This phase II clinical trial tests how well the cytomegalovirus-modified vaccinica Ankara (CMV-MVA) Triplex vaccine given to human leukocyte antigens (HLA) matched related stem cell donors works to prevent cytomegalovirus (CMV) infection in patients undergoing hematopoietic stem cell transplant. The CMV-MVA Triplex vaccine works by causing an immune response in the donors body to the CMV virus, creating immunity to it. The donor then passes that immunity on to the patient upon receiving the stem cell transplant. Giving the CMV-MVA triplex vaccine to donors may help prevent CMV infection of patients undergoing stem cell transplantation.
PRIMARY OBJECTIVE: I. To determine whether multi-peptide CMV-modified vaccinia Ankara vaccine (Triplex) is safe and effective in protecting against CMV events defined as viremia requiring antiviral preemptive therapy (PET) or CMV end organ disease. SECONDARY OBJECTIVE: I. To examine if Triplex vaccination of hematopoietic stem cell transplant (HCT) donors has an impact on CMV events. OUTLINE: Donors are randomized to 1 of 2 arms. ARM I: DONORS: Donors receive Triplex vaccine intramuscularly (IM) on day 0 and then undergo stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) on days 5 to 9 and apheresis for peripheral blood stem cell collection on days 10 to 14 per standard of care. Donors may optionally undergo blood sample collection on study. RECIPIENTS: Recipients undergo pre-transplant conditioning on days -60 to 0 and undergo HCT with the donor peripheral blood stem cells within 9 weeks of donor vaccination on day 0. Recipients undergo blood sample collection on study. ARM II: DONORS: Donors receive placebo IM on day 0 and undergo stem cell mobilization with G-CSF on days 5 to 9 and apheresis for peripheral blood stem cell collection on days 10 to 14 per standard of care. Donors may optionally undergo blood sample collection on study. RECIPIENTS: Recipients undergo pre-transplant conditioning on days -60 to 0 and undergo HCT with the donor peripheral blood stem cells within 9 weeks of donor vaccination on day 0. Recipients undergo blood sample collection on study. After completion of study treatment, donors follow up on days 90, 180 and 365 after vaccination and recipients follow up on days 14, 28, 42, 56, 70, 100, 140, 180, 270, and 365 after transplantation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
216
Undergo HCT with donor peripheral blood stem cells
Undergo blood sample collection
Undergo stem cell mobilization with G-CSF
Receive pre transplant conditioning
Given IM
Undergo apheresis
Given IM
Undergo stem cell mobilization with G-CSF
City of Hope Medical Center
Duarte, California, United States
RECRUITINGNorthside Hospital
Atlanta, Georgia, United States
RECRUITINGDFCI/BWH Brigham and Women's Hospital
Boston, Massachusetts, United States
RECRUITINGTime from transplantation to cytomegalovirus (CMV) disease or pre-emptive treatment following CMV reactivation (efficacy)
A stratified Cox regression analysis of time to CMV disease or positron emission tomography (PET) following CMV reactivation prior to Day 180 post-HCT will be performed. The estimated hazard ratio and its 95% confidence interval will be calculated. Secondary analyses will include the Fine-Gray model for competing risk.
Time frame: From hematopoietic stem cell transplantation (HCT) to day 180
Occurrence of non-relapse mortality (safety in HCT-recipients)
A stratified Cox regression analysis of time to CMV disease or PET following CMV reactivation prior to Day 180 post-HCT will be performed. The estimated hazard ratio and its 95% confidence interval will be calculated. Secondary analyses will include the Fine-Gray model for competing risk.
Time frame: Up to day 100 post HCT
Incidence of severe acute graft versus host disease (aGHVD) (safety in HCT-recipients)
Severe aGHVD defined as grades 3-4. A stratified Cox regression analysis of time to CMV disease or PET following CMV reactivation prior to Day 180 post-HCT will be performed. The estimated hazard ratio and its 95% confidence interval will be calculated. Secondary analyses will include the Fine-Gray model for competing risk.
Time frame: Up to 100 days post HCT
Incidence of severe adverse events (AEs) (safety in HCT-recipients)
Probably or definitely related to the vaccination per Common Terminology Criteria for Adverse Events version 5.0. A stratified Cox regression analysis of time to CMV disease or PET following CMV reactivation prior to Day 180 post-HCT will be performed. The estimated hazard ratio and its 95% confidence interval will be calculated. Secondary analyses will include the Fine-Gray model for competing risk.
Time frame: Within 2 weeks from transplantation and up to 1 year post HCT
Incidence of grade 3 and higher AEs (safety in HCT-donors)
A stratified Cox regression analysis of time to CMV disease or PET following CMV reactivation prior to Day 180 post-HCT will be performed. The estimated hazard ratio and its 95% confidence interval will be calculated. Secondary analyses will include the Fine-Gray model for competing risk.
Time frame: Within 14 days
Time-to viremia (CMV-related events)
The number and percentage of recipients who receive treatment prior to the study recommended level of CMV viremia for PET will be tabulated by treatment group. Total days on antivirals for CMV reactivation (induction, maintenance, and total) will be assessed for each HCT recipient with treatment groups compared using Wilcoxson's rank sum test. Other characterizations of viremia and response to therapy will be descriptive in nature.
Time frame: From transplantation to the date of two consecutive CMV quantitative polymerase chain reaction (qPCR) > 500 gc/mL/465 IU/mL or single event of CMV qPCR >1500 CMV gc/mL/1,395 IU/mL, assessed up to 1 year post HCT
Duration of viremia (CMV-related events)
The number and percentage of recipients who receive treatment prior to the study recommended level of CMV viremia for PET will be tabulated by treatment group. Total days on antivirals for CMV reactivation (induction, maintenance, and total) will be assessed for each HCT recipient with treatment groups compared using Wilcoxson's rank sum test. Other characterizations of viremia and response to therapy will be descriptive in nature.
Time frame: Up to 1 year post HCT
Incidence of late CMV viremia (CMV-related events)
The number and percentage of recipients who receive treatment prior to the study recommended level of CMV viremia for PET will be tabulated by treatment group. Total days on antivirals for CMV reactivation (induction, maintenance, and total) will be assessed for each HCT recipient with treatment groups compared using Wilcoxson's rank sum test. Other characterizations of viremia and response to therapy will be descriptive in nature.
Time frame: Between days 100-365 post HCT
Use of antiviral drugs (CMV-related events)
Triggered by clinically significant viremia or CMV disease.
Time frame: Up to 1 year post HCT
Cumulative number of CMV specific antiviral treatment days (CMV-related events)
Time frame: Up to 1 year post HCT
Incidence of CMV disease (CMV-related events)
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Time frame: Up to 1 year post HCT
Time to engraftment (transplant-related events)
Time frame: Up to 1 year post HCT
Incidence of aGVHD and chronic GVHD (transplant-related events)
Estimated using the Kaplan-Meier or Fine-Gray estimators, as appropriate, and compared using the log-rank test or the corresponding sub-distribution test of Gray.
Time frame: Up to 1 year post HCT
Incidence of relapse (transplant-related events)
Estimated using the Kaplan-Meier or Fine-Gray estimators, as appropriate, and compared using the log-rank test or the corresponding sub-distribution test of Gray.
Time frame: Up to 1 year post HCT
Non-relapse mortality (transplant-related events)
Time frame: Up to 1 year post HCT
All-cause mortality (transplant-related events)
Time frame: Up to 1 year post HCT
Incidence of infections (transplant-related events)
Estimated using the Kaplan-Meier or Fine-Gray estimators, as appropriate, and compared using the log-rank test or the corresponding sub-distribution test of Gray.
Time frame: Up to 1 year post HCT
Levels and kinetics of CMV-specific T cell immunity, combined with immunophenotyping, and functional studies (immunological function)
Generalized estimating equations will be used to estimate the effect of Triplex on log10-transformed concentration of CMV-specific T cells measured post-HCT. Initial regression model will include an indicator variable for Triplex vaccine status of the donor, study day as a categorical variable, and vaccine status by study day interaction term (saturated model). For each post-HCT day, difference in average log-10 concentration between study arms and its 95% confidence interval will be calculated. Primary analysis will include all post-HCT measurements. Additional analyses will be conducted in which measurements after CMV reactivation are excluded.
Time frame: Up to 1 year post HCT