Multi-antigen CMV-Modified Vaccinia Ankara Vaccine in Reducing CMV Related Complications in Patients With Blood Cancer Undergoing Donor Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To determine if multi-antigen CMV-modified vaccinia Ankara vaccine (CMV-modified vaccinia
Ankara [MVA] triplex) reduces the frequency of CMV events, defined as reactivation or CMV
disease in CMV+, haploidentical hematopoietic cell transplantation (haploHCT) recipients.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of CMV-MVA triplex in vaccinated, haploHCT
recipients by assessing the following: non-relapse mortality (NRM) at 100 days post
hematopoietic cell transplantation (HCT), severe (grade 3-4) acute graft versus host disease
(GVHD), and grade 3-4 adverse events (AEs) probably or definitely related to the vaccination
within 2 weeks from each vaccination.

II. To characterize CMV related events in recipients of CMV-MVA triplex compared to placebo,
by assessing time to viremia (number of days from transplantation to the date of >= 1250
IU/mL), duration of viremia, recurrence of viremia, incidence of late CMV viremia/disease (>
100 and =< 360 days post HCT), use of antiviral drugs (triggered by clinically significant
viremia of >= 1250 IU/mL), cumulative number of CMV specific antiviral treatment days.

III. To evaluate the impact of CMV-MVA triplex on transplant related outcomes by assessing
the incidence of acute graft versus host disease (aGVHD), chronic GVHD, relapse, non-relapse
mortality, all-cause mortality, infections.

IV. To determine if CMV-MVA 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 cell.

VI. To compare GVHD biomarkers between the vaccine and placebo groups.

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM I: Patients receive multi-antigen CMV-modified vaccinia Ankara vaccine intramuscularly
(IM) on days 28 and 56 post-HCT.

ARM II: Patients receive placebo IM on days 28 and 56 post-HCT.

After completion of study treatment, patients are followed up at 100, 140, 180, 270, and 365
days, and then periodically for 3 years.

Inclusion Criteria:

- All subjects must have the ability to understand and the willingness to sign a written
informed consent

- Participant must be willing to comply with study and/or follow-up procedures,
including willingness to be followed for one year post-HCT

- 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; adults with aplastic
anemia are excluded; patients undergoing a second haploHCT are not eligible
(patients who have undergone a previous autologous HCT are eligible)

- Patients receiving myeloablation (MA) or reduced intensity conditioning (RIC) are
allowed

- CMV seropositive (recipient)

- Planned related HCT with molecular 3/6 (haploidentical) intermediate/high resolution
human leukocyte antigen (HLA) donor allele matching

- Planned HCT with minimal to no-T cell depletion of graft

- Conditioning and immunosuppressive regimens according to institutional guidelines are
permitted

- Negative serum or urine beta-human chorionic gonadotropin (HCG) test (female patient
of childbearing potential only) within two weeks of registration

- Seronegative for human immunodeficiency virus (HIV), hepatitis C virus (HCV) and
active hepatitis B virus (HBV) (surface antigen negative) within 2 months of
registration and no history of disseminated cutaneous human papillomavirus (HPV)
related disease

- Agreement by females of childbearing potential and sexually active males to use an
effective method of contraception (hormonal or barrier method of birth control or
abstinence) prior to study entry and for up to 90 days post-HCT; should a woman become
pregnant or suspect that she is pregnant while participating on the trial, she should
inform her treating physician immediately

Exclusion Criteria:

- Any prior investigational CMV vaccine

- Experimental anti-CMV chemotherapy in the last 6 months

- Live attenuated vaccines

- Medically indicated subunit (Engerix-B for HBV, Gardasil for HPV) or killed vaccine
(e.g. influenza, pneumococcal, or allergy treatment with antigen injections)

- Allergy treatment with antigen injections

- Alemtuzumab or any equivalent in vivo T-cell depleting agent (or CD34+ selection)

- Antiviral medications with known therapeutic effects on CMV such as
ganciclovir/valganciclovir (GCV/VAL), foscarnet (FOS), Cidofovir, CMX-001, maribavir;
acyclovir has no known therapeutic efficacy against CMV and is allowable as standard
of care to prevent herpes simplex virus (HSV)

- Prophylactic therapy with CMV immunoglobulin or prophylactic antiviral CMV treatment

- Conditioning regimens 30 days (d) prior to trial participation and up to d28 post-HCT

- Disease-based radiation therapy (not total body irradiation)

- Other investigational product-concurrent enrollment in other clinical trials using any
investigational new drug (IND) drugs with unknown effects on CMV or with unknown
toxicity profiles is prohibited

- Other medications that might interfere with the evaluation of the investigational
product

- Patients with active autoimmune conditions requiting systemic immunosuppressive
therapy within the previous 5 years at not eligible

- Patients considered by PIs/protocol team to have a complicated prior therapy or HCT
regimen, or who have a low survival probability (e.g., refractory leukemia and/or
undergoing 2nd HCT)

- Poor risk disease/disease status including: chronic myeloid leukemia (CML) in blast
crisis, acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) beyond 2nd
remission, multiple myeloma, and aplastic anemia

- Pregnant women and women who are lactating; breastfeeding should be discontinued if
the mother is enrolled on this study

- Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns or compliance
with clinical study procedures, e.g., social/psychological issues, etc

- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)