Adoptive T Lymphocyte Administration for Chronic Norovirus Treatment in Immunocompromised Hosts

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Brief Title

Adoptive T Lymphocyte Administration for Chronic Norovirus Treatment in Immunocompromised Hosts

Official Title

Adoptive T Lymphocyte Administration for Chronic Norovirus Treatment in Immunocompromised Hosts

Brief Summary

      This is a Phase I dose-escalation study to evaluate the safety of norovirus -specific T-cell
      (NST) therapy for chronic norovirus infection in participants following hematopoietic stem
      cell transplantation (HSCT) or with primary immunodeficiency disorders (PID) who have not
      undergone HSCT.
    

Detailed Description

      This is an open label, phase I study of norovirus-specific T-cell immunotherapy for treatment
      of participants with primary immunodeficiency disorders (PID) and chronic norovirus. This
      study is designed to assess the safety of norovirus-specific T-cell (NST) infusion in this
      population. There are two arms in this study:

        1. Arm A: Participants who receive donor derived NST therapy after HSCT

        2. Arm B: Participants who receive partially HLA matched NSTs. The following participants
           apply:

             -  Participants with PID who have not undergone HSCT

             -  Participants who undergo HSCT but do not have available donor derived NSTs

             -  Participants who have donors from whom NSTs cannot be generated due to norovirus
                seronegativity Participants will be monitored for infusion-related reactions and
                GVHD for 1 year following first infusion. During this time, participants will be
                accessed with regard to the length and quantity of norovirus shedding in stool, and
                gastrointestinal and constitutional symptoms will be scored by clinicians and
                participants. Correlative studies of T-cell immune reconstitution against
                norovirus, norovirus genomic sequences, and composition of the fecal microbiome
                will also be accessed.

      The primary purpose of this phase I study is to assess the safety of administering
      donor-derived or partially HLA-matched NSTs in immunocompromised participants with chronic
      norovirus infections. Related and unrelated donors of participants who have chronic norovirus
      infection after HSCT will be enrolled for screening and production of NSTs from peripheral
      blood. Following product manufacturing, participants who have undergone HSCT (Arm A) will
      receive donor-derived NSTs. For participants with PID who have not undergone HSCT (Arm B),
      high-resolution HLA typing of the participant will be utilized for an inquiry of the NST bank
      to determine if a partially HLA-matched NST product exists that has antiviral activity
      mediated through one or more shared HLA alleles. Participants who have undergone HSCT but
      either do not have available donors for NST generation, or who have donors from whom NSTs
      cannot be generated due to norovirus seronegativity will also be eligible for inquiry for
      treatment with partially HLA-matched NSTs if available under study Arm B.

      This will be a dose escalation study with two arms. Participants who have undergone HSCT will
      be enrolled on Arm A and receive NSTs derived from their HSCT donor. Participants with a
      diagnosis of PID who have not undergone HSCT, or participants who have undergone HSCT but do
      not have available donor-derived NSTs will be enrolled on Arm B and receive partially-HLA
      matched NSTs. Investigators will test three doses: 1 x 10^7 /m^2, 2 x 10^7 /m^2, and 4 x 10^7
      /m^2. Investigators will have a 45-day safety monitoring period for immediate toxicities
      following infusion.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Incidence of acute GvHD (grade III-IV)

Secondary Outcome

 Antiviral activity

Condition

Viral Infection

Intervention

Norovirus -specific T-cell (NST) therapy

Study Arms / Comparison Groups

 Norovirus -specific T-cell (NST) therapy for chronic norovirus infection
Description:  This is a Phase I dose-escalation study to evaluate the safety of norovirus -specific T-cell (NST) therapy for chronic norovirus infection in participants following hematopoietic stem cell transplantation (HSCT) or with primary immunodeficiency disorders (PID) who have not undergone HSCT. There are two arms in this study:
Arm A: Participants who receive donor-derived NST therapy after HSCT
Arm B: Participants who receive partially HLA matched NSTs. The following participants apply:
Participants with PID who have not undergone HSCT
Participants who undergo HSCT but do not have available donor derived NSTs
Participants who have donors from whom NSTs cannot be generated due to norovirus seronegativity

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

48

Start Date

October 26, 2020

Completion Date

October 2026

Primary Completion Date

August 2025

Eligibility Criteria

        Inclusion Criteria:

        Participant Inclusion Criteria for NST Infusion:

          1. Participants must meet one of the following criteria:

               1. Recipient of prior myeloablative or non-myeloablative allogeneic hematopoieic
                  stem cell transplant using either bone marrow or peripheral blood stem cells or
                  single or double cord blood, OR

               2. Primary immunodeficiency disorder (as defined by clinical and laboratory
                  evaluations) and have not undergone HSCT.

          2. Documentation of chronic norovirus infection:

             a. Chronic norovirus infections will be defined as having consecutive positive
             norovirus stool tests (2 or more) spanning a minimum three month period with
             attributable signs and symptoms of norovirus disease.

          3. Participants receiving steroids for treatment of GVHD or for other reasons, dosage
             must have been tapered to <0.5 mg/kg/day of prednisone (or equivalent) a minimum of 7
             days prior to infusion.

             a. Treatment with enteral topical steroids such as Budesonide at standard doses may be
             continued if previously utilized, but should not be newly initiated in the 3 months
             after NST therapy.

          4. For participants who have undergone HSCT, participants must have stable donor
             chimerism at the time of NST infusion.

             a. Stability will be defined as i. >95% donor chimerism in CD33 and/or whole blood
             chimerism OR ii. >90% donor chimerism with <5% change between subsequent tests
             separated by at least 1 week.

          5. Karnofsky/Lansky score > 50

          6. 3 months to 80 years of age at enrollment

          7. ANC ≥ 500/ul

          8. Hemoglobin ≥ 7.0g/dl (level can be achieved with transfusion)

          9. Platelets ≥ 20 K/ul (level can be achieved with transfusion)

         10. Bilirubin < 2x upper limit normal

         11. AST < 3x upper limit normal

         12. Serum creatinine < 2x upper limit normal

         13. Pulse oximetry of ≥ 90% on room air

         14. Negative pregnancy test in female participant of childbearing age.

         15. Written informed consent and/or signed assent line from participant, parent or
             guardian.

        Donor Inclusion Criteria:

          1. Donors who have fulfilled eligibility as per FDA regulations outlined in 21 CFR 1271
             subpart C. This includes that donors have been deemed in good health by donor
             physician based on physical examination and laboratory testing. If a donor has been
             chosen for the transplant based on urgent medical need that same donor will also be
             used for NST generation provided that there are no new reasons for ineligibility since
             the stem cell collection.

          2. Be between 2 to 35 years of age (females) or 2 to 40 years of age (males)

          3. Donor or guardian of pediatric donor capable of providing informed consent

          4. Donor must have completed infectious Disease (ID) testing up to 7 days before or after
             the collection of blood from the donor (related or unrelated) for TAA-T manufacturing.
             The following tests will be performed:

               -  AbO/Rh

               -  HBsAg

               -  HB Core antibody

               -  HIV1/2 NAT

               -  Syphilis (T. Pallidum IgG)

               -  HTLV I/II

               -  CMV total

               -  HBV/HCV NAT

               -  West Nile Virus NAT.

               -  Cruz (Chagas) antibody

               -  Hepatitis C

          5. Female donors of childbearing age must have a negative pregnancy test and not be
             lactating.

        Exclusion Criteria:

        Participants Exclusion Criteria for NST Infusion:

          1. Participants receiving biological or immunosuppressive monoclonal antibodies targeting
             T-cells within 28 days prior to NST infusion, including ATG, Alemtuzumab, Basiliximab,
             Tociluzimab, Brentuximab, or other medications under this category as determined by
             the investigators.

             a. If alemtuzumab has been received within 6 weeks prior to NST infusion, plasma
             levels should be obtained to ensure drug clearance (≤0.16 pg/ml).

          2. Participants who have received donor lymphocyte infusion (DLI), chimeric antigen
             receptor T-cell infusion, or other experimental cellular therapies within 28 days
             prior to NST infusion.

          3. Participants with SCID who undergone alpha/BetaTCR depleted HSCT within the past 100
             days.

          4. Participants who have received ruxolitinib or other JAK inhibitors within 7 days prior
             to NST infusion.

          5. Participants with uncontrolled or progressing infections other than norovirus.
             Uncontrolled infections are defined as bacterial, fungal, or non-targeted viral
             infections with either clinical signs of worsening despite standard therapy, or
             chronic gastrointestinal symptoms that may be attributed to the uncontrolled
             infection. Progressing infection is defined as hemodynamic instability, worsening
             physical signs, or radiographic findings attributable to infection. Persisting fever
             without other signs or symptoms will not be interpreted as progressing infection.

               1. For bacterial infections, participants must be receiving definitive therapy and
                  have no signs of progressing infection within 7 days prior to NST infusion and or
                  no chronic gastrointestinal symptoms associated with this bacterial infection.

               2. For fungal infections, participants must be receiving definitive systemic
                  anti-fungal therapy and have no signs of progressing infection within 7 days
                  prior to NST infusion.

          6. Participants must not have other active gastrointestinal infections to which symptoms
             may be attributable, including parasitic infections (cryptosporidium, giardiasis),
             viral infections aside from norovirus (CMV colitis, rotavirus, adenovirus), or
             bacterial infections with C. difficile, Yersinia, Campylobacter, Salmonella, Shigella,
             or enteroinvasive or enterotoxigenic E. coli.

             a. Testing for unrelated GI infections must be performed within 14 days prior to NST
             infusion, and must include: i. Crytosporidium/Giardia testing via antigen or PCR
             testing ii. Stool viral testing for rotavirus and adenovirus via antigen or PCR
             testing iii. Stool bacterial culture iv. C. difficile toxin PCR b. Determination of
             active infection versus chronic carriage / shedding will be made by the investigators
             and clinical providers, and will depend on the presence of clinical symptoms
             corresponding with the timing of positive test results, presence of a clinical
             response to targeted therapy, and by histological or other testing if clinically
             indicated.

          7. Participants with active and uncontrolled relapse of malignancy (if applicable).

               1. Failure of primary engraftment is defined as failure to achieve platelet and/or
                  neutrophil engraftment (ANC< 500/ul and/or platelets <20 K/ul) following HSCT.

               2. Secondary graft failure is defined as <5% donor chimerism (CD3+ or CD34+) or
                  permanent loss of neutrophil and/or platelet engraftment (ANC< 500/ul and/or
                  platelets<20 K/ul) at any time after primary engraftment.

          8. Participants with symptomatic gastrointestinal conditions aside from norovirus,
             including active inflammatory bowel disease or graft versus host disease (grade
             II-IV).

          9. Participants receiving checkpoint inhibitors within the previous 3 months prior to NST
             infusion, including nivolumimab, pembroluzimab, or other related medications.

         10. Participants receiving oral immunoglobulin, nitazoxanide, or other experimental
             therapies for norovirus infection within 28 days prior to NST infusion.

        Donor Exclusion Criteria:

        1. Donation of cells would pose a physical or psychological risk to the donor
      

Gender

All

Ages

3 Months - 80 Years

Accepts Healthy Volunteers

No

Contacts

Michael Keller, MD, 202-476-5843, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04691622

Organization ID

Pro00014658


Responsible Party

Principal Investigator

Study Sponsor

Children's National Research Institute


Study Sponsor

Michael Keller, MD, Principal Investigator, CNH


Verification Date

December 2021