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Treatment of Cytomegalovirus (CMV) Infections With Viral-Specific T Cells

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ClinicalTrials.gov Identifier: NCT03798301
Recruitment Status : Recruiting
First Posted : January 9, 2019
Last Update Posted : April 8, 2019
Sponsor:
Collaborators:
University of Wisconsin Program for Advanced Cell Therapy (PACT)
University of Wisconsin Carbone Cancer Center (UWCCC)
University of Wisconsin School of Medicine and Public Health (UWSMPH)
UW Health
Information provided by (Responsible Party):
University of Wisconsin, Madison

Brief Summary:

The present trial will consist of the treatment of 20 pediatric and adult Hematopoietic Stem Cell Transplantation (HSCT) recipients or immunocompromised participants diagnosed with opportunistic Cytomegalovirus (CMV) infections with virus-specific, antigen-selected T-cells. CMV-specific T-cells will be isolated from donor leukapheresis products using the CliniMACS® Prodigy. Prior studies on transfer of CMV specific T-cells have been shown to be safe and efficacious in the treatment of CMV infections.

The main trial objective is to evaluate the feasibility and safety of CMV-specific T-cell transfer in adult and pediatric participants suffering from CMV infections or reactivation following HSCT or due to other immunocompromised states (e.g.; primary immunodeficiency, cytotoxic therapy).

Participants will be followed for one year.


Condition or disease Intervention/treatment Phase
CMV Infection Cytomegalovirus Infections CMV Viremia Opportunistic Infections Biological: CMV-specific T-cells Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Intervention Model Description: single-center, open-label, single-arm, pilot study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of CMV Infections With Viral-Specific T Cells Against CMV in Pediatric and Adult Immunocompromised Patients or Recipients of Allogeneic Stem Cell Transplantation
Estimated Study Start Date : May 1, 2019
Estimated Primary Completion Date : September 1, 2023
Estimated Study Completion Date : September 1, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment Arm
Suspension of CMV-specific T-cells in 10 mL of 0.9% NaCl with 2% HSA. Single dose max. 25,000 T cells/kg body weight (BW) of the recipient delivered via IV bolus injection.
Biological: CMV-specific T-cells
Naturally occurring, allogeneic donor lymphocytes derived from a leukapheresis or a whole blood product, enriched for CMVspecific CD4+ and CD8+ T-cells




Primary Outcome Measures :
  1. Feasibility: Number of Participants Who Drop-Out Before T-Cell Transfer [ Time Frame: up to 21 days ]
    The primary endpoint by which to assess the feasibility is the number of dropped out participants before T-Cell Transfer.

  2. Feasibility: Number of Days from Participant Enrollment to Administration of CMV-VST [ Time Frame: up to 21 days ]
    The feasibility of this intervention will in part be accomplished by measuring the amount of time from participant enrollment to administration of Cytomegalovirus-Viral Specific T-Cells (CMV-VST).

  3. Feasibility: Number of Participants with Expansion of CMV-VST from Donors [ Time Frame: up to 29 weeks ]
    The feasibility of this intervention will in part be accomplished by measuring the expansion of Cytomegalovirus-Viral Specific T-Cells (CMV-VST) after T-cell transfer procedure.

  4. Safety: Number of Participants who Experience Acute or Chronic GVHD [ Time Frame: up to 15 weeks ]
    Number of participants who experience chronic Graft-vs-Host Disease (GVHD) or acute GVHD of any grade.

  5. Safety: Time to Occurrence of GVHD [ Time Frame: up to 15 weeks ]
    Time to occurrence of acute GVHD of any grade or to occurrence of chronic GVHD will be evaluated using the Kaplan-Meier method to assess incidence and severity of acute or chronic GVHD from day of T-cell transfer. The first day of GVHD onset at a certain grade will be used to calculate a cumulative incidence curve for that GVHD grade, acute or chronic. Overall cumulative incidence curves will be computed along with the 95% confidence intervals until Week 12 after T-cell transfer with death considered as a competing risk.


Secondary Outcome Measures :
  1. Efficacy: Percentage of Participants with a >1 log decrease in CMV viral load [ Time Frame: up to 15 weeks ]
    Evaluation of efficacy will in part be measured by percentage of participants with a >1 log decrease in CMV viral load at Week 12. (T-cells will be administered at up to 3 weeks)

  2. Efficacy: Time to >1 log change in viral load [ Time Frame: up to 15 weeks ]
    Evaluation of efficacy will in part be measured by time to >1 log change in viral load in days. (T-cells will be administered at up to 3 weeks)

  3. Efficacy: Number of Participants with CMV Clearance [ Time Frame: up to 15 weeks ]
    Evaluation of efficacy will in part be measured by the number of patients with CMV clearance, defined as negative Polymerase Chain Reaction (PCR) from Day 7 to Week 12 after T-cell transfer. (T-cells will be administered at up to 3 weeks)

  4. Efficacy: Time to CMV Clearance [ Time Frame: up to 15 weeks ]
    Evaluation of efficacy will in part be measured by the time to CMV clearance (defined as negative PCR) from Day 0 to first day of two subsequent negative CMV PCR studies. (T-cells will be administered at up to 3 weeks)

  5. Efficacy: Number of Participants with Reduction or Clearance of Clinical Symptoms [ Time Frame: up to 15 weeks ]
    Evaluation of efficacy will in part be measured by the number of participants with reduction or clearance of clinical symptoms of underlying CMV infection from Day 7 to Week 12 after T-cell transfer as compared to Day 0. (T-cells will be administered at up to 3 weeks)

  6. Efficacy: Number of CMV Reactivations Following Initial Viral Clearance [ Time Frame: up to 55 weeks ]
    Evaluation of efficacy will in part be measured by the number of CMV reactivations following initial viral clearance until Week 52. (T-cells will be administered at up to 3 weeks)

  7. Efficacy: Overall Survival [ Time Frame: up to 55 weeks ]
    Evaluation of efficacy will in part be measured by the overall survival. Overall survival rate (OS): time from T-cell transfer (Day 0) to death or last follow-up throughout the study from Day 1 to Week 52. (T-cells will be administered at up to 3 weeks)



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Ages Eligible for Study:   1 Month and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult or pediatric patient suffering from CMV reactivation/infections following HSCT or due to other immunocompromised states (e.g.; primary immunodeficiency, cytotoxic therapy).

    • CMV reactivation/viremia defined as positive (>500 copies/ml) CMV qPCR and/or
    • Presence of symptoms secondary to CMV infection or evidence of invasive CMV infection (e.g. pneumonitis, colitis) AND
    • Patients must have ONE OF THE FOLLOWING CRITERIA:

      • Absence of an improvement of viral load after ≥ 14 days of antiviral therapy with ganciclovir, valganciclovir or foscarnet (decrease by at least 1 log, i.e. 10-fold), or
      • New, persistent and/or worsening CMV-related symptoms, signs and/or markers of end organ compromise while on antiviral therapy with ganciclovir, valganciclovir or foscarnet, or
      • Have contraindications or experience adverse effects of antiviral therapy with ganciclovir, valganciclovir or foscarnet, or
      • Known resistance to ganciclovir and/or foscarnet based on molecular testing.
  2. Recipients of an allogeneic HSCT must be 28 days after stem cell infusion at the time of T-cell transfer.
  3. Written informed consent given by patient or legal representative.
  4. Minimum patient age 1 month.
  5. Minimum weight 7 lbs.
  6. Female patients of childbearing age with negative pregnancy tests.
  7. Patient Karnofsky/Lansky Performance Status >30%.
  8. Donor eligible based on FACT infectious screening requirements.

Exclusion Criteria:

  1. Patient with acute GVHD > grade 2 or active moderate or severe chronic GVHD at time of T-cell transfer
  2. Patient receiving steroids (>0.5 mg/kg body weight (BW) prednisone equivalent) at the time of T-cell transfer
  3. Patient received allogeneic HSCT less than 28 days prior to T-cell transfer
  4. Patient treated with donor lymphocyte infusion (DLI) within 28 days prior to T-cell transfer
  5. Patient treated with Thymoglobulin (ATG), Alemtuzumab or T-cell immunosuppressive monoclonal antibodies within 28 days.
  6. Patient with organ dysfunction or failure as determined by Karnofsky (patients >16 years) or Lansky (patients ≤16 years) score ≤30% (Appendix 5)
  7. Patients with CMV retinitis
  8. Concomitant enrollment in another clinical trial with endpoints interfering with this study
  9. Any medical condition which could compromise participation in the study according to the investigator's assessment
  10. Known HIV infection
  11. Female patient who is pregnant or breast-feeding, or adult of reproductive potential not willing to use an effective method of birth control during study treatment. Note: Women of childbearing potential must have a negative serum pregnancy test at study entry.
  12. Patients unwilling or unable to comply with the protocol or unable to give informed consent.

Donor Eligibility:

The original donor will be the first choice as source of T cells. If the original donor is not available for donation (such as NMDP donor, cord blood unit, or related donor not available) of peripheral mononuclear cells or does not meet all donor eligibility criteria (including donor selection criteria based on University of Wisconsin - Madison Standard Operating Procedures for the selection of allogeneic donors), alternative related donors will be selected, with preference for those who have full HLA matching in 6/6 loci over those with partial HLA matching (≥ 3/6 HLA loci). See Appendix 1 and 2 for patient and donor screening procedures.

  1. All donors must be ≥ 18 years old, available, CMV IgG positive, eligible and capable of undergoing a single standard 2 blood volume leukapheresis. If original HSCT donor is not available, CMV IgG negative or ineligible, a CMV IgG positive fully matched or haploidentical family donor will be used.
  2. Related donors must be at least partially HLA compatible, matching with recipient in at least 3/6 HLA loci (HLA-A, HLA-B and HLA-DRB1 will be considered for this).
  3. Donors must be CMV IgG seropositive.
  4. Donors must show CMV T-cell activation after incubation with MACS GMP PepTivator Peptide Pools of CMV pp65 before undergoing leukapheresis.
  5. Donor must meet the criteria for donor selection defined in the Standard Operating Procedures of the University of Wisconsin Hospitals and Clinics Stem Cell Transplant Program and in FACT standards.

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): NCT03798301


Contacts
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Contact: Cancer Connect 800-622-8922 cancerconnect@uwcarbone.wisc.edu

Locations
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United States, Wisconsin
University of Wisconsin Carbone Cancer Center Recruiting
Madison, Wisconsin, United States, 53705
Contact: Jenny Weiland    608-890-8070    jlweiland@pediatrics.wisc.edu   
Principal Investigator: Inga Hofmann, MD         
Sponsors and Collaborators
University of Wisconsin, Madison
University of Wisconsin Program for Advanced Cell Therapy (PACT)
University of Wisconsin Carbone Cancer Center (UWCCC)
University of Wisconsin School of Medicine and Public Health (UWSMPH)
UW Health
Investigators
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Principal Investigator: Inga Hofmann, MD University of Wisconsin, Madison
Study Director: Jacques Galipeau, MD University of Wisconsin, Madison

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Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT03798301     History of Changes
Other Study ID Numbers: UW18073
2018-1278 ( Other Identifier: Institutional Review Board )
NCI-2019-00245 ( Registry Identifier: NCI CTRP )
First Posted: January 9, 2019    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Wisconsin, Madison:
Immunocompromised
Allogeneic Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT)
T-cell

Additional relevant MeSH terms:
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Cytomegalovirus Infections
Infection
Communicable Diseases
Opportunistic Infections
Viremia
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Parasitic Diseases
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes