Letermovir Prophylaxis for Cytomegalovirus in Pediatric Hematopoietic Cell Transplantation
Overview
- Phase
- Phase 3
- Status
- Recruiting
- Sponsor
- Children's Oncology Group
- Enrollment
- 105
- Locations
- 48
- Primary Endpoint
- Clinically significant cytomegalovirus (CMV) infection
Overview
Brief Summary
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.
Detailed Description
PRIMARY OBJECTIVE:
I. To evaluate the efficacy of letermovir prophylaxis in the prevention of clinically significant CMV infection through Week 14 (~100 days) post-transplant in children and adolescents receiving allogeneic hematopoietic cell transplant (allo-HCT).
SECONDARY OBJECTIVE:
I. To evaluate the efficacy of letermovir prophylaxis as assessed by CMV-free survival through 24 weeks (~6 months) post-transplant in pediatric patients.
EXPLORATORY OBJECTIVES:
I. To evaluate the incidence of clinically significant CMV infection through 24 and 52 weeks post-transplant in patients who receive letermovir prophylaxis.
II. To evaluate overall survival post-transplant in patients who receive letermovir prophylaxis.
III. To evaluate time to engraftment and describe the cumulative incidence of non-engraftment among patients who receive letermovir.
IV. To examine the following clinically significant adverse events among patients exposed to letermovir: 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 among patients who receive letermovir prophylaxis.
VI. To describe immune reconstitution and CMV-specific immunity among patients who receive letermovir prophylaxis.
OUTLINE: Enrolled patients will be added to the single arm of the study and receive letermovir prophylaxis.
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 (CLOSED TO ACCRUAL 09/29/2025): 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Single (Outcomes Assessor)
Eligibility Criteria
- Ages
- 2 Years to 18 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
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
Arms & Interventions
ARM A (Letermovir prophylaxis)
Patients receive letermovir PO or IV over 60 minutes QD starting on day +1 post-transplant for 14 weeks. 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.
Intervention: Biospecimen Collection (Procedure)
ARM A (Letermovir prophylaxis)
Patients receive letermovir PO or IV over 60 minutes QD starting on day +1 post-transplant for 14 weeks. 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.
Intervention: Letermovir (Drug)
Arm B (No prophylaxis)
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. (CLOSED TO ACCURAL 09/29/2025)
Intervention: Biospecimen Collection (Procedure)
Outcomes
Primary Outcomes
Clinically significant cytomegalovirus (CMV) infection
Time Frame: Up to week 14 post-transplant
Clinically significant CMV is defined as the first of (1) initiation of anti-CMV preemptive therapy for documented CMV DNAemia or (2) onset of CMV end-organ disease. Will estimate the cumulative incidence of clinically significant CMV at 14-weeks post-transplant and will report the corresponding 95% confidence interval.
Secondary Outcomes
- Detection of CMV DNAemia(Up to week 14 post-transplant)
- CMV-free survival(Up to 24 weeks post-transplant)