Donor Cytomegalovirus-Specific Cytotoxic T-Lymphocytes in Treating Patients With a Persistent Cytomegalovirus Infection

Study Overview
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Brief Summary
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This phase II trial studies how well donor cytomegalovirus-specific cytotoxic T-lymphocytes work in treating patients with a cytomegalovirus infection that has come back or has not gotten better despite standard therapy. White blood cells from donors who have been exposed to cytomegalovirus may be effective in treating patients with a cytomegalovirus infection.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess the efficacy, feasibility and safety of administering most closely human leukocyte antigen (HLA)-matched cytomegalovirus (CMV) specific cytotoxic T-lymphocytes (HMC-CTLs) generated by gamma-catch to mediate antiviral activity in hematopoietic stem cell transplantation (HSCT) recipients with CMV infections. SECONDARY OBJECTIVE: I. To assess the persistency of the administered HMC-CTLs generated by gamma-catch and their contribution immune reconstitution. OUTLINE: Patients receive allogeneic cytomegalovirus-specific cytotoxic T-lymphocytes intravenously (IV). Patients with partial response, stable disease, or progressive disease may receive an additional dose of allogeneic cytomegalovirus-specific cytotoxic T-lymphocytes at a minimum of 2 weeks from the first infusion. After completion of study treatment, patients are followed up periodically for 12 months.

Official Title
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Most Closely HLA Matched Allogeneic CMV Specific Cytotoxic T-Lymphocytes (CTL) to Treat CMV Infection After Hemapoietic Stem Cell Transplantation (HSCT)

Conditions
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Cytomegaloviral Infection, Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm

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 with or without a malignancy; and/or any type of autologous or allogeneic HSCT; and/or patients who are immunocompromised with CMV infection will be included Persistent CMV infection despite optimum anti-viral therapy Patients with CMV disease: defined as the demonstration of CMV by biopsy specimen from visceral sites (by culture or histology) or the detection of CMV by culture or direct fluorescent antibody stain in bronchoalveolar lavage fluid in the presence of new or changing pulmonary infiltrates; OR Failure of antiviral therapy: defined as the continued presence of deoxyribonucleic acid (DNA)emia (defined as >= 137 copies/ml by polymerase chain reaction [PCR]) for at least 2 weeks of CMV antiviral therapy; OR Optimum therapy is defined as at least 14 days of therapy with ganciclovir, foscarnet, cidofovir, or valganciclovir for patients with disease or CMV viremia Relapse while on CMV antiviral therapy defined as recurrence of DNAemia while being on at least 2 weeks of antiviral therapy OR Patients who cannot tolerate standard anti-viral therapy and cannot continue anti-viral treatment due to side effect profile will be eligible independent of anti-viral therapy duration Clinical status at enrollment to allow tapering of steroids equal to or less than 0.5 mg/kg/day of prednisone Patients with chronic graft-versus-host disease (GVHD) if on prednisone equal to or less than 0.5 mg/kg and not receiving second-line GVHD treatments like pentostatin, infliximab, etanercept, etc Written informed consent and/or signed assent line from patient, parent or guardian Negative pregnancy test in female patients of childbearing potential Exclusion Criteria: Patients receiving prednisone > 0.5 mg/kg/day at time of enrollment, or have received anti-thymocyte globulin (ATG), donor lymphocyte infusion (DLI) or Campath within 28 days of enrollment Patients with other uncontrolled infections; for bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment; for fungal infections patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment; progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection; persisting fever without other signs or symptoms will not be interpreted as progressing infection; patients with ongoing viral infections are excluded Patients with active acute GVHD grades II-IV Active and uncontrolled relapse of malignancy
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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 (allogeneic CMV-specific cytotoxic T-lymphocytes)<br>Patients receive allogeneic cytomegalovirus-specific cytotoxic T-lymphocytes IV. Patients with partial response, stable disease, or progressive disease may receive an additional dose of allogeneic cytomegalovirus-specific cytotoxic T-lymphocytes at a minimum of 2 weeks from the first infusion. | Biological: Allogeneic Cytomegalovirus-Specific Cytotoxic T lymphocytes<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success, defined as R1 and R2 without treatment failure | The best outcome is defined as R1 = in complete response (CR) for 4 consecutive weeks, starting at week 2, without the need for a second cytotoxic T-lymphocyte (CTL) infusion. The second best outcome is defined as R2 = not in CR at week 2, 3, or 4, but in CR or partial response (PR) 4 weeks after the second CTL infusion. | Up to 4 weeks after second CTL infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival time | Will be analyzed as a function of patient covariates using standard statistical methods, including Bayesian survival regression analysis and ordinal regression. Unadjusted event time distributions will be estimated using the Kaplan-Meier method. | Up to 12 months | 
| Disease-free survival time | Will be analyzed as a function of patient covariates using standard statistical methods, including Bayesian survival regression analysis and ordinal regression. Unadjusted event time distributions will be estimated using the Kaplan-Meier method. | Up to 12 months | 
| Graft-versus-host disease | Will be analyzed as a function of patient covariates using standard statistical methods, including Bayesian survival regression analysis and ordinal regression. | Up to 12 months | 
| Secondary graft failure | Will be analyzed as a function of patient covariates using standard statistical methods, including Bayesian survival regression analysis and ordinal regression. | Up to 12 months |