Summary

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.

Objectives

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.

Eligibility

1. DONORS: Documented informed consent of the participant. This can be done in person or informed consent can be obtained remotely. * Remote consent, when appropriate, will be obtained per institutional guidelines. * Assent, when appropriate, will be obtained per institutional guidelines. * Adult subjects who require a legally authorized representative (LAR) will not be permitted to be enrolled under this protocol.
2. DONORS: Age: 18 - 75.
3. DONORS: Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
4. DONORS: Agreement by females and males of childbearing potential* to use an effective method of birth control (hormonal or barrier method) or abstain from heterosexual activity prior to study entry and for up to 90 days post-vaccination. * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).
5. RECIPIENTS: Documented informed consent of the participant and/or legally authorized representative. This can be done in person or informed consent can be obtained remotely. * Remote consent, when appropriate, will be obtained per institutional guidelines. * Assent, when appropriate, will be obtained per institutional guidelines. * Adult subjects who require a legally authorized representative (LAR) will not be permitted to be enrolled under this protocol.
6. RECIPIENTS: Participant must be willing to comply with study and/or follow-up procedures, including willingness to be followed for one year post-HCT.
7. RECIPIENTS: Age: 18 - 75.
8. RECIPIENTS: Planned peripheral blood stem cell (PBSC) or bone marrow (BM) HCT for the treatment of the following hematologic malignancies: * Lymphoma (Hodgkin and Non-Hodgkin). * Myelodysplastic syndrome. * Acute lymphoblastic leukemia in first or second remission (for acute lymphoblastic leukemia/lymphoblastic lymphoma, the disease status must be in hematologic remission by bone marrow and peripheral blood. Persistent lymphadenopathy on computed tomography (CT) or CT/positron emission tomography(PET) scan without progression is allowed.) *Acute myeloid leukemia in first or second remission. * Chronic myelogenous leukemia in first chronic or accelerated phase, or in second chronic phase. * Other hematologic malignancies judged appropriate by the clinical principal investigators (PIs), including chronic lymphocytic leukemia, myeloproliferative disorders and myelofibrosis. Patients with multiple myeloma and those with non-malignant disease such as aplastic anemia are excluded**. ** Adult cases of multiple myeloma (MM) are excluded as HCT is not standard of care for MM and is only performed in very advanced cases with an associated high risk of relapse and non-relapse mortality (NRM). Adults with aplastic anemia are excluded because their standard management includes T cell depletion with agents such as antithymocyte globulin (ATG), which is not permissible on this protocol. Patients undergoing a second haploHCT are not eligible (patients who have undergone a previous autologous HCT are eligible).
9. RECIPIENTS: Patients receiving myeloablative (MA) or reduced intensity conditioning (RIC) are allowed.
10. RECIPIENTS: CMV seropositive.
11. RECIPIENTS: Eligible haploidentical donors will have 2-4 mismatches if human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 typing is used; 2-5 mismatches if HLA-A, -B, -C, -DRB1, and -DQB1 typing is used; and 2-6 mismatches if HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 typing is used. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must demonstrate that they are a full haplotype match by being identical at a minimum of one allele (at high resolution deoxyribonucleic acid [DNA]-based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1 if 8 allele typing is used; HLA-A, -B, -C, -DRB1, and -DQB1 if 10 allele typing is used; and HLA-A, -B, -C, -DRB1-, DQB1, and -DPB1 is 12 allele typing is used.
12. RECIPIENTS: Planned HCT with minimal to no-T cell depletion of graft.
13. RECIPIENTS: Conditioning and immunosuppressive regimens according to institutional guidelines are permitted.
14. RECIPIENTS: Total bilirubin = 1.5 X upper limit of normal (ULN) (unless has Gilbert’s disease) (to be performed within 45 days prior to day 1 of protocol therapy).
15. RECIPIENTS: Aspartate aminotransferase (AST) =< 2.5 x ULN (to be performed within 45 days prior to day 1 of protocol therapy).
16. RECIPIENTS: Alanine aminotransferase (ALT) =< 2.5 x ULN (to be performed within 45 days prior to day 1 of protocol therapy).
17. RECIPIENTS: Estimated creatinine clearance acceptable per institutional guidelines (to be performed within 45 days prior to day 1 of protocol therapy).
18. RECIPIENTS: Left ventricular ejection fraction (LVEF) = 50%. * Note: To be performed within 45 days prior to day 1 of protocol therapy.
19. RECIPIENTS: If able to perform pulmonary function tests: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and carbon monoxide diffusing capability (DLCO) (diffusion capacity) = 50% of predicted (corrected for hemoglobin). * If unable to perform pulmonary function tests: Oxygen (O2) saturation > 92% on room air. * Note to be performed within 45 days prior to day 1 of protocol therapy.
20. RECIPIENTS: Seronegative for HIV antigen (Ag)/antibody (Ab) combination (combo), hepatitis c virus (HCV)*, active hepatitis b virus (HBV) (surface antigen negative) and syphilis (RPR) within 2 months of registration and no history of disseminated cutaneous human papillomavirus (HPV) related disease. *If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. Viral load must be undetectable.
21. RECIPIENTS: Meets other institutional and federal requirements for infectious disease titer requirements. * Note Infectious disease testing to be performed within 45 days prior to day 1 of protocol therapy.
22. RECIPIENTS: Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (to be performed within 45 days prior to day 1 of protocol therapy).
23. RECIPIENTS: Agreement by females and males of childbearing potential* to use an effective method of birth control (hormonal or barrier method) or abstain from heterosexual activity prior to study entry and up to 90 days post-HCT. * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).

Treatment Sites in Georgia