Multi-antigen CMV-Modified Vaccinia Ankara Vaccine in Treating Pediatric Patients With Positive Cytomegalovirus Undergoing Donor Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To investigate the optimal dose of multi-antigen CMV-modified vaccinia ankara vaccine
(Triplex) in CMV-positive pediatric patients receiving human leukocyte antigen (HLA) matched
or mismatched hematopoietic cell transplantation (HCT). (Phase I)

II. To evaluate the safety profile of Triplex in this patient population. (Phase I)

III. To determine if Triplex reduces the frequency of CMV events when compared to historical
data. (Phase II)

SECONDARY OBJECTIVES:

I. To characterize CMV reactivation and disease by assessing: time to CMV reactivation,
duration of viremia, recurrence of viremia, incidence of late CMV viremia/disease (defined as
> 100 days and =< 365 days post HCT), use of anti-viral drugs triggered by rising CMV viremia
or viremia >= 3750 IU/mL, cumulative number of CMV specific antiviral treatment days.

II. To evaluate the impact of Triplex on transplant related outcomes by assessing the
incidence of acute and chronic graft versus host disease (GVHD), relapse, non-relapse
mortality (NRM), all-cause mortality, infections.

III. To investigate the impact of Triplex on cellular immunity by investigating: the level,
function and kinetics of CMV-specific T-cell immunity, the changes in adaptive natural killer
(NK) cell population and highly cytotoxic memory NKG2C+ NK cells, and changes in GVHD
biomarkers.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

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

After completion of study treatment, patients are followed up for up to 365 days.

Inclusion Criteria:

- All subjects (or their guardians) must have the ability to understand and the
willingness to sign a written informed consent; age appropriate assent will be
obtained per institutional guidelines; to allow non-English patients to participate in
this study, bilingual health services will be provided in the appropriate language
when feasible

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

- Planned allogenic (allo)-HCT, with 9/10 or 10/10 (A, B, C, DRB1, DQB1)
high/intermediate resolution HLA donor allele matching and with no T-cell depletion of
graft

- Planned related HCT with molecular 3/6 HLA donor allele matching (haploidentical) (for
phase I only)

- CMV seropositive at the time of HCT

- 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, if
hepatitis B virus (HBV) core seropositive, absence of HBV deoxyribonucleic acid (DNA)
within 2 months of registration

- 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:

- TRANSPLANT RELATED CRITERIA: Patients undergoing cord blood transplant (CB-HCT)

- Any prior investigational CMV vaccine

- Anti-CMV therapy in the last 6 months

- Live attenuated vaccines

- Medically indicated subunit (Engerix-B for HBV; Gardasil for human papillomavirus
[HPV]) or killed vaccine (e.g. influenza, pneumococcal)

- Allergy treatment with antigens injections

- Alemtuzumab, cyclophosphamide, ATG or any equivalent in vivo T-cell depleting agent;
Note: Pre transplant ATG is permitted

- Antiviral medications with known therapeutic effects on CMV such as ganciclovir
(GCV)/valine (VAL), 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;
intravenous immunoglobulin therapy (IVIG) is allowed

- 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 congenital immune deficiency

- Patients with active autoimmune conditions requiring systemic immunosuppressive
therapy within the previous 5 years are not eligible, the exception to this is
patients with aplastic anemia, who are eligible

- 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 issue related to
feasibility/logistics)