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A Dose-Escalation Study Evaluating Safety and Tolerability of Viral-Specific T Cells Against CMV in Adult Kidney Transplant Recipients

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ClinicalTrials.gov Identifier: NCT03950414
Recruitment Status : Recruiting
First Posted : May 15, 2019
Last Update Posted : August 15, 2019
Sponsor:
Collaborators:
University of Wisconsin Program for Advanced Cell Therapy (PACT)
University of Wisconsin School of Medicine and Public Health (UWSMPH)
UW Health
Information provided by (Responsible Party):
University of Wisconsin, Madison

Brief Summary:
Kidney transplantation is the ideal treatment for patients with end-stage kidney disease.However, kidney transplantation is associated with a great risk of morbidity and mortality due to infections, especially viral infections such as Cytomegalovirus(CMV) .This study measures the tolerability of viral-specific T cells against CMV in adult kidney transplant recipients. Participants are expected to be on study for 52 +/- 3 weeks.

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

Detailed Description:

Viral infections, or their reactivation in the immunocompromised host, remain serious complications that adversely affect outcomes of transplantation. These infections may be refractory to pharmacologic treatment and result in increased morbidity and mortality after transplantation. Furthermore, the available pharmacologic therapies can result in severe toxicities.

Once an infection occurs, adequate immune reconstitution is decisive for recovery from viral disease after kidney transplantation. The present trial will consist of the treatment of kidney transplant recipients diagnosed with severe CMV infection when standard antiviral therapy is ineffective (disease progression on therapy, decline in viral load less than 10-fold in 2 weeks, known drug resistance), or toxic (end-organ damage), with virus-specific T cells using the CliniMACS® Prodigy System. As described in the background section, these are the patients with the greatest unmet need and greatest risk or morbidity and allograft loss due to CMV infection. 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 primary objective of this Phase I trial is to evaluate the safety and tolerability of CMV-specific T-cell transfer in adult patients suffering from CMV infections following kidney transplantation using a dose escalation design. The incubation with viral antigens (MACS GMP PepTivator) allows the enrichment of CMV-specific CD4+(Cluster of Differentiation 4) and CD8+(Cluster of Differentiation 8) T cells. Increasing evidence of the safety and efficacy of CMV-specific T-cell is available. Furthermore, the safety and efficacy of the specific manufacturing approach using the fully automated protocol of the ClinMACS® Prodigy for the isolation of CMV-specific T cells against CMV has been described and demonstrated that these cells retain their biological properties.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Intervention Model Description: 3+3 dose-escalation, open label, non-randomized, non-placebo controlled, single group assignment study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Dose-Escalation Study Evaluating Safety and Tolerability of Viral-Specific T Cells Against CMV in Adult Kidney Transplant Recipients
Estimated Study Start Date : August 13, 2019
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tier 1
3 participants enrolled at dose level 5x10^3 cells/kg of CMV viral specific T-cells
Biological: CMV specific T-cells

Naturally occurring, allogeneic donor lymphocytes derived from a leukapheresis or a whole blood product, enriched for CMV-specific CD4+ and CD8+ T cells Suspension of CMV-specific T cells in 10 mL of 0.9% NaCl with 2% Human Serum Albumin(HSA) via IV bolus injection

  • Low Dose Tier - Viral-Specific T cell infusion 5 x10^3 cells/kg body weight(BW)
  • Mid Dose Tier - Viral-Specific T cell infusion 1.25 x10^4 cells/kg BW
  • High Dose Tier - Viral-Specific T cell infusion 2.5 x10^4 cells/kg BW Product will be administered fresh intravenously to recipient within four hours of collection.




Primary Outcome Measures :
  1. Safety and Tolerability:Time of Occurence of Acute GVHD [ Time Frame: up to 15 weeks ]
    Time to occurrence of acute GVHD of any grade will be evaluated using the Kaplan-Meier method to assess incidence and severity of acute 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. 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.

  2. Safety and Tolerability: Number of infusion-related adverse events [ Time Frame: up to 7 weeks ]
    Incidence of grades 3-5 infusion-related adverse events, grades 4-5 non-hematological adverse events within four weeks of the CMV-VST dose that are not due to the pre-existing infection or original malignancy or pre-existing co-morbidities

  3. Incidence of acute infusion-related toxicity [ Time Frame: from T-cell transfer to 4 hours post injection, upto 3 weeks ]
    Incidence of acute infusion-related toxicity as assessed by maximum toxicity on the day of T-cell transfer, evaluated by measuring vital signs prior to and at different times after the T-cell transfer and monitoring of specific adverse events (chills, nausea, vomiting, diarrhea, abdominal pain, allergic reactions, respiratory dysfunction or headache from T-cell transfer to 4 hours post injection)

  4. Severity of acute infusion-related toxicity as measured by Cytokine release syndrome (CRS) Grading criteria [ Time Frame: from T-cell transfer to 4 hours post injection, upto 3 weeks ]

    Severity of acute infusion-related toxicity will be assessed by CRS grading criteria.

    Grade 1 Symptoms are not life threatening and require symptomatic treatment only, (e.g., fever, nausea, fatigue, headache, myalgias, malaise) Grade 2 Symptoms require and respond to moderate intervention Grade 3 Symptoms require and respond to aggressive intervention Grade 4 Life-threatening symptoms Grade 5 Death

    Any grade 3 or greater occurrence of CRS will be considered a serious adverse event for this study.


  5. Number of Participants of Newly Occurring Acute Rejection after T-cell Transfer [ Time Frame: up to 15 weeks ]
    Incidence and severity of acute rejection of the kidney allograft will in part be measured by number of participants of newly occurring acute rejection after T-cell transfer

  6. Incidence of de novo Antibodies against Kidney Allograft Donor (dnDSA) after T-cell Transfer [ Time Frame: up to 55 weeks ]
    Incidence and severity of acute rejection of the kidney allograft will in part be measured by presence of de novo antibodies against kidney allograft donor (dnDSA) after T-cell transfer

  7. Incidence of GVHD Grade ≥1 [ Time Frame: up to 15 weeks ]
    Incidence and severity of Graft-versus-host disease (GVHD) will be measured by occurrence of acute GVHD grade ≥1 or aggravation of pre-existing acute GVHD after T-cell transfer


Secondary Outcome Measures :
  1. Feasibility: Was production of CMV Virus specific T lymphocyte (VST) from donors accomplished? [ Time Frame: up to 3 weeks ]

    There is no minimum cell count required for the study as it can vary. Successful production of CMV Virus specific T lymphocyte (VST) from donors will be tracked by a Yes/No question.

    Production of cell accomplished: yes/no


  2. Feasibility: Participant Drop-out rate [ Time Frame: up to 3 weeks ]
    Evaluation of feasibility of CMV specific T cell transfer in adult patients suffering from severe CMV infection following kidney transplantation in part will be measured by participant drop out rate

  3. Feasibility: Time from patient inclusion to administration of CMV-VST [ Time Frame: up to 21 days ]
    Evaluation of feasibility of CMV specific T cell transfer in adult patients suffering from severe CMV infection following kidney transplantation in part will be measured by the amount of time from patient inclusion to administration of CMV-VST

  4. Efficacy: Percentage of patients with ≥1 log decrease in CMV viral load [ Time Frame: up to 15 weeks ]
    Evaluation of efficacy of CMV-specific T-cell transfer in adult patients suffering from severe CMV infection following kidney transplantation in part will be measured in terms of percentage of patients with ≥1 log decrease in CMV viral load at Week 12

  5. Efficacy:Time to 1 log change in CMV viral load [ Time Frame: up to 15 weeks ]
    Evaluation of efficacy of CMV-specific T-cell transfer in adult patients suffering from severe CMV infection following kidney transplantation in part will be measured in terms of time to 1 log change in CMV viral load

  6. Efficacy:Number of Participants with CMV clearance [ Time Frame: up to 15 weeks ]
    Efficacy evaluation in part will be measured by number of participants with CMV clearance. Either negative polymerase chain reaction (PCR) or <250 copies/mL will be considered as CMV clearance.

  7. Efficacy: Time of clearance of CMV [ Time Frame: up to 55 weeks ]
    Efficacy evaluation in part will be measured by number of days to achieve CMV clearance. Either negative polymerase chain reaction [PCR] or <250 copies/mL)will be considered as CMV clearance.

  8. Efficacy: Number of participants having CMV reactivation [ Time Frame: up to 55 weeks ]
    Efficacy in part will be measured by number of participants with CMV reactivations following initial viral clearance

  9. Efficacy: Overall Survival of Participant [ Time Frame: up to 55 weeks ]
    Overall survival rate of participants will be measured by time from T-cell transfer to death, graft loss, or last follow-up throughout the study

  10. Efficacy:Number of Participants with Clinical response/resolution of symptoms of underlying viral infection [ Time Frame: up to 15 weeks ]
    Efficacy in part will be measured by number of patients with resolution of clinical symptoms of underlying CMV infection from Day 7 (Week 1) to Week 12 after T-cell transfer as compared to Day 0



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult (age ≥ 18 and ≤75) patients suffering from CMV reactivation/infections following kidney transplantation

    • CMV reactivation/viremia defined as positive (>250 copies/mL) CMV qPCR(quantitative polymerase chain reaction) AND/OR
    • Presence of symptoms secondary to CMV infection or evidence of invasive CMV infection (e.g. pneumonitis, colitis)

    AND ONE OF THE FOLLOWING CRITERIA:

    • Absence of an improvement of viral load after ≥ 14 days of standard 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 anti-viral therapy with medications such as ganciclovir, acyclovir, valganciclovir, foscarnet, cidofovir, IVIG(Intravenous immunoglobulin), and/or letermovir, or
    • Have contraindications or experience adverse effects of anti-viral therapy with medications such as ganciclovir, acyclovir, valganciclovir, foscarnet, cidofovir, IVIG, and/or letermovir, or
    • Known resistance to the anti-viral medications ganciclovir, foscarnet and/or cidofovir based on molecular testing
  2. Original donor > 18 years if available, CMV IgG (Immunoglobin G) positive, eligible and capable of undergoing a single standard 2 blood volume leukapheresis or donation of one unit of whole blood OR If original donor is not available, CMV IgG negative OR ineligible, then a CMV IgG positive at least haploidentical (at least 3/6 HLA-A, -B, -DRB1) family donor will be used
  3. Written informed consent given by patient
  4. Written informed consent given by donor
  5. Donor eligible based on FACT(Foundation for the Accreditation of Cellular Therapy) infectious screening requirements

Exclusion Criteria:

  1. Non-kidney organ transplant recipient
  2. Patient with acute rejection of the kidney allograft at time of T-cell transfer
  3. Patient receiving steroids (>0.5 mg/kg body weight (BW) prednisone equivalent) at the time of T-cell transfer
  4. Patient treated with Thymoglobulin (ATG), Alemtuzumab or T-cell immunosuppressive monoclonal antibodies within 28 days
  5. Patients with CMV retinitis
  6. Concomitant enrollment in another clinical trial interfering with endpoints of this study
  7. Any medical condition which could compromise participation in the study according to the investigator's assessment
  8. Known HIV infection
  9. 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.
  10. Patients unwilling or unable to comply with the protocol or unable to give informed consent

Donor Eligibility

Donor selection priority: The original donor will be the first choice as source of T cells. If the original donor is not available for donation (such as National Marrow Donor Program (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 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.

    OR If original kidney transplant 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): NCT03950414


Contacts
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Contact: to be determined

Locations
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United States, Wisconsin
University of Wisconsin School of Medicine and Public Health Recruiting
Madison, Wisconsin, United States, 53705
Contact: Christopher Roginski    608-263-4505    ccrogins@clinicaltrials.wisc.edu   
Principal Investigator: Arjang Djamali, MD, MS, FASN         
Sponsors and Collaborators
University of Wisconsin, Madison
University of Wisconsin Program for Advanced Cell Therapy (PACT)
University of Wisconsin School of Medicine and Public Health (UWSMPH)
UW Health
Investigators
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Principal Investigator: Arjang Djamali, MD, MS, FASN 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: NCT03950414     History of Changes
Other Study ID Numbers: 2019-0060
PACT VST-C-002 ( Other Grant/Funding Number: GALIPEAU SMPH START UP-PACT SUPPORT )
First Posted: May 15, 2019    Key Record Dates
Last Update Posted: August 15, 2019
Last Verified: August 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:
T-cell
immunotherapy

Additional relevant MeSH terms:
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Infection
Communicable Diseases
Cytomegalovirus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases