A Study of the Drug Letermovir as Prevention of Cytomegalovirus Infection After Stem Cell Transplant in Pediatric Patients

This phase III single arm trial determines whether taking prophylactic letermovir will reduce the likelihood of infection with cytomegalovirus (CMV) in children and adolescents after stem cell transplant compared to estimated rate of infection without prophylaxis. The treatments used to prepare for HCT reduce the body's natural infection-fighting ability and increase the likelihood of an infection with a virus called cytomegalovirus. "Prophylaxis" means to take a drug to prevent a disease or side effect. Letermovir is an antiviral drug that stops cytomegalovirus from multiplying and may prevent cytomegalovirus infection and make the disease less severe.

Inclusion Criteria

• >= 2 years and < 18 years at the time of enrollment
• Weight must be >= 6 kg at the time of enrollment
• Planned allogeneic HCT (bone marrow, peripheral blood stem cell, or cord blood transplant)

• Patient must be CMV sero-positive (i.e., recipient CMV immunoglobulin G positive)

  • Note: If a patient has hypogammaglobulinemia but has previously been documented as CMV sero-positive, that is acceptable for study inclusion. For all patients already confirmed to be CMV IgG seropositive, repeat testing is not required within 7 days prior to enrollment. However, the laboratory data determining eligibility must be available in the patient's medical/research record for verification

• Patient is eligible for entry only if it is feasible for plasma CMV PCR testing to be sent and resulted within the protocol mandated time period

  • Reminder: To limit the likelihood of positive plasma CMV PCR post-enrollment and prior to start of study treatment period, it is recommended that patient enrollment proceed after patients start their transplant preparative regimen

• Patient must have a performance status corresponding to Lansky/Karnofsky scores > 50

  • Note: Use Lansky for patients =< 16 years of age and Karnofsky for patients > 16 years of age. For further reference, see performance status scales scoring under the standard sections for protocols among protocol reference materials provided on the Children's Oncology Group (COG) member website: https://members.childrensoncologygroup.org/prot/reference_materials.asp
• Estimated glomerular filtration rate > 10 mL/min/1.73 m^2 and not receiving dialysis

• Direct bilirubin =< 2 mg/dL and serum glutamate-pyruvate transaminase (SPGT) (alanine transaminase [ALT]) =<10 x upper limit of normal (ULN) for age

  • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L

Exclusion Criteria

• Expected inability to tolerate oral formulation of letermovir
• Hypersensitivity to letermovir or any component of the formulation

• History of CMV end organ disease within 6 months (180 days) prior to enrollment

  • Note: CMV end organ disease based on proposed definitions by Ljungman et al. and inclusive of proven, probable or possible disease
• Receipt of prior allogeneic HCT within one year of study enrollment

• Planned prophylactic administration of other anti-CMV medications or cellular products during the study, including:

  • High dose acyclovir (defined as doses >= 1500 mg/m^2 IV or >= 3200 mg oral (patients >= 40 kg) or >= 2400 mg/m^2 (patients < 40 kg) per day)
  • High dose valacyclovir (defined as doses >= 3000 mg/day in patients > 20 kg)
  • Foscarnet
  • Ganciclovir
  • Valganciclovir
  • CMV-directed cytotoxic T lymphocytes

• Planned receipt of the following contraindicated medications during the study treatment period; contraindicated medications must be discontinued at least 14 days prior to Day +1

  • Contraindicated medications for all patients:

    • Pimozide
    • Ergot alkaloids

  • Contraindicated medications for patients planned to receive cyclosporine:

    • Bosentan
    • Pitavastatin
    • Simvastatin
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted in certain animal reproduction studies with letermovir. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants

• Sexually active female patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their letermovir treatment and through at least 4 weeks after the last dose of letermovir.

  • Note: No contraception measures are needed specifically during letermovir treatment for male trial participants who have pregnant or non-pregnant female partner(s) of reproductive potential. Contraception measures may be required for other aspects of the HCT procedure.
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met