Clinical trial NCT03798301: Treatment of Cytomegalovirus (CMV) Infections With Viral-Specific T Cells
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: CMV Infection
Cytomegalovirus Infections
CMV Viremia
Opportunistic Infections
Keywords: Immunocompromised
Allogeneic Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT)
T-cell
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
First posted: 2019-01-09
Enrollment: 3
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: single-center, open-label, single-arm, pilot study
Primary purpose: TREATMENT

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.


Eligibility 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 (\>1.0 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).

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.

Primary outcomes:
measure: Feasibility: Number of Participants Who Drop-Out Before T-Cell Transfer
timeFrame: up to 21 days from enrollement
measure: Feasibility: Number of Days from Participant Enrollment to Administration of CMV-VST
timeFrame: up to 21 days from enrollment
measure: Feasibility: Successful production of CMV-VST from donors
timeFrame: up to 21 weeks from enrollment
measure: Safety: Number of Subjects who experience infusion-related adverse events following CMV-VST infusion
timeFrame: up to 4 hours after CMV-VST infusion
measure: Safety: Number of Subjects who experience newly occurring acute GVHD grade 1
timeFrame: up to 12 weeks from CMV-VST infusion
measure: Safety: Number of subjects experiencing newly occurring acute GVHD grade ≥ 2 or experience aggravation of pre-existing acute GVHD
timeFrame: up to 12 weeks from CMV-VST infusion
measure: Safety: Number of subjects experiencing chronic GVHD
timeFrame: up to 12 weeks from CMV-VST infusion
measure: The number of severe infusion-related adverse events or severe non-hematological adverse events
timeFrame: up to 28 days from CMV-VST infusion
measure: Safety: Time to Occurrence of GVHD
timeFrame: up to 12 weeks from CMV-VST infusion
Secondary outcomes:
measure: Efficacy: Percentage of Participants with a ≥1 log decrease in CMV viral load
timeFrame: up to 12 weeks from CMV-VST infusion
measure: Efficacy: Time to ≥1 log change in viral load
timeFrame: up to 12 weeks from CMV-VST infusion
measure: Efficacy: Number of Participants with CMV Clearance
timeFrame: up to 12 weeks from CMV-VST infusion
measure: Efficacy: Time to CMV Clearance
timeFrame: up to 12 weeks from CMV-VST infusion
measure: Efficacy: Number of Participants with Reduction or Clearance of Clinical Symptoms
timeFrame: up to 12 weeks from CMV-VST infusion
measure: Efficacy: Number of CMV Reactivations Following Initial Viral Clearance
timeFrame: up to 52 weeks from CMV-VST infusion
measure: Efficacy: Overall Survival
timeFrame: up to 52 weeks
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Christain Capitini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Jacques Galipeau, MD
role: STUDY_DIRECTOR
References: