Clinical Trials /

Tumor Associated Antigen Specific T Cells (TAA-T) With PD1 Inhibitor for Lymphoma

NCT03843294

Description:

This is a Phase I, open-label multi-site trial designed to evaluate the safety of administering rapidly-generated Tumor associated antigen specific T cells (TAA-T) with the Programmed Death1 (PD-1) inhibitor Nivolumab, in relapsed/refractory lymphoma (rel/ref) patients with measurable disease (group A) or as adjunctive therapy following autologous hematopoeitic stem cell transplant(HSCT) for patients at high risk of relapse (group B). The purpose of this study is to find out if the tumor specific T cells given with Nivolumab are safe and to learn what the side effects are and if the combination can help patients with relapsed lymphomas.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Tumor Associated Antigen Specific T Cells (TAA-T) With PD1 Inhibitor for Lymphoma
  • Official Title: Phase I Study Utilizing Tumor Associated Antigen Specific T Cells (TAA-T) With PD1 Inhibitor Nivolumab for Relapsed/Refractory Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: SUSTAIN
  • NCT ID: NCT03843294

Conditions

  • Hodgkin Lymphoma
  • Diffuse Large B Cell Lymphoma

Interventions

DrugSynonymsArms
TAA-T cellsNivolumab with TAA-T cell
NivolumabNivolumab with TAA-T cell

Purpose

This is a Phase I, open-label multi-site trial designed to evaluate the safety of administering rapidly-generated Tumor associated antigen specific T cells (TAA-T) with the Programmed Death1 (PD-1) inhibitor Nivolumab, in relapsed/refractory lymphoma (rel/ref) patients with measurable disease (group A) or as adjunctive therapy following autologous hematopoeitic stem cell transplant(HSCT) for patients at high risk of relapse (group B). The purpose of this study is to find out if the tumor specific T cells given with Nivolumab are safe and to learn what the side effects are and if the combination can help patients with relapsed lymphomas.

Detailed Description

      This Phase I, open-label multi-site trial is designed to evaluate the safety of administering
      rapidly-generated multi-antigen-specific T lymphocytes with the PD1 inhibitor Nivolumab, to
      relapsed/refractory (rel/ref) lymphoma patients with measurable disease (group A) or as
      adjunctive therapy following autologous HSCT (group B).

      This study will first enroll 6 patients total (in Groups A and B) in the initial safety
      monitoring or DLT group prior to the expansion phase where additional 12 patients (6 in Group
      A and 6 in Group B) will be enrolled. TAA-T cells will be generated from patient's
      lymphocytes obtained from patient's PBMC.

      If patient meets eligibility criteria for TAA-T cell infusion, the patient (Group A or Group
      B) will receive two TAA-T cell infusions given 2 weeks apart, where the expected volume of
      infusion is 1 to 10 cc.

      Both TAA-T cells and Nivolumab will be given at the doses below with allowed de-escalation of
      both doses as follows:

        -  TAA-T cell dose: 2 x 107 cells/m2 per infusion

        -  Nivolumab: For patients <18 years, 3 mg/kg/dose (maximum 240mg/dose) every 2 weeks. For
           adult patients ≥18 years, a dose of 240mg every 2 weeks or 480mg every 4 weeks

      From the first 2 enrolled patients, if at least one patient meets dose limiting toxicity
      criteria (as described in section 6.4.1) at the above mentioned combination dose level, then
      the next 2 patients will receive TAA-T cells at 1 x 107 cells/m2 without a change in
      Nivolumab dose. If toxicity criteria are met by at least one patient from these 2 patients,
      then the dose of Nivolumab will be reduced to 1mg/kg/dose for patients <18 years or 100mg if
      receiving 240mg dosing or 200mg if receiving 480mg dosing for adult patients ≥18 years for
      next 2 patients and TAA-T cells will be given at the same de-escalated dose of 1x 107
      cells/m2.

      In case the patient experiences toxicity from Nivolumab prior to the first TAA-T cell
      infusion, they can receive the TAA-T cells after resolution of the Nivolumab toxicities and
      steroid dosing has been reduced less than 0.5mg/kg/day.

      After the safety phase is complete, additional 12 patients total will be enrolled on
      expansion cohort.

      Patients will receive doses Nivolumab at a minimum of 8 weeks prior to first TAA-T cell
      infusion and additional dose(s) of Nivolumab will be given after 4 weeks following second
      TAA-T cell infusion starting at week 7 from first infusion of TAA-T.. Delays >3 days for the
      Nivolumab will not be considered protocol violations if discussed with the PI.

      If the TAA-T cells are not ready after the initial doses of Nivolumab prior to the first
      TAA-T infusion, then the patients can continue Nivolumab infusions for an additional 8 weeks
      at the PI's discretion. If there is insufficient number of TAA-Ts for the two planned
      infusions, then additional blood may be drawn and patients can continue on Nivolumab unless
      they rapidly progress with disease requiring urgent therapy. If there is insufficient number
      of TAA-Ts to meet study dose, a lower dose of TAA-T may be infused at the discretion of the
      PI.

      Only group A patients are eligible for additional doses ( 3 to 8) if they have stable disease
      or response, do not have ≥ grade 3 toxicity attributed to TAA-T cells and do not have
      clinical evidence of rapidly progressing disease requiring urgent therapy.

      For Group B patients, blood for generation for TAA-T cells (non-mobilized) will be collected
      prior to the stem cell collection or any time after Day 30 post auto-HSCT. Treatment with
      Nivolumab will begin any time after Day 30 post auto-HSCT. Patients are eligible for Group B
      if they have no evidence of metabolically active disease by PET/CT (Deauville Score of 3 or
      less) at time of starting treatment with Nivolumab. Patients eligible for Group B with
      <CMR)/CR (by PET/CT) prior to auto-HSCT will need to be in CR (Deauville Score of 3 or less)
      prior to the start of Nivolumab or can be moved to Group A if they have metabolically active
      disease (Deauville Score of 4 or more) by PET/CT.

      Patients should not receive other systemic antineoplastic agents including Nivolumab for at
      least 6 weeks after the first infusion of TAA-specific T-cells (for purposes of evaluation),
      although such treatment may be added if deemed critical for patient care by the attending
      physician.

      Patients in Group A will not be able to receive additional doses (3-8) of TAA-T cells until
      the initial 6 weeks evaluation for toxicity and efficacy following the first TAA-T cell
      infusion.

      Patients (Group A and B) will not receive subsequent doses of Nivolumab until the safety
      evaluation for TAA-T is over (at least 6 weeks from the first infusion).
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab with TAA-T cellExperimentalPatients will receive doses of Nivolumab at a minimum of 8 weeks prior to first TAA-T cell infusion and additional dose(s) of Nivolumab will be given after 4 weeks following second TAA-T cell infusion starting at week 7 from first infusion of TAA-T.If patient meets eligibility criteria for TAA-T cell infusion, the patient will receive two TAA-T cell infusions given 2 weeks apart
  • TAA-T cells
  • Nivolumab

Eligibility Criteria

        Disease Specific Inclusion Criteria

        Group A (patients with measurable disease) Relapsed/Refractory Hodgkin Lymphoma (HL) and
        Diffuse Large B cell Lymphoma (DLBCL) DLBCL

          -  Patients who have failed at least 2 lines of prior therapy with a failed attempt at
             both an autologous stem cell transplant and chimeric antigen receptor T cell therapy.

          -  Patients who are deemed autologous stem cell transplant ineligible and have failed
             only one line of prior therapy.

          -  Systemic therapies to treat prior indolent lymphomas count towards previous DLBCL
             lines of therapy unless the treatment was anti-CD20 antibody monotherapy.

        HL

          -  Rel/ref HL failing more than or equal to 1 salvage regimens, including prior
             Brentuximab Vedotin (BV)

          -  Rel/ref after autologous HSCT

        Group B (consolidation after auto-HSCT for patients at high risk for relapse) DLBCL

          -  Patients with < CMR/CR (by PET/CT) with initial treatment regimen

          -  Patients with relapse <12 months from diagnosis or <6 months from completion of
             initial therapy

          -  Patients with <CMR/CR (by PET/CT) prior to autologous HSCT

          -  Patients requiring >1 salvage regimen prior to autologous HSCT HL

          -  Patients with relapse <12 months from diagnosis or <6 months from completion of
             initial therapy

          -  Patients with <CMR/CR (by PET/CT) prior to autologous HSCT

          -  Patients requiring >1 salvage regimen prior to autologous HSCT

        Recipient Inclusion Criteria for Initial and Subsequent Procurements (TAA-T Cell
        Generation):

          -  Age >12 years

          -  Karnofsky/Lansky score of more than or equal to 50 (see appendix C).

          -  ALC > 600

          -  Patients receiving Granulocyte colony-stimulating factor (G-CSF) are recommended a
             washout period of a minimum of two weeks before procurement

          -  Agree to use contraceptive measures during study protocol participation (when age
             appropriate)

          -  Patient or parent/guardian capable of providing informed consent

        Recipient Exclusion Criteria for Initial and Subsequent Procurements (TAA-T Cell
        Generation):

          -  Prior allogeneic BMT

          -  Prior solid organ transplant

          -  Patient who has received ATG, Campath or other immunosuppressive T cell monoclonal
             antibodies within 28 days of screening for enrollment

          -  Patient with uncontrolled infections

          -  Patient with active HIV

          -  Pregnancy or lactating

          -  Failure to meet institutional guidelines for treatment with Nivolumab

        Recipient Inclusion Criteria for Initial and Subsequent TAA-T Cell Infusions:

          -  Age >12 years

          -  Patient has received at least 8 weeks of Nivolumab

          -  Patients with Grade 1 toxicities attributed to Nivolumab will be eligible at the
             discretion of the PI. Toxicities include but not limited to: laboratory abnormalities
             in thyroid function tests suggestive of hypothyroidism, thyroiditis or thyroid
             dysfunction adequately managed with thyroid hormone replacement, or abnormalities in
             amylase, lipase

          -  Steroids less than 0.5 mg/kg/day prednisone or equivalent

          -  Karnofsky/Lansky score of more than or equal to 50

          -  Pulse oximetry of > 90% on room air

          -  Bilirubin less than or equal to 2.5 mg/dL, AST/ALT less than or equal to 5x upper
             limit of normal, serum creatinine < 1.0 or 2x the upper limit of normal (whichever is
             higher)

          -  Absolute neutrophil count > 250/µL (may be supported with GCSF)

          -  Agree to use contraceptive measures during study protocol participation (when age
             appropriate)

          -  Patient or parent/guardian capable of providing informed consent

        Recipient Exclusion Criteria for Initial and Subsequent TAA-T Cell Infusions:

          -  Investigational therapies within 28 days prior to screening for enrollment

          -  Uncontrolled infections

          -  Patient with ≥ grade 1 or symptomatic non-hematologic toxicities from prior therapies
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Product-Emergent Adverse Events
Time Frame:6 weeks from the first TAA-T cell administrations
Safety Issue:
Description:Number of participants with grades 3-5 infusion-related and grades 4-5 non-hematological adverse events that are not due to the original malignancy, or pre-existing co-morbidities at least 6 weeks of the first dose of TAA-T infusion as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, change from baseline up to week 6.

Secondary Outcome Measures

Measure:Tumor response to combination immunotherapy
Time Frame:1 year
Safety Issue:
Description:Number of patients with tumor associated antigen lymphocytes (TAA-T) with Nivolumab response, change from baseline at year one. Response will be assessed by imaging using the Lugano criteria. Response is defined as any patient who does not progress on this study, including patients with active disease who achieve Complete Metabolic Response (CMR)/Complete Response (CR), Partial Metabolic Response (PMR)/ Partial Response (PR), or No Metabolic Response(NMR)/Stable Disease (SD) by PET/CT.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Catherine Bollard

Last Updated

July 16, 2021