This phase Ib trial tests the safety, side effects, and how well cytomegalovirus (CMV)-modified vaccinia Ankara (MVA) Triplex vaccine works in enhancing CMV-specific immunity and preventing CMV viremia in patients undergoing haploidentical hematopoietic stem cell transplant. Haploidentical stem cell transplantation (haploHCT) has advanced to become the predominant procedure for patients lacking a matched donor. Compared to matched related donor transplants, the rate of significant CMV infection is higher in patients undergoing a haploHCT. Significant CMV infection is associated with an increased risk of complications and death. Vaccination is the main preventative approach to limit complications and death in immunocompromised patients at high risk of post-stem cell transplant infections. CMV-MVA Triplex vaccine, is a CMV vaccine based on the attenuated poxvirus, modified vaccinia Ankara (MVA), developed to enhance CMV-specific immunity in both healthy stem cell transplant donors and stem cell transplant patients to prevent significant CMV infection post-stem cell transplant. Giving CMV-MVA triplex vaccine may be safe, tolerable and/or effective in enhancing cytomegalovirus (CMV)-specific immunity and preventing CMV viremia in patients undergoing a haploHCT.
PRIMARY OBJECTIVE: I. To evaluate whether the multi-peptide cytomegalovirus-modified vaccinia Ankara vaccine (CMV-MVA Triplex \[Triplex\]) vaccination of stem cell donors (D) and recipients (R) alone or in combination with letermovir safely protects against CMV events for day (d)100 in the absence of preemptive therapy (PET) and to determine the recommended duration of letermovir use as phase 2 modality in the haploidentical stem cell transplantation (haploHCT)-R. SECONDARY OBJECTIVES: I. To evaluate safety of Triplex in the haploHCT-R. II. To evaluate cumulative incidence of CMV events up to d180 post-hematopoietic stem cell transplant (HCT). III. To evaluate CMV viremia levels over time in the HCT-R. IV. To evaluate cumulative incidence of CMV disease. V. To evaluate use of PET by the HCT-R. EXPLORATORY OBJECTIVES: I. To assess levels and durability of CMV specific T cell immunity. II. To assess polyfunctional T cell responses and cell-surface memory markers until d180 post-HCT. OUTLINE: DONORS: Participants receive CMV-MVA Triplex vaccine intramuscularly (IM) once and then receive granulocyte colony stimulating factor (G-CSF) on study. Additionally, participants undergo apheresis on study as well as blood sample collection on study and may optionally undergo blood sample collection during follow up. RECIPIENTS: Patients are assigned to 1 of 3 modalities. MODALITY 1: Patients receive myeloablative conditioning during screening and undergo HCT from haploidentical vaccinated donor on day 0. Patients receive CMV-MVA Triplex vaccine IM once daily (QD) on days 28, 56 and 100 and receive letermovir intravenously (IV) over 1 hour or orally (PO) QD on days 7 to 100. Treatment continues in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study. MODALITY 2: Patients receive myeloablative conditioning during screening and undergo HCT from haploidentical vaccinated donor on day 0. Patients receive CMV-MVA Triplex vaccine IM QD on days 28, 56 and 100 and receive letermovir IV over 1 hour or PO QD on days 7 to 28. Treatment continues in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study. MODALITY 3: Patients receive myeloablative conditioning during screening and undergo HCT from haploidentical vaccinated donor on day 0. Patients receive CMV-MVA Triplex vaccine IM QD on days 28, 56 and 100. Treatment continues in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study. After completion of study treatment, patients are followed up every 2 weeks until day 180 and then at day 365.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
46
Undergo blood sample collection
Ancillary studies
Undergo HCT
Given IV or PO
Given IM
Receive myeloablative conditioning
Undergo apheresis
Given G-CSF
City of Hope Medical Center
Duarte, California, United States
Northside Hospital
Atlanta, Georgia, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Cytomegalovirus (CMV) reactivation prompting antiviral therapy
Will evaluate for CMV reactivation prompting antiviral therapy. Will be evaluated in patients that received a stem cell infusion from a Triplex vaccinated haploidentical donor and received the first Triplex vaccination.
Time frame: From day 0 to day 100 post-hematopoietic stem cell transplant (HCT)
CMV disease
Will evaluate for CMV disease based on histology. Will be evaluated in patients that received a stem cell infusion from a Triplex vaccinated haploidentical donor and received the first Triplex vaccination.
Time frame: From day 0 to day 100 post-HCT
Unacceptable toxicity
Will evaluate for grade 3-4 adverse events based on Common Terminology Criteria for Adverse Events version 5.0 probably or definitely attributable to vaccination in both recipients and donors. Descriptive statistics will be used to summarize recipients and donor adverse events.
Time frame: Up to 28 days after the last Triplex vaccination
Serious adverse events (SAE)
Will evaluate for SAEs that are at least possibly related to Triplex vaccination in donors.
Time frame: Up to 365 days after Triplex vaccination
Incidence of acute graft-versus-host disease (GVHD)
Will evaluate for grade 3-4 acute GVHD. Documented/biopsy proven acute GVHD is graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) grading. Cumulative incidence curves will be used to estimate acute GVHD.
Time frame: Up to day 180 post-HCT
Non-relapse mortality (NRM)
Will evaluate occurrence of NRM. Cumulative incidence curves will be used to estimate NRM.
Time frame: From HCT to death from other causes than disease relapse or progression, assessed up to day 180 post-HCT
CMV events
Will evaluate for CMV events. Death or relapse/progression prior to day 180 post-HCT will be counted as competing risk events. Patients who are alive and free of CMV events and relapse/progression at the last follow-up or day 180 post-HCT, whichever comes first, will be censored. Cumulative incidence curves will be used to estimate CMV events.
Time frame: Up to day 180 post-HCT
CMV viremia
Will evaluate for CMV viremia. Cumulative incidence curves will be used to estimate CMV viremia.
Time frame: From HCT to the date of two consecutive CMV quantitative polymerase chain reaction (qPCR) > 500 gc/mL/465 IU/mL, single event of CMV qPCR > 1500 CMV gc/mL/1,395 IU/mL, or CMV disease, whichever occurs first, assessed up to day 180 post-HCT
Incidence of late CMV viremia
Will evaluate for incidence of late CMV viremia. Cumulative incidence curves will be used to estimate CMV viremia.
Time frame: From HCT to the date of two consecutive CMV qPCR > 500 gc/mL/465 IU/mL, single event of CMV qPCR > 1500 CMV gc/mL/1,395 IU/mL, or CMV disease, whichever occurs first, assessed from day 100 to day 365 post-HCT
Neutrophil engraftment
Will evaluate time to neutrophil engraftment.
Time frame: From HCT to the first of 3 consecutive days with neutrophil count ≥ 0.5 X 10^3/uL
Platelet engraftment
Will evaluate time to platelet engraftment.
Time frame: From HCT to the first day of platelet count ≥ 20 X 10^3/uL independent of platelet transfusion support (date should reflect no transfusions in previous 7 days, and the first of 3 consecutive lab values on different days)
Incidence of severe acute GVHD
Will evaluate for grade 2-4 acute GVHD. Documented/biopsy proven acute GVHD is graded according to MAGIC grading. Cumulative incidence curves will be used to estimate acute GVHD.
Time frame: Up to day 180 post-HCT
Incidence of severe chronic GVHD
Will evaluate sever chronic GVHD. Documented/biopsy proven chronic GVHD is scored according to National Institutes of Health consensus staging. Cumulative incidence curves will be used to estimate chronic GVHD.
Time frame: Up to day 180 post-HCT
NRM
Will evaluate occurrence of NRM. Cumulative incidence curves will be used to estimate NRM.
Time frame: From HCT to death from other causes than disease relapse or progression, assessed up to day 365 post-HCT
Relapse
Will evaluate time to relapse. NRM is the competing risks event. Cumulative incidence curves will be used to estimate relapse.
Time frame: From HCT to the first observation of disease relapse or progression, assessed up to day 365 post-HCT
Overall survival (OS)
Will evaluate OS. OS is censored at the last follow-up if the last known status is alive. Kaplan-Meier curves will be used to estimate OS.
Time frame: From HCT to the date of death regardless of cause, assessed up to day 365 post-HCT
CMV-specific T cell immunity
Will evaluate levels and kinetics of CMV-specific T cell immunity, combined with immunophenotyping and functional studies. Repeated measures analysis of variance analyses will be used for immunological functions over time.
Time frame: Up to day 365 post-HCT
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.