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

NCT03950414 | Terminated Phase 1 DMC FDA Drug

• 3 other identifiers: 2019-0060PACT VST-C-002Protocol Version 11/1/2021
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

This study measures the tolerability of viral-specific T cells against Cytomegalovirus (CMV) in adult solid organ transplant (SOT) recipients. Participants are expected to be on study for 52 +/- 3 weeks.

Conditions

Cytomegalovirus Infections; Solid Organ Transplant

Keywords

T-cell; immunotherapy

Outcome Measures

Primary Outcomes (7)

• Safety and Tolerability:Time of Occurence of Acute GVHD

  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.

  up to 15 weeks

• Safety and Tolerability: Number of infusion-related adverse events

  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

  up to 7 weeks

• Incidence of acute infusion-related toxicity

  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)

  from T-cell transfer to 4 hours post injection, upto 3 weeks

• Severity of acute infusion-related toxicity as measured by Cytokine release syndrome (CRS) Grading criteria

  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.

  from T-cell transfer to 4 hours post injection, upto 3 weeks

• Number of Participants of Newly Occurring Acute Rejection after T-cell Transfer

  Incidence and severity of acute rejection of the organ allograft will in part be measured by number of participants of newly occurring acute rejection after T-cell transfer

  up to 15 weeks

• Incidence of de novo Antibodies against Organ Allograft Donor (dnDSA) after T-cell Transfer

  Incidence and severity of acute rejection of the organ allograft will in part be measured by presence of de novo antibodies against organ allograft donor (dnDSA) after T-cell transfer

  up to 55 weeks

• Incidence of GVHD Grade ≥1

  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

  up to 15 weeks

Secondary Outcomes (10)

• Feasibility: Was production of CMV Virus specific T lymphocyte (VST) from donors accomplished?

  up to 3 weeks

• Feasibility: Participant Drop-out rate

  up to 3 weeks

• Feasibility: Time from patient inclusion to administration of CMV-VST

  up to 21 days

• Efficacy: Percentage of patients with ≥1 log decrease in CMV viral load

  up to 15 weeks

• Efficacy:Time to 1 log change in CMV viral load

  up to 15 weeks

Study Arms (1)

Tier 1

EXPERIMENTAL

3 participants enrolled at dose level 5x10\^3 cells/kg of CMV viral specific T-cells

Biological: CMV specific T-cells

Interventions

CMV specific T-cells BIOLOGICAL

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.

Tier 1

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult (age ≥ 18 and ≤75) patients suffering from CMV reactivation/infections following solid organ transplantation (e.g., liver, pancreas, lung, heart, and multi-solid organ)
• 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
• Availability of eligible donor
• Written informed consent given by patient

You may not qualify if:

• Patient with acute rejection of allograft at time of T-cell transfer
• Patient receiving steroids (\>0.5 mg/kg body weight (BW) prednisone equivalent) at the time of T-cell transfer
• Patient treated with Thymoglobulin (ATG), Alemtuzumab or T-cell immunosuppressive monoclonal antibodies within 28 days
• Patients with CMV retinitis
• Concomitant enrollment in another clinical trial interfering with endpoints of this study
• Any medical condition which could compromise participation in the study according to the investigator's assessment
• Known HIV infection
• 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.
• 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 the source of T cells. If donation from the original organ donor is not possible (e.g., donor is unavailable or ineligible), then an alternative related donor will be selected, with preference for those who have full HLA matching in 6/6 loci over those with partial HLA matching (≥ 2/6 HLA loci). See Appendix 1 for patient and donor screening procedures.
• ≥ 18 years old
• Available and capable of undergoing a single standard 2 blood volume leukapheresis or donation of one unit of whole blood.
• If the original transplant donor is not eligible, then an eligible fully matched or eligible partially matched family member will be used as the donor.
• Related donors must be at least partially HLA compatible, matching with recipient in at least 2/6 HLA loci (HLA-A, HLA-B and HLA-DRB1 will be considered for this).

Sponsors & Collaborators

• University of Wisconsin, Madison: lead

Study Sites (1)

University of Wisconsin School of Medicine and Public Health

Madison, Wisconsin, 53705, United States

Location

MeSH Terms

Conditions

Cytomegalovirus Infections

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Study Officials

• Sandesh Parajuli, MBBS

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

• Jacques Galipeau, MD

  University of Wisconsin, Madison

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 3+3 dose-escalation, open label, non-randomized, non-placebo controlled, single group assignment study

Study Record Dates

• First Submitted: April 15, 2019
• First Posted: May 15, 2019
• Study Start: September 27, 2019
• Primary Completion: July 11, 2022
• Study Completion: July 11, 2022
• Last Updated: February 20, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)