Clinical trial NCT03665675: Donor Virus-Specific CMV or AdV CTL to Treat CMV or AdV Reactivation or Disease After Solid Organ or HCT
Official title: Pilot Study of Haploidentical or Matched Donor Virus-Specific T-cells (Cytomegalovirus (CMV) or Adenovirus (AdV)) to Treat CMV or AdV Reactivation or Disease in Patients After Solid Organ or Hematopoietic Stem Cell Transplantation (HCT)
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: EARLY_PHASE1
Conditions: Allogeneic Hematopoietic Stem Cell Transplantation Recipient
Cytomegalovirus
Donor
Solid Organ Transplantation Recipient
Adenovirus
Lead sponsor: Ohio State University Comprehensive Cancer Center
Sponsor class: OTHER
First posted: 2018-09-11
Enrollment: 20
Sex: ALL
Minimum age (years): 1
Maximum age (years): 85
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

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.

Primary outcomes:
measure: Incidence of adverse events defined by the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0
timeFrame: Up to 30 days post infusion
measure: Feasibility defined as identifying a suitable donor within 4 weeks and meeting minimum T cell doses in the final product
timeFrame: Up to 1 year
Secondary outcomes:
measure: Antiviral activity defined as response to viral load
timeFrame: At day 28
measure: Persistence of infused CTLs as measured by T cell gene rearrangement and effects on clinical signs of viral infection
timeFrame: Up to 1 year
measure: Overall survival
timeFrame: From last CTL infusion till death, assessed at 6 and 12 months
measure: Risk for chronic GVHD
timeFrame: At 6 and 12 months post CTL infusion
measure: Systemic infections
timeFrame: Within 6 months of CTL infusion
measure: Secondary graft failure
timeFrame: 30 days post-CTL infusion
measure: Effects of cytomegalovirus (CMV) specific-CTL on viral loads assessed by weekly reverse transcriptase-polymerase chain reaction
timeFrame: Up to 1 year
measure: Viral reactivations
timeFrame: Up to 6 months
measure: Clinical response to CTL infusions
timeFrame: At 6 weeks and 3 months
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0".
timeFrame: Up to 1 year
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Ohio State University Comprehensive Cancer Center
name: Sumithira Vasu, MBBS
role: PRINCIPAL_INVESTIGATOR
References: