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

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ClinicalTrials.gov Identifier: NCT02789228
Recruitment Status : Recruiting
First Posted : June 2, 2016
Last Update Posted : January 16, 2018
Sponsor:
Information provided by (Responsible Party):
HMeany, Children's Research Institute

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Solid Tumors Biological: Tumor associated antigen lymphocytes (TAA-CTL) Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Study Start Date : October 2016
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : April 2020

Arm Intervention/treatment
Experimental: Tumor associated antigen lymphocytes (TAA-CTL)

Tumor 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.

Biological: Tumor associated antigen lymphocytes (TAA-CTL)
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 to receive Tumor Antigen Associated Cytotoxic T Lymphocytes (TAA CTL). The goal of this cell infusion will be to initiate an immune response against solid tumors that includes multiple antigens and may prevent tumor evasion (through decreased expression of a single antigen).




Primary Outcome Measures :
  1. Incidence of Product-Emergent Adverse Events [ Time Frame: Within 45 days of the last dose of TAA-CT ]
    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 :
  1. Tumor associated antigen lymphocytes (TAA-CTL) responses [ Time Frame: 2 years ]
    o determine the number of patients who respond to tumor associated antigen lymphocytes (TAA-CTL)



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 <2x upper limit normal
  • AST < 5 x upper limit normal
  • Serum creatinine < 2 x upper limit normal
  • Hgb >8.0 g/dL(level can be achieved with transfusion)
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02789228


Contacts
Contact: Holly Meany, MD 202-476-2800 HMeany@childrensnational.org
Contact: Fahmida Hoq, MD 202-476-3634 fhoq@cnmc.org

Locations
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Holly Meany, MD    202-476-2800    HMeany@childrensnational.org   
Sponsors and Collaborators
Children's Research Institute

Responsible Party: HMeany, Associate Professor and Hematology-Oncology Fellowship Director, Children's Research Institute
ClinicalTrials.gov Identifier: NCT02789228     History of Changes
Other Study ID Numbers: 7497
First Posted: June 2, 2016    Key Record Dates
Last Update Posted: January 16, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No