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

Brief Title

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

Official Title

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

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
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Incidence of treatment emergent adverse events (TEAE)

Secondary Outcome

 Incidence and severity of grade III and IV acute GvHD

Condition

AML - Acute Myeloid Leukemia

Intervention

T-allo10

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

30

Start Date

August 30, 2017

Completion Date

July 2022

Primary Completion Date

July 2021

Eligibility Criteria

        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
      

Gender

All

Ages

3 Years - 45 Years

Accepts Healthy Volunteers

No

Contacts

Rajni Agarwal, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03198234

Organization ID

SU-IRB-38734


Responsible Party

Principal Investigator

Study Sponsor

Stanford University


Study Sponsor

Rajni Agarwal, MD, Principal Investigator, Stanford University


Verification Date

August 2019