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Multi-institutional Prospective Research of Expanded Multi-antigen Specifically Oriented Lymphocytes for the Treatment of VEry High Risk Hematopoietic Malignancies (RESOLVE)

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ClinicalTrials.gov Identifier: NCT02203903
Recruitment Status : Recruiting
First Posted : July 30, 2014
Last Update Posted : July 14, 2020
Sponsor:
Collaborators:
Children's National Research Institute
Johns Hopkins University
Information provided by (Responsible Party):
Catherine Bollard, Children's National Research Institute

Brief Summary:
This Phase I dose-escalation trial is designed to evaluate the safety of administering rapidly -generated tumor multi-antigen associated -specific cytotoxic T lymphocytes, to HSCT recipients (Arm A) or future HSCT recipients (Arm B) for the treatment of high-risk or relapsed or refractory hematopoietic malignancies. In addition to safety, this study will also evaluate if event-free survival (EFS) is improved with TAA-T administration at six months after HSCT for patients with high risk AML and MDS (Arm C).

Condition or disease Intervention/treatment Phase
Relapsed/Refractory Hematopoietic Malignancies, Acute Myeloid Leukemia and MDS Biological: Tumor associated antigen lymphocytes (TAA-T) Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multi-institutional Prospective Phase I Research of Expanded Multi-antigen Specifically Oriented Lymphocytes for the Treatment of VEry High Risk Hematopoietic Malignancies
Actual Study Start Date : January 1, 2015
Estimated Primary Completion Date : November 30, 2024
Estimated Study Completion Date : June 28, 2025


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

For Arm A Patients (post-HSCT): TAA-T will be infused any time after neutrophil engraftment post-HSCT or day 30, whichever comes first.

For Arm B Patients (pre-HSCT): TAA-T will be infused any time > 7 days after previous therapy for relapsed disease.

For Arm C Patients (post-HSCT): TAA-T will be infused any time after neutrophil engraftment post-HSCT or day 30, whichever comes first. All infusions will be within 5 months post-HSCT.

Five different dosing levels will be evaluated. Two to four patients will be evaluated on each dosing schedule (see below). This protocol is designed as a phase I dose-escalation study.

Dose Level One: 5 x 106 cells/m2 Dose Level Two: 1 x 107 cells/m2 Dose Level Three: 2 x 107 cells/m2 Dose Level Four: 4 x 107 cells/m2 Dose Level Five: 1 x 108 cells/m2 (ONLY applicable to Arm A patients)

Arm C patients will ONLY be enrolled at: Dose Level Four (4 x 107 cells/m2)

Biological: Tumor associated antigen lymphocytes (TAA-T)
TAA-T may be generated from donors or recipients and will be tested for specificity to 3 tumor antigens commonly found in hematological malignancies (WT1, PRAME, and SURVIVIN,). The goal of this cell infusion will be to initiate an immune response to residual leukemia or lymphoma that includes multiple antigens and may prevent tumor evasion (through decreased expression of a single antigen).




Primary Outcome Measures :
  1. Safety of investigational product (TAA-T) [ Time Frame: within 45 days of the last dose of TAA-T ]
    Safety including acute GVHD grades III-IV within 45 days of the last dose of TAA-T or grades 3-5 infusion-related adverse events within 45 days of the last TAA-T dose or grades 4-5 non-hematological attributable adverse events within 45 days of the last TAA-T dose and that are not due to the pre-existing infection or the original malignancy or pre-existing co-morbidities as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. For Arm C, the primary endpoint is to determine if event-free survival (EFS) is improved with TAA-T administration at six months after HSCT for patients with high risk acute myeloid leukemia and MDS.


Secondary Outcome Measures :
  1. Tumor associated antigen lymphocytes (TAA-T) responses [ Time Frame: 2 years ]
    - To determine the number of patients who respond to tumor associated antigen lymphocytes (TAA-T) for the treatment for relapsed/refractory hematopoietic malignancies as defined by those who achieve CR, PR, MR, or SD following cell infusion and evaluate if this was associated with in vivo persistence of TAA-T.


Other Outcome Measures:
  1. The incidence and severity of acute and/or chronic GVHD [ Time Frame: 2 years ]
    To determine the incidence and severity of acute and/or chronic GVHD in patients treated with TAA-T and compare this to historical controls

  2. Event free and overall survival [ Time Frame: 1 year ]
    - Event free and overall survival at 1 year for patients enrolled under Arm A and B. Event-free survival at 6 months and overall survival at 1 year after HSCT for patients enrolled under Arm C.



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Ages Eligible for Study:   6 Months to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Recipient procurement Inclusion criteria:

  • Aged 6 months to 80 years
  • Received prior or anticipated myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant
  • Patients (Arm A) who have undergone allo-HSCT with high risk or relapse or residual/recurrent disease (see below) OR patients (Arm B) with high risk or relapsed/refractory disease (> 2 regimens with greater than M1 marrow or persistent HD) with anticipated allo-HSCT:

    • Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML), Ambiguous lineage leukemia or lymphoma, Chronic Myelogenous leukemia (CML), CMML, MDS:
    • Evidence of active leukemia or lymphoma disease by flow cytometry, morphology, or cytogenetic evaluation within the marrow or extramedullary sites.
    • Hodgkin's Lymphoma that has failed or are intolerant of Brentuximab, Non-Hodgkin Lymphoma (NHL) including Grey Zone Lymphoma, Anaplastic large cell lymphoma (ALCL), and mantle cell lymphoma:
    • Evidence of lymphoma by morphology, Positron Emission Tomography (PET)/ Computed tomography (CT) uptake in a site of previous disease in the absence of other etiologies.
    • ARM C only includes patients with high risk AML and MDS who have received an allo-HSCT and have not had hematologic relapse of disease.
  • Karnofsky/Lansky score of ≥ 50
  • Agree to use contraceptive measures during study protocol participation (when age appropriate)
  • Patient or parent/guardian capable of providing informed consent.
  • T cell chimerism > 94% if collected from recipient of allo-HSCT (performed within the last 6 months)
  • If the product is procured from the recipient in the autologous (Arm B) setting, the absolute lymphocyte count should be greater than or equal to 600 for procurement. Please note: If a patient has already undergone an allogeneic HSCT, it is NOT allowed to generate TAA-T from patient blood collected post-HSCT under Arm A or C

Recipient Procurement Exclusion Criteria:

  • Patients with uncontrolled infections
  • Current evidence of GVHD > grade 2 or bronchiolitis obliterans syndrome, sclerotic GVHD, or serositis Pregnancy or lactating (female of childbearing potential) Recipient Inclusion criteria for initial TAA-T administration and for subsequent infusions
  • Patients (Arm A) who have undergone allo-HSCT with high risk or relapse or residual/recurrent disease (see below) OR patients (Arm B) with high risk or relapsed/refractory disease (> 2 regimens with greater than M1 marrow or persistent HD) with anticipated allo-HSCT:

    o Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML), Ambiguous lineage leukemia or lymphoma, Chronic Myelogenous leukemia (CML), CMML, MDS: Evidence of active leukemia or lymphoma disease by flow cytometry, morphology, or cytogenetic evaluation within the marrow or extramedullary sites.

    o Hodgkin's Lymphoma that has failed or are intolerant of Brentuximab, NHL including Grey Zone Lymphoma, ALCL, and mantle cell lymphoma: Evidence of lymphoma by morphology, PET/CT uptake in a site of previous disease in the absence of other etiologies.

    o ARM C only includes patients with high risk AML and MDS who have received an allo-HSCT and have not had hematologic relapse of disease.

  • Steroids less than 0.5 mg/kg/day prednisone or equivalent.
  • Karnofsky/Lansky score of ≥ 50.
  • Bilirubin < 2.5 mg/dL, AST/ALT <5x upper limit of normal, Serum creatinine < 1.0 or 2x the upper limit of normal (whichever is higher).
  • Pulse oximetry of > 90% on room air.
  • Absolute neutrophil count > 250/ µL (may be supported with Granulocyte colony-stimulating factor (GCSF)).
  • Agree to use contraceptive measures during study protocol participation (when age appropriate).
  • Patient or parent/guardian capable of providing informed consent.
  • LVEF > 50% or LVSF > 27% (performed within the last 6 months) if history of TBI >500 cGy for arm A and B.
  • Total chimerism > 50%; or if cancer cells preclude this, donor T cell chimerism > 50% (performed within the last 6 months).

Recipient Exclusion criteria for initial and subsequent TAA-T infusions

  • Patients who received ATG, Campath, or other T cell immunosuppressive monoclonal antibodies within 28 days prior to TAA-T infusion.
  • No investigational therapies (under IND, not extensively studied in the current clinical context) within 28 days prior to TAA-T infusion.

For allogeneic HSCT recipients PD-1 inhibitors or other T cell activating agents will be excluded. For Arm B, if the patient has tolerated these agents without autoimmunity, these may be continued with the TAA-T infusion.

  • Uncontrolled infections
  • Active Bronchiolitis obliterans syndrome, sclerotic GVHD, or serositis
  • Current evidence of GVHD > grade 2 for Arm A and B; Active GVHD of any grade is exclusion for arm C patients.
  • Pregnancy or lactating (female of childbearing potential)

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): NCT02203903


Contacts
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Contact: Fahmida Hoq, MBBS, MS 202-476-3634 fhoq@cnmc.org

Locations
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United States, District of Columbia
Childrens National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: David Jacobsohn, MD    202-476-6250    DAJacobs@childrensnational.org   
Principal Investigator: David Jacobsohn, MD         
United States, Maryland
Kenneth R. Cooke, MD Recruiting
Baltimore, Maryland, United States, 21287
Contact: Kenneth R. Cooke, MD       kcooke5@JHMI.edu   
Principal Investigator: Kenneth R. Cooke, MD         
Sponsors and Collaborators
Catherine Bollard
Children's National Research Institute
Johns Hopkins University
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Responsible Party: Catherine Bollard, Director- Center for Cancer and Immunology Research, Children's National Research Institute
ClinicalTrials.gov Identifier: NCT02203903    
Other Study ID Numbers: Pro00005533
First Posted: July 30, 2014    Key Record Dates
Last Update Posted: July 14, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Hematologic Diseases