This phase II trial studies how well Triplex vaccine works in preventing cytomegalovirus (CMV) infection in patients undergoing a hematopoietic stem cell transplantation. CMV is a virus that may be carried for life and does not cause illness in most healthy individuals. However, in people whose immune systems are lowered (such as those undergoing stem cell transplantation), CMV can reproduce and cause disease and even death. The Triplex vaccine is made up of 3 small pieces of CMV deoxyribonucleic acid (DNA) (the chemical form of genes) placed into a weakened virus called modified vaccinia Ankara (MVA) that may help produce immunity (the ability to recognize and respond to an infection) and reduce the risk of developing complications related to CMV infection.
PRIMARY OBJECTIVE: I. To determine if CMV-MVA multi-peptide CMV-modified vaccinia Ankara vaccine (Triplex) reduces the frequency of clinically significant CMV reactivation in CMV positive (+) haploidentical hematopoietic cell transplantation (haploHCT) adult recipients from when letermovir (Prevymis) prophylaxis is stopped at day (d)100 until d180 post HCT. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of Triplex in vaccinated, haploHCT recipients by assessing the following: non-relapse mortality (NRM) at d180 post-HCT, severe (grade 3-4) acute graft versus host disease (GVHD), and grade 3-4 adverse events (AEs) (Common Terminology Criteria for Adverse Events \[CTCAE\] 5.0) probably or definitely related to the vaccination within 2 weeks from each vaccination at d180 post-HCT. II. To characterize CMV related events in recipients of Triplex compared to placebo, by assessing time-to viremia (number of days from d100 to the date of \>= 625 IU/mL), duration of viremia, recurrence of viremia, incidence of late CMV viremia/disease (\>= 625 IU/mL, \> 200 and =\< 365 days post-HCT), use of antiviral drugs (triggered by clinically significant viremia), cumulative number of CMV specific antiviral treatment days. III. To evaluate the impact of Triplex on transplant related outcomes up to d365 post-HCT by assessing the incidence of acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, non-relapse mortality, all-cause mortality, infections. IV. To determine if Triplex increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated compared to placebo treated, CMV seropositive HCT-recipients. V. To determine whether vaccination induces adaptive natural killer (NK) cell population changes, and increase in the highly cytotoxic memory NKG2C+ NK cells. VI. To compare GVHD biomarkers between the vaccine and placebo groups up to d365 post-HCT. VII. To determine if immunity to 3 CMV antigens contained in the Triplex vaccine correlates with protection against CMV events, and if T-cell increases reflect vaccine response and exceed placebo immune response levels up to d365 post-HCT. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive letermovir per standard of care (SOC) on days 7-100 and multi-peptide CMV-modified vaccinia Ankara vaccine intramuscularly (IM) on days 100 and 128 post-HCT. ARM II: Patients receive letermovir per SOC on days 7-100 and placebo IM on days 100 and 128 post-HCT. After completion of study treatment, patients are followed up to 365 days post-HCT and then for an additional 2 years post-HCT.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
DOUBLE
Enrollment
7
City of Hope Medical Center
Duarte, California, United States
Number of Participants With Cytomegalovirus (CMV) Events
Cytomegalovirus (CMV) event was defined as CMV reactivation (DNAemia \>625 IU/ml by qPCR), viremia treated by antivirals, or detection of CMV by tissue histology (end-organ disease), from Day 100 post-HCT to Day 180 post-HCT. Trial participants were quantitatively monitored for viremia, by plasma qPCR test once every two weeks (+/- 5d) from Day 100 to Day 180. CMV monitoring used standard qPCR clinical laboratory methods to evaluate CMV viral load and possible vaccine failure.
Time frame: From Day 100 to Day 180 post-hematopoietic stem cell transplant (HCT)
Non-Relapse Mortality at Day 180 Post-Transplant
Non-relapse mortality (NRM) was defined as death without recurrent or progressive disease after transplant. NRM was estimated with the use of cumulative incidence curves, with relapse viewed as a competing risk.
Time frame: From time of transplant (Day 0) to Day 365
Number of Participants With Severe (Grade 3-4) Acute Graft Versus Host Disease (GVHD) at Day 100
Acute GVHD was assessed and graded according to the Keystone Consensus grading system (Przepiorka, D., et al., 1994 Consensus Conference on Acute GVHD Grading).
Time frame: From time of transplant (Day 0) to Day 100
Number of Grade 3-4 Adverse Events
Adverse events probably or definitely related to the vaccination and modified vaccinia Ankara vector persistence were evaluated by NCI Common Terminology Criteria for Adverse Events v5.0.
Time frame: From time of transplant (Day 0) to Day 365
Duration of Viremia
Duration of viremia was defined as the number of days from CMV qPCR \>625 IU/mL to serum viral clearance (no detectable CMV DNA in serial blood samples).
Time frame: From time of transplant (Day 0) to Day 200
Number of Patients With Recurrence of CMV Viremia
CMV viremia was defined CMV qPCR \>625 IU/mL from samples collected within the past 7 days.
Time frame: From time of transplant (Day 0) to Day 200
Days From Transplant to ANC Engraftment
Date of ANC engraftment was defined as the first date of ANC of ≥ 0.5 x 109/L achieved for 3 consecutive lab tests on 3 different days.
Time frame: From time of transplant to date of ANC engraftment, up to Day 365.
Cumulative Incidence of Acute GVHD
Acute graft versus host disease is graded according to the 1994 Keystone Consensus Grading. The first day of acute GVHD onset was used to calculate the cumulative incidence. Relapse/death prior to onset was considered competing events.
Time frame: From time of transplant (Day 0) to Day 100
Cumulative Incidence of Chronic GVHD at Day 365
Cumulative incidence of Chronic GVHD (cGVHD) was estimated with the use of cumulative incidence curves. The first day of cGVHD onset was used to calculate the cumulative incidence. Relapse/death prior to onset was considered competing events.
Time frame: From time of transplant (Day 0) to Day 365
Cumulative Incidence of Relapse at Day 365
Cumulative incidence of relapse was estimated with the use of cumulative incidence curves, with death viewed as a competing risk.
Time frame: From time of transplant (Day 0) to Day 365
Number Of Participants Died at Day 365
Number of participants, who died due to all causes, at Day 365 post-transplant.
Time frame: From time of transplant (Day 0) to Day 365
Overall Survival at Day 365
Estimates was calculated using the Kaplan-Meier method, Greenwood formula was used to calculate SE, and loglog transformation method was used to construct 95% confidence intervals. Each patient's vital status was monitored per clinical standard operating procedure. For this endpoint failure is defined as death (from any cause). Patients not experiencing a death event was censored at his/her date of last contact.
Time frame: From time of transplant (Day 0) to Day 365
Non-Relapse Mortality (NRM) at Day 365
Non-relapse mortality (NRM) was defined as death without recurrent or progressive disease after transplant. NRM was estimated with the use of cumulative incidence curves, with relapse viewed as a competing risk.
Time frame: From time of transplant (Day 0) to Day 365
Days From Transplant to Platelet Engraftment
Date of platelet engraftment was defined as the first date of platelet value of ≥ 20 x 109/L achieved for 3 consecutive lab tests on 3 different days (without platelet transfusion in the previous 7 days).
Time frame: From time of transplant to date of platelet engraftment, up to Day 365
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