Clinical Trials /

Multi-antigen T Cell Infusion Against Neuro-oncologic Disease

NCT03652545

Description:

This Phase I dose-escalation trial is designed to determine the safety and feasibility of rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA-T) in patients with newly diagnosed diffuse intrinsic pontine gliomas DIPGs or recurrent, progressive, or refractory non-brainstem CNS malignancies Pediatric and adult patients who have high-risk CNS tumors with known positivity for one or more Tumor Associated Antigens (TAA) (WT1, PRAME and/or survivin) will be eligible to receive Tumor Antigen Associated Cytotoxic T Lymphocytes (TAA-T). Patients will be enrolled in one of two groups: Group A includes patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) who will undergo irradiation as part of their upfront therapy and Group B includes patients with recurrent, progressive or refractory CNS tumors including medulloblastoma, non-brainstem high-grade glioma, and ependymoma, among others. TAA-T will be generated from patient's peripheral blood mononuclear cells (PBMCs) or by apheresis. This protocol is designed as a phase I dose-escalation study. Group A patients (DIPG patients): TAA-T will be infused any time > 2 week after completion of radiotherapy. Group B patients (other recurrent/progressive/refractory CNS tumors): TAA-T will be infused any time > 2 weeks after completing most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria.

Related Conditions:
  • Central Nervous System Embryonal Carcinoma
  • Choroid Plexus Carcinoma
  • Diffuse Intrinsic Pontine Glioma
  • Ependymoma
  • High-Grade Glioma, NOS
  • Medulloblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Multi-antigen T Cell Infusion Against Neuro-oncologic Disease
  • Official Title: Phase I REsearch on Multi-antigen T Cell Infusion Against Neuro-oncologic Disease

Clinical Trial IDs

  • ORG STUDY ID: REMIND
  • NCT ID: NCT03652545

Conditions

  • Brain Tumor

Interventions

DrugSynonymsArms
TAA-TTAA-T

Purpose

This Phase I dose-escalation trial is designed to determine the safety and feasibility of rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA-T) in patients with newly diagnosed diffuse intrinsic pontine gliomas DIPGs or recurrent, progressive, or refractory non-brainstem CNS malignancies Pediatric and adult patients who have high-risk CNS tumors with known positivity for one or more Tumor Associated Antigens (TAA) (WT1, PRAME and/or survivin) will be eligible to receive Tumor Antigen Associated Cytotoxic T Lymphocytes (TAA-T). Patients will be enrolled in one of two groups: Group A includes patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) who will undergo irradiation as part of their upfront therapy and Group B includes patients with recurrent, progressive or refractory CNS tumors including medulloblastoma, non-brainstem high-grade glioma, and ependymoma, among others. TAA-T will be generated from patient's peripheral blood mononuclear cells (PBMCs) or by apheresis. This protocol is designed as a phase I dose-escalation study. Group A patients (DIPG patients): TAA-T will be infused any time > 2 week after completion of radiotherapy. Group B patients (other recurrent/progressive/refractory CNS tumors): TAA-T will be infused any time > 2 weeks after completing most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria.

Detailed Description

      This Phase I dose-escalation trial is designed to determine the safety and feasibility of
      rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA-T) in
      patients with newly diagnosed diffuse intrinsic pontine gliomas DIPGs or recurrent,
      progressive, or refractory non-brainstem CNS malignancies. Patients who have high-risk CNS
      tumors with known positivity for one or more Tumor Associated Antigens (TAA) (WT1, PRAME
      and/or survivin) will be eligible to receive Tumor Antigen Associated Cytotoxic T Lymphocytes
      (TAA-T). Patients will be enrolled in one of two groups: Group A includes patients with newly
      diagnosed diffuse intrinsic pontine gliomas (DIPGs) who will undergo irradiation as part of
      their upfront therapy and Group B includes patients with recurrent, progressive or refractory
      CNS tumors including medulloblastoma, non-brainstem high-grade glioma, and ependymoma, among
      others. TAA-T will be generated from patient's peripheral blood mononuclear cells (PBMCs) or
      by apheresis.

      Group A patients (DIPG patients): TAA-T will be infused any time > 2 week after completion of
      radiotherapy.

      Group B patients (other recurrent/progressive/refractory CNS tumors): TAA-T will be infused
      any time > 2 weeks after completing most recent course of conventional (non-investigational)
      therapy for their disease AND after appropriate washout periods as detailed in eligibility
      criteria.

      This protocol is designed as a phase I dose-escalation study. In each treatment group (A and
      B), patients will be enrolled to one of the following TAA-T dose levels:

      Dose Level 1 2 x 107 cells/m2 Dose Level 2 4 x 107 cells/m2 Dose Level 3 8 x 107 cells/m2

      Two patients will be initially enrolled to the lowest dose level cohort (separately on each
      arm) and followed for 45 days after initial TAA-T for dose limiting toxicity (DLT)
      evaluations. The decision on whether it is safe to escalate to next dose level or not will be
      made after at least two patients in each dose level have finished their 45-days toxicity
      follow up after initial TAA-T. If the first two patients have not finished their 45 days
      follow-up, up to two additional incoming patients can be enrolled at the current dose level.

      Two to four patients will be enrolled at each dose level (separately on each arm). Each
      patient will receive at least one TAA-T infusion and may receive a maximum of 8 doses if
      TAA-T is available. The first and second doses will be administered 45 days apart then
      additional doses will be spaced every 28 days. The expected volume of each infusion is 1 to
      10 cc.

      Group A and Group B patients will separately use the dose escalation strategy described
      above. Ideally, patients should not receive other systemic antineoplastic agents for at least
      45 days after the infusion of TAA-T, although such treatment may be added if deemed critical
      for patient care by the attending physician.

      If patients with measurable or evaluable disease have a response of stable disease or better
      by Response Assessment in Neuro-oncology (RANO) criteria at the day 28 evaluation after dose
      2 or subsequent evaluations, they are eligible to receive up to 6 additional doses of TAA-T
      at 28 day intervals, if TAA-T supply allows. Each subsequent dose will be at the enrollment
      dose level (i.e. no subsequent dose escalation). The first and second doses will be
      administered 45 days apart then additional doses will be spaced every 28 days. Following dose
      number 1, if a patient's TAA-T supply is insufficient for subsequent doses at the enrollment
      dose level, further treatments may be administered at a lower dose level at the treating
      physician's discretion.
    

Trial Arms

NameTypeDescriptionInterventions
TAA-TExperimentalThree different dosing schedules will be evaluated. Dose Level One: 2 x 107 cells/m2 Dose Level Two: 4 x 107 cells/m2 Dose Level Three: 8 x 107 cells/m2 Group A patients (DIPG patients): TAA-T will be infused any time > 14 days after completion of radiotherapy. Group B patients (other recurrent/progressive/refractory CNS tumors): TAA-T will be infused any time > 14 days after completing most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria. Ideally, patients should not receive other systemic antineoplastic agents for at least 45 days after the infusion of TAA-T, although such treatment may be added if deemed critical for patient care by the attending physician.

    Eligibility Criteria

            Inclusion Criteria:
    
            Recipient procurement inclusion criteria (Please see Appendix A1)
    
              -  Diagnosis of high-risk CNS tumors: DIPG, high-grade glioma, medulloblastoma,
                 ependymoma, embryonal tumors, choroid plexus carcinoma, other aggressive CNS
                 malignancies.
    
              -  Group A (newly diagnosed DIPG): planned completion of standard radiotherapy before
                 receiving TAA-T therapy and radiographic diagnosis with DIPG defined as tumors with a
                 pontine epicenter and diffuse intrinsic involvement of the pons
    
              -  Group B: Recurrent, progressive, or refractory disease after standard treatment.
                 Refractory disease includes high-risk tumors with residual disease after completion of
                 standard treatment.
    
              -  Measureable disease - patients must have measureable disease in 2-dimensions on MRI
                 scan of the brain and/or spine.
    
              -  6 months to 80 years of age at enrollment
    
              -  Karnofsky/Lansky score of ≥ 60% (see appendix B).
    
              -  Organ function:
    
              -  ANC >750L
    
              -  Platelets >75K
    
              -  Bilirubin <1.5x ULN
    
              -  AST/ALT < 5x ULN
    
              -  Serum creatinine <1.0mg/dL or 1.5x ULN for age (whichever is higher)
    
              -  Pulse oximetry > 90% on room air
    
              -  Agree to use contraceptive measures during study protocol participation (when age
                 appropriate)
    
              -  Patient or parent/guardian capable of providing informed consent
    
              -  Available pre-trial tumor tissue (Group B)
    
            Recipient procurement exclusion criteria
    
              -  Patients with uncontrolled infections
    
              -  Patients with HIV infection
    
              -  Pregnancy or lactating females
    
              -  Prior immunotherapy with an investigational agent within the last 28 days prior to
                 procurement
    
              -  Patients with previous history of allogeneic stem cell transplantation (however,
                 patients who have received autologous stem-cell infusions will remain eligible)
    
              -  Bulky tumor
    
              -  Group B - patients who have bulky tumor on imaging are ineligible. These include the
                 following:
    
              -  Tumor with any evidence of uncal herniation or significant midline shift
    
              -  Tumor with a significant brainstem component
    
              -  Patients who are deemed to have overly bulky tumor by the PI of the study
    
            Exclusion Criteria:
    
            Recipient inclusion criteria for initial TAA-T administration and for subsequent infusions
            (Please see Appendix A2)
    
              -  Steroids < 0.5 mg/m2 dexamethasone or equivalent per day
    
              -  Karnofsky/Lansky score of ≥ 60%
    
              -  Organ function:
    
              -  ANC >750L
    
              -  Platelets >75K
    
              -  Bilirubin <1.5x ULN
    
              -  AST/ALT < 5x ULN
    
              -  Serum creatinine <1.0mg/dL or 1.5x ULN for age (whichever is higher)
    
              -  Pulse oximetry > 90% on room air
    
              -  Patients must have received their last dose of known:
    
              -  Myelosuppressive chemotherapy (including completing radiotherapy for group A
                 patients): ≥ 14 days prior to TAA-T infusion or demonstrated count recovery
    
              -  Investigational/biologic agent: seven days prior to TAA-T infusion. For agents that
                 have known adverse events occurring beyond seven days after administration, this
                 period must be extended beyond the time when new adverse events are known to commonly
                 occur.
    
              -  Surgery: patients must have recovered from all acute effects of prior surgical
                 intervention
    
              -  Neurologic status: Patients with neurologic deficits must have deficits that are
                 stable for a minimum of 7 days prior to TAA-T infusions
    
            Recipient exclusion criteria for initial and subsequent TAA-T infusions
    
              -  Patients with uncontrolled infections
    
              -  Bulky tumor
    
              -  Group B patients who have bulky tumor on imaging are not eligible to receive TAA-T
                 infusion. These include the following:
    
              -  Tumor with evidence of uncal herniation or significant midline shift
    
              -  Tumor with a significant brainstem component
    
              -  Patients who are deemed to have overly bulky tumor by the PI of the study
    
              -  Patients who received ATG, Campath or other immunosuppressive T cell monoclonal
                 antibodies within 28 days of TAA-T cell infusion.
    
              -  Pregnancy or lactating females
          
    Maximum Eligible Age:80 Years
    Minimum Eligible Age:6 Months
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Incidence of Product- Adverse Events
    Time Frame:45 days after the first TAA-T dose
    Safety Issue:
    Description:Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.03, change from Baseline Infusion related toxicity at 45 days.

    Secondary Outcome Measures

    Measure:TAA-T responses
    Time Frame:1 year
    Safety Issue:
    Description:Determine the number of patients who respond to tumor associated antigen lymphocytes from base line to one year.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Catherine Bollard

    Last Updated

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