Title
Letermovir Prophylaxis for Cytomegalovirus in Pediatric Hematopoietic Cell Transplantation

Description
This phase III trial determines whether taking prophylactic letermovir will reduce the likelihood of infection with cytomegalovirus (CMV) in children and adolescents after stem cell transplant. 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.

Objective
PRIMARY OBJECTIVE:

I. To evaluate the efficacy of letermovir compared to no prophylaxis in the prevention of clinically significant cytomegalovirus (CMV) infection through Week 14 (~100 days) post-transplant in children and adolescents receiving allogeneic hematopoietic cell transplant (allo-HCT).

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of letermovir compared to no prophylaxis as assessed by time to onset of any CMV DNAemia through week 14 (~100 days) post transplant.

II. To evaluate CMV-free survival through 24 weeks post transplant in pediatric patients who receive letermovir compared to those who do not.

EXPLORATORY OBJECTIVES:

I. To evaluate the efficacy of letermovir as assessed by time to onset of clinically significant CMV infection through weeks 24 (~6 months) and 48 (~1 year) post-transplant.

II. To evaluate overall survival through weeks 24 and 48 post-transplant in patients who receive letermovir versus those who do not.

III. To compare time to engraftment and describe the cumulative incidence of non-engraftment among patients who receive letermovir and those who do not.

IV. To examine the rates of several clinically significant adverse events among patients exposed to letermovir versus those who are not including: the total duration of neutropenia through week 14 (~100 days) post-transplant, the cumulative incidence of acute kidney injury and chronic kidney disease by 52 weeks post-transplant, and total inpatient hospital days by 14 weeks (~100 days) and 52 weeks post-transplant.

V. Describe patterns of anti-viral resistance at the onset of CMV DNAemia after allo-HCT.

VI. To compare immune reconstitution and CMV-specific immunity in pediatric patients treated with letermovir prophylaxis versus no prophylaxis.

Treatment OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive letermovir orally (PO) or intravenously (IV) over 60 minutes once daily (QD) starting on day +1 post-transplant for 14 weeks. Patients undergo collection of blood samples for CMV polymerase chain reaction (PCR) analysis weekly for 14 weeks, every 2 weeks until week 24, week 32, week 40 and week 52.

ARM B: Patients undergo collection of blood samples for CMV PCR analysis weekly for 14 weeks, every 2 weeks until week 24, week 32, week 40 and week 52.

Key Eligibility Inclusion Criteria:

>= 2 years and < 18 years at the time of enrollment

Weight must be >= 18 kg. For patients < 12 years of age and expected to receive cyclosporine, weight must be >= 30kg

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)

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 > 15 mL/min/1.73 m^2 and not receiving dialysis

Total bilirubin =< 2.5 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

Applicable Disease Sites
Hematologic cancers, other; Leukemia; Lymphoma

Participating Institutions
Gundersen Health System; UW Health University Hospital