplantation (HSCT) for Blood Disorders
Acronym
T-allo10
Official Title
Use of T-allo10 Cell Infusions Combined With Mismatched Related or Mismatched Unrelated Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 30, 2017 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
July 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Roncarolo, Maria Grazia, MD
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
AML - Acute Myeloid Leukemia, MDS (Myelodysplastic Syndrome), Mixed Phenotype Acute Leukemia, NHL - Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, ALL
Keywords
Pediatric, GvHD, Hematopoietic Stem Cell Transplantation, Stem Cells, Transplant, BMT - bone marrow transplant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Participants will receive 1 X 10^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant)
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Participants will receive 3 X 10^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant)
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
Participants will receive 9 X 10^6/kg (± 10%) T-allo10 cells infused intravenously on Day -1 (day before transplant)
Intervention Type
Biological
Intervention Name(s)
T-allo10
Intervention Description
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).
Primary Outcome Measure Information:
Title
Incidence of treatment emergent adverse events (TEAE)
Description
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 Frame
Time of T-allo10 cell infusion until 28 days following the infusion.
Title
Severity of treatment emergent adverse events (TEAE)
Description
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 Frame
Time of T-allo10 cell infusion until 28 days following the infusion.
Title
Safety of T-allo10 will be measured by the time to stem cell engraftment after Hematopoietic Stem Cell Transplant.
Description
Stem cell engraftment is evaluated by clinical laboratory studies including absolute neutrophil count, hematopoiesis, chimerism analysis, and minimal residual disease (MRD) assay.
Time Frame
42 days
Title
Feasibility defined by the successful manufacture of the T-allo10 product
Description
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.
Time Frame
By Day -9
Secondary Outcome Measure Information:
Title
Incidence and severity of grade III and IV acute GvHD
Description
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
Time Frame
Study visits through Day +100
Other Pre-specified Outcome Measures:
Title
Incidence and severity of chronic GvHD
Description
The incidence and severity of chronic GvHD will be assessed by an independent evaluator.
Time Frame
After Day +100 through Day +365,
Title
Time to immune reconstitution
Description
Immune reconstitution will be evaluated by clinical laboratory studies of CD3+ T cells, assessed by the time to reach >200/microliter CD3+ T cells.
Time Frame
Up to Day 365
Title
Disease Free Survival
Description
Disease free survival is defined as the absence of minimal residual disease in the bone marrow. The investigators will use bone marrow aspirate examination, minimal residual disease (MRD) assay, and donor chimerism by STR analysis to evaluate disease free survival.
Time Frame
At Day +365

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rajni Agarwal, MD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Lucile Packard Children's Hospital
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
SCGT Clinical Trials Program
Phone
650-725-9250
Email
DL-SCTIntakeCoordinators@stanfordchildrens.org

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
There is no plan to share the individual participant data.

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

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