Donor Virus-Specific CMV or AdV CTL to Treat CMV or AdV Reactivation or Disease After Solid Organ or HCT

Early Phase 1

Recruiting

• Conditions: Donor; Cytomegalovirus; Solid Organ Transplantation Recipient; Adenovirus; Allogeneic Hematopoietic Stem Cell Transplantation Recipient
• Interventions: Biological: Allogeneic Adenovirus-specific Cytotoxic T Lymphocytes; Biological: Allogeneic Cytomegalovirus-Specific Cytotoxic T lymphocytes

• Registration Number: NCT03665675
• Lead Sponsor: Sumithira Vasu

Brief Summary

This trial studies the side effects and how well allogeneic cytomegalovirus-specific cytotoxic T lymphocytes (donor cytomegalovirus \[CMV\] specific cytotoxic T-lymphocytes \[CTLs\]) or allogeneic adenovirus-specific cytotoxic T lymphocytes (donor adenovirus-specific \[AdV\] specific CTLs) work in treating CMV or AdV reactivation or infection in participants who have undergone stem cell transplant or solid organ transplant. White blood cells from donors may be able to kill cancer cells in patients with cytomegalovirus or adenovirus that has come back after a stem cell or solid organ transplant.

Detailed Description

PRIMARY OBJECTIVE I. Assess the safety and feasibility of administering virus specific-CTLs from haploidentical donors in transplant patients both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT) with CMV/AdV infection despite standard therapy.

OUTLINE:Patients are assigned to 1 of 2 Cohorts.

COHORT A: Patients receive allogeneic cytomegalovirus-specific cytotoxic T lymphocytes intravenously (IV). Patients undergo blood, urine, saliva, cerebrospinal fluid (CSF), and bronchoalveolar fluid sample collection on the trial.

COHORT B: Patients receive allogeneic adenovirus-specific cytotoxic T Lymphocytes IV. Patients undergo blood, urine, saliva, CSF, and bronchoalveolar fluid sample collection on the trial.

After completion of study treatment, participants are followed up at 1 year.

Study Timeline

• Study First Submitted: 2018-08-13
• Study First Submitted QC: 2018-09-07
• Study First Posted: 2018-09-11
• Study Start: 2020-11-07
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-06
• Last Update Posted: 2024-03-08
• Primary Completion: 2024-12-31
• Study Completion: 2024-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Patients must have solid organ transplant or have received allogeneic hematopoietic stem cell transplant.

• • Cohort A (CMV): Must have documented CMV disease or reactivation, as by:

  • Viremia as detected by quantitative polymerase chain reaction (PCR) (> 500 IU/ml) in the peripheral blood requiring treatment OR

  • High risk for antiviral failure due to history of recurrent CMV reactivations or evidence of antiviral drug resistance, OR

  • Unable to tolerate antiviral drugs due to renal toxicity, bone marrow suppression, transfusion dependent anemia and thrombocytopenia or neutropenia requiring growth factor support or other related organ injury

    • Cohort B (AdV): Must have documented AdV infection or reactivation, as by:

  • Symptomatic subject with any detectable viral load in blood, OR

  • Symptomatic subject with qualitative AdV detection in compartment of current symptomatology, including stool, urine, and/or other specimens (bronchoalveolar lavage (BAL), nasal swab, CSF, etc.), irrespective of blood viral load, OR

  • New, persistent, and/or worsening AdV-related symptoms, signs, and/or markers of end organ compromise while receiving antiviral therapy (ie cidofovir), OR

  • Asymptomatic with a viral load > 1000 copies/ml in peripheral blood, OR

  • Unable to tolerate antiviral treatment due to renal toxicity, bone marrow suppression, transfusion dependent anemia and thrombocytopenia or neutropenia requiring growth factor support or other related organ injury

    • Karnofsky (age > 16 years) or Lansky performance score > 70 (age < 16)
    • Available seropositive haploidentical or matched donor who is without evidence of infection that would otherwise preclude donation
    • Negative pregnancy test in female patients if applicable (childbearing potential, has not received a full-intensity conditioning regimen
    • Written informed consent and/or signed assent line from patient, parent or guardian
    • DONOR
    • Human leukocyte antigen (HLA)-haploidentical or full-match to the patient as determined by institutional standards
    • Cohort A: CMV seropositive, defined as detection of serum CMV immunoglobulin G (IgG)
    • Cohort B: AdV seropositive, defined as detection of serum AdV IgG
    • Age 18 or over
    • Meet donor eligibility or suitability according to institutional standards. If the donor is deemed ineligible according to Foundation for the Accreditation of Cellular Therapy (FACT) standards, but is suitable for donation per institutional standards, the donor will be eligible for the protocol

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Exclusion Criteria

• Receipt of anti-thymocyte globulin (ATG), alemtuzumab, or other T-cell depleting agents within 21 days of screening for enrollment.

• Receipt of > 0.5mg/kg/day of prednisone or steroid equivalent at the time of enrollment. Stable GVHD is permitted as long as patients are on stable dose steroids of less than or equal to 0.5 mg/kg/day of prednisone or steroid equivalent.

• Evidence of uncontrolled infection as follows:

  • Bacterial infections - patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment.
  • Fungal infections - patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment.
  • Patients with hemodynamic instability attributable to bacterial sepsis or new symptoms, worsening physical signs or radiographic findings attributable to concomitant bacterial or fungal infection are excluded. Patients who require ventilator support for CMV pneumonitis are not excluded. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.

• Receipt of donor lymphocyte infusion (DLI) within 28 days.

• Patients with active acute graft versus host disease (GvHD) grades II-IV requiring > 0.5 mg/kg/day of prednisone or steroid equivalent or T-cell depleting immunosuppression.

• Acute graft rejection in solid organ transplantation requiring augmented immunosuppression with T-cell depleting agents or steroids as mentioned above.

• Active and uncontrolled relapse of malignancy.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment (AdV-specific CTLs)	Allogeneic Adenovirus-specific Cytotoxic T Lymphocytes	Patients receive allogeneic adenovirus-specific cytotoxic T Lymphocytes IV. Participants with persistent infection are eligible for second infusion after 28 days.
Treatment (CMV-specific CTLs)	Allogeneic Cytomegalovirus-Specific Cytotoxic T lymphocytes	Participants receive allogeneic cytomegalovirus-specific cytotoxic T lymphocytes IV. Participants with persistent infection are eligible for second infusion after 28 days.

Primary Outcome Measures

Name	Time	Method
Feasibility defined as identifying a suitable donor within 4 weeks and meeting minimum T cell doses in the final product	Up to 1 year
Incidence of adverse events defined by the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0	Up to 30 days post infusion	Measured as the proportion of patients with acute (a) graft versus host disease (GvHD) grades III-IV or graft rejection/failure within 30 days of the last dose of cytotoxic T-lymphocytes (CTLs) or grades 3-5 infusion-related adverse events within 7 days of the last does of CTLs or grades 4-5 non-hematological adverse events within 30 days of the last dose of CTLs and that are not due to the pre-existing infection or the original malignancy or pre-existing co-morbidities. Will be calculated by dividing by all evaluable patients and the corresponding 95% confidence intervals will be calculated.

Secondary Outcome Measures

Name	Time	Method
Persistence of infused CTLs as measured by T cell gene rearrangement and effects on clinical signs of viral infection	Up to 1 year
Antiviral activity defined as response to viral load	At day 28	Complete response, partial response, stable disease or progression will be defined and proportion of each outcome will be calculated.
Effects of cytomegalovirus (CMV) specific-CTL on viral loads assessed by weekly reverse transcriptase-polymerase chain reaction	Up to 1 year
Overall survival	From last CTL infusion till death, assessed at 6 and 12 months	Kaplan-Meier survival function will be used to estimate the survival probability.
Systemic infections	Within 6 months of CTL infusion	Will be reported by etiologic agent, site of disease, date of onset, and severity.
Secondary graft failure	30 days post-CTL infusion	Proportion of secondary graft failure for both populations will be assessed at 30 days post CTL infusion will be calculated and 95% confidence intervals will be estimated accordingly.
Risk for chronic GVHD	At 6 and 12 months post CTL infusion	Survival analysis method will be applied. Time to chronic GVHD will be defined from time of the last CTL infusion to the onset of chronic GVHD, or the last clinical assessment date if no chronic GVHD. Cumulative incidence of chronic GVHD at 6 and 12 months will be estimated.
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0".	Up to 1 year
Viral reactivations	Up to 6 months	Proportion of viral reactivations within 6 months will be calculated and 95% confidence intervals will be estimated accordingly.
Clinical response to CTL infusions	At 6 weeks and 3 months

Trial Locations

Locations (2)

Ohio State University Comprehensive Cancer Center; 🇺🇸 Columbus, Ohio, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States