Clinical Trials /

Research Study Utilizing Expanded Multi-antigen Specific Lymphocytes for the Treatment of Solid Tumors

NCT02789228

Description:

Patients with high-risk solid tumors, those that are refractory to standard up front therapy or relapse after completion of therapy, have a very poor prognosis despite attempts to induce remission with salvage regimen. Novel therapies are critical for this patient population with high-risk cancer. The ability of tumors to be recognized and lysed by the immune system offers a unique opportunity to aid in tumor eradication by expanding and activating these anti-tumor cells. Through this ability to harness sophisticated and specific immunotherapy, residual or relapsed disease that is resistant to chemotherapy and/or radiotherapy could be eradicated. Prior studies have suggested both safety of expanded specific T cells and efficacy in the setting of melanoma, lymphoma or viral eradication. While this therapy has previously been limited by the versatility of the tumor to down-regulate antigens and evade a single immune-target, the use of multi-antigen specific T cells may permit better and more durable anti-tumor immunity. Thus, the investigators propose to infuse these specific multi-antigen anti-tumor T lymphocytes into patients with high risk solid tumors. This trial will be conducted to demonstrate safety of these cells and generate efficacy and biology data that may be important for future studies that may enhance tumor immunotherapy.

Related Conditions:
  • Adenocarcinoma
  • Esophageal Carcinoma
  • Ewing Sarcoma
  • Neuroblastoma
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Soft Tissue Sarcoma
  • Wilms Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Research Study Utilizing Expanded Multi-antigen Specific Lymphocytes for the Treatment of Solid Tumors
  • Official Title:

Clinical Trial IDs

  • ORG STUDY ID: 7497
  • NCT ID: NCT02789228

Conditions

  • Solid Tumors

Interventions

DrugSynonymsArms
Tumor associated antigen lymphocytes (TAA-CTL)Tumor associated antigen lymphocytes (TAA-CTL)

Purpose

Patients with high-risk solid tumors, those that are refractory to standard up front therapy or relapse after completion of therapy, have a very poor prognosis despite attempts to induce remission with salvage regimen. Novel therapies are critical for this patient population with high-risk cancer. The ability of tumors to be recognized and lysed by the immune system offers a unique opportunity to aid in tumor eradication by expanding and activating these anti-tumor cells. Through this ability to harness sophisticated and specific immunotherapy, residual or relapsed disease that is resistant to chemotherapy and/or radiotherapy could be eradicated. Prior studies have suggested both safety of expanded specific T cells and efficacy in the setting of melanoma, lymphoma or viral eradication. While this therapy has previously been limited by the versatility of the tumor to down-regulate antigens and evade a single immune-target, the use of multi-antigen specific T cells may permit better and more durable anti-tumor immunity. Thus, the investigators propose to infuse these specific multi-antigen anti-tumor T lymphocytes into patients with high risk solid tumors. This trial will be conducted to demonstrate safety of these cells and generate efficacy and biology data that may be important for future studies that may enhance tumor immunotherapy.

Detailed Description

      This phase I dose-escalation trial is designed to evaluate the safety of administering
      rapidly generated TAA CTL to patients who have undergone allogeneic HSCT or conventional
      therapy for a high-risk solid tumor due to the presence of refractory, relapsed and/or
      residual detectable disease.

      Pediatric and adult patients who have high-risk solid tumors with known positivity for one
      or more Tumor Antigen Associated (TAA) (WT1, PRAME and/or survivin) will be eligible.
      Patients will be enrolled in one of two groups: group A includes patients who have undergone
      an allogeneic HSCT as part of their prior therapy and group B includes patients who have
      undergone standard therapy which does not include an allogeneic HSCT. TAA CTL may be
      generated from donor lymphocytes (group A) obtained from either patient peripheral blood
      mononuclear cells (PBMC) or donor PBMC or host lymphocytes (group B).

      Group A patients (post allogeneic HSCT): TAA-CTL will be infused any time after neutrophil
      engraftment post-HSCT or day 30, whichever comes first.

      Group B patients (no prior allogeneic HSCT): TAA-CTL will be infused any time >1 week after
      completing most recent course of conventional (non-investigational) therapy for their
      disease.

      This protocol is designed as a phase I dose-escalation study. Three different TAA CTL dose
      levels will be evaluated in each treatment group (A and B) (see below) with 2 to 4 patients
      enrolled at each dose level.

      Dose Level One: 1 x 107 cells/m2 Dose Level Two: 2 x 107 cells/m2 Dose Level Three: 4 x 107
      cells/m2

      Patients will receive cells due to the presence of refractory disease and/or high risk for
      disease relapse and/or residual detectable disease following conventional therapy at the
      time of the infusion. Ideally, patients should not receive other systemic antineoplastic
      agents for at least 6 weeks after infusion of TAA CTL (for purposes of evaluation), although
      such treatment may be added if deemed critical for patient care by the attending physician.

      Each patient will receive at least one TAA CTL infusion and may receive a maximum of 8
      doses. The first and second doses will be administered 45 days apart then additional doses
      will be spaced every 4 weeks. The expected volume of each infusion is 1 to 10 cc.

      If patients with measurable or evaluable disease have a response of stable disease or better
      by RECIST criteria at the day 28 evaluation after dose 2 or subsequent evaluations they are
      eligible to receive up to 6 additional doses of CTLs at monthly intervals. Each subsequent
      dose will be at the enrollment dose level (i.e. no subsequent dose escalation). Patients
      will not be able to receive additional doses until the initial safety profile is completed
      at day 28 following the second infusion.
    

Trial Arms

NameTypeDescriptionInterventions
Tumor associated antigen lymphocytes (TAA-CTL)ExperimentalTumor associated antigen lymphocytes (TAA-CTL). Three different dosing schedules will be evaluated. Dose Level One: 1 x 107 cells/m2 Dose Level Two: 2 x 107 cells/m2 Dose Level Three: 4 x 107 cells/m2 Patients will receive cells due to the presence of refractory disease and/or high risk for disease relapse and/or residual detectable disease following conventional therapy at the time of the infusion. Ideally, patients should not receive other systemic antineoplastic agents for at least 6 weeks after infusion of TAA CTL (for purposes of evaluation), although such treatment may be added if deemed critical for patient care by the attending physician.

    Eligibility Criteria

            Inclusion Criteria:
    
            Recipient procurement inclusion criteria
    
              -  Diagnosis of high-risk solid tumors: Ewing sarcoma, Wilms tumor, neuroblastoma,
                 rhabdomyosarcoma, soft tissue sarcomas, osteosarcoma, and adenocarcinoma
    
              -  Refractory disease, residual detectable disease following conventional therapy or
                 relapsed disease
    
              -  6 months to 60 years of age at enrollment
    
              -  Karnofsky/Lansky score of ≥ 50%
    
              -  Absolute neutrophil count > 500/ µL (may be supported with G-CSF)
    
              -  Bilirubin ≤ 2.5 mg/dL
    
              -  AST/ALT ≤ 5x the upper limit of normal for age
    
              -  Serum creatinine < 1.0 or 2x the upper limit of normal for age (whichever is higher)
    
              -  Pulse oximetry of > 90% on room air
    
              -  Agree to use contraceptive measures during study protocol participation (when age
                 appropriate)
    
              -  LVEF > 50% or LVSF > 27% if history of TBI (may be performed within the last 6
                 months)
    
              -  Patient or parent/guardian capable of providing informed consent
    
            Recipient inclusion criteria for initial CTL administration and for subsequent infusions
    
              -  Steroids less than 0.5 mg/kg/day prednisone or equivalent
    
              -  Karnofsky/Lansky score of ≥ 50%
    
              -  Bilirubin ≤ 2.5 mg/dL
    
              -  AST/ALT ≤ 5x the upper limit of normal for age
    
              -  Serum creatinine < 1.0 mg/dL or 2x the upper limit of normal for age (whichever is
                 higher)
    
              -  Pulse oximetry of > 90% on room air
    
            Exclusion Criteria:
    
            Recipient Procurement exclusion criteria
    
              -  Patients with uncontrolled infections
    
              -  Patients with HIV infection
    
              -  Current evidence of GVHD > grade 2 or chronic GVHD manifestations: bronchiolitis
                 obliterans syndrome, sclerotic GVHD, or serositis.
    
              -  Pregnancy or lactating females
    
              -  Prior immunotherapy with an investigational agent
    
            Recipient exclusion criteria for initial and subsequent CTL infusions
    
              -  Patients with uncontrolled infections
    
              -  Patients who received ATG, Campath or other immunosuppressive T cell monoclonal
                 antibodies within 28 days of screening for enrollment.
    
              -  Acute GVHD > grade 2 or chronic GVHD manifestations: bronchiolitis obliterans
                 syndrome, sclerotic GVHD, or serositis.
    
              -  Pregnancy or lactating females
          
    Maximum Eligible Age:60 Years
    Minimum Eligible Age:6 Months
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Incidence of Product-Emergent Adverse Events
    Time Frame:Within 45 days of the last dose of TAA-CT
    Safety Issue:
    Description:Primary endpoint of the study is defined grade ≥3 infusion-related adverse event occurring within 45 days of the last TAA-CTL dose, grade ≥4 non-hematologic adverse event occurring within 45 days of the last TAA-CTL dose and that are not due to the patient's underlying malignancy or pre-existing co-morbidities or grade ≥3 acute GVHD occurring within 45 days of the last TAA-CTL dose, or any unexpected toxicity of any grade attributed to the infusion of TAA-CTL occurring within 45 days of the last TAA-CTL dose. Toxicities will be defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03

    Secondary Outcome Measures

    Measure:Tumor associated antigen lymphocytes (TAA-CTL) responses
    Time Frame:2 years
    Safety Issue:
    Description:o determine the number of patients who respond to tumor associated antigen lymphocytes (TAA-CTL)

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Children's Research Institute

    Last Updated

    October 19, 2016