Haploidentical Donor CMV Specific CTL to Treat CMV Reactivation or Infection After Solid Organ & HCT

Study Overview
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Brief Summary
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This trial studies the side effects and how well allogeneic cytomegalovirus-specific cytotoxic T lymphocytes (donor cytomegalovirus [CMV] specific cytotoxic T-lymphocytes [CTLs]) works in treating CMV 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 that has come back after a stem cell or solid organ transplant.

Detailed Description
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PRIMARY OBJECTIVE I. Assess the safety and feasibility of administering high-throughput antigen stimulation/interferon gamma capture system (Miltenyi Biotec, CliniMACS Prodigy System) generated CMV specific- CTLs from haploidentical donors in transplant patients both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT) with CMV infection despite standard therapy. OUTLINE: Participants receive allogeneic cytomegalovirus-specific cytotoxic T lymphocytes intravenously (IV). Participants with partial response, may receive up to 2 additional doses at monthly intervals. After completion of study treatment, participants are followed up at 1 year.

Official Title
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Pilot Study of Haploidentical Donor Cytomegalovirus (CMV) Specific Cytotoxic T-Lymphocytes (CTL) to Treat CMV Reactivation or Infection After Solid Organ and Hematopoietic Stem Cell Transplantation (HCT)

Conditions
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Allogeneic Hematopoietic Stem Cell Transplantation Recipient, Cytomegalovirus, Donor, Solid Organ Transplantation Recipient

Intervention / Treatment
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* Biological: Allogeneic Cytomegalovirus-Specific Cytotoxic T lymphocytes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have solid organ transplant or have received allogeneic hematopoietic stem cell transplant and be greater than 30 days post-transplant at the time of registration. Persistent CMV viremia after standard therapy for >= 7 days with or without proven, probable or possible CMV specific organ involvement. Receipt of an allogeneic HCT using bone marrow, peripheral blood, or umbilical cord stem cells. SOT recipients including but not limited to renal, heart, lung, liver, pancreas, small bowel, and multi-visceral transplants. Treatment of reactivation or infection with CMV: Reactivation is defined as detection of CMV by quantitative polymerase chain reaction (PCR) from the blood. If any patient develops CMV deoxyribonucleic acid (DNA)emia or has clinical evidence of CMV infection (defined as the demonstration of CMV by biopsy specimen from visceral sites by culture or histology) either pre or after CTL infusions, standard treatment with ganciclovir, valganciclovir, cidofovir and/or foscarnet will be initiated per physician discretion. Patients may receive CMV CTLs alone for elevated blood viral loads without evidence of visceral infection. Administration of less than or equal to 0.5 mg/kg/day of prednisone or steroid equivalent. Serum creatinine less than 2 x (upper level of normal (ULN). Available CMV seropositive haploidentical donor who is without evidence infection that would otherwise preclude donation. Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen). Written informed consent and/or signed assent line from patient, parent or guardian. DONOR: Donors will be deemed eligible if they are haploidentical matched to the patient and are CMV seropositive, defined as detection of serum CMV IgG. Donor will be screened and determined if acceptable as determined by the full donor evaluation and transplant physician evaluation. Exclusion Criteria: Receipt of anti-thymocyte globulin (ATG), alemtuzumab, or other T-cell depleting agents within 28 days of screening for enrollment. Receiving > 0.5mg/kg/day of prednisone or steroid equivalent at the time of enrollment. 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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (CMV-specific CTLs)<br>Participants receive allogeneic cytomegalovirus-specific cytotoxic T lymphocytes IV. Participants with partial response, may receive up to 2 additional doses at monthly intervals. | Biological: Allogeneic Cytomegalovirus-Specific Cytotoxic T lymphocytes<br>* Given intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events defined by the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 | 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. | Up to 30 days post infusion | 
| Feasibility defined as identifying a suitable donor within 4 weeks and meeting minimum T cell doses in the final product |  | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antiviral activity defined as response to viral load | Complete response, partial response, stable disease or progression will be defined and proportion of each outcome will be calculated. | At day 28 | 
| Persistence of infused CTLs as measured by T cell gene rearrangement and effects on clinical signs of viral infection |  | Up to 1 year | 
| Overall survival | Kaplan-Meier survival function will be used to estimate the survival probability. | From last CTL infusion till death, assessed at 6 and 12 months | 
| Risk for chronic GVHD | 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. | At 6 and 12 months post CTL infusion | 
| Systemic infections | Will be reported by etiologic agent, site of disease, date of onset, and severity. | Within 6 months of CTL infusion | 
| Secondary graft failure | 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. | 30 days post-CTL infusion | 
| Effects of cytomegalovirus (CMV) specific-CTL on viral loads assessed by weekly reverse transcriptase-polymerase chain reaction |  | Up to 1 year | 
| Viral reactivations | Proportion of viral reactivations within 6 months will be calculated and 95% confidence intervals will be estimated accordingly. | Up to 6 months | 
| Clinical response to CTL infusions |  | At 6 weeks and 3 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0. |  | Up to 1 year |