Clinical trial NCT05711667: A Study of the Drug Letermovir as Prevention of Cytomegalovirus Infection After Stem Cell Transplant in Pediatric Patients
Official title: Letermovir Prophylaxis for Cytomegalovirus in Pediatric Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Hematopoietic and Lymphoid Cell Neoplasm
Malignant Solid Neoplasm
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
First posted: 2023-02-03
Enrollment: 143
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

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.

Eligibility criteria: 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

Exclusion Criteria:

* Expected inability to tolerate oral formulation (e.g., unable swallow whole tablets) of letermovir

  * Note: Determination of ability to tolerate the oral formulation will be based on a self-assessment or caregiver assessment; eligible subjects and their caregiver will be shown a life size picture of a tablet (or actual tablet) and confirm ability to swallow whole tablet in order to meet study eligibility
* 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
    * Lovastatin
    * Pitavastatin
    * Rosuvastatin
    * 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

Primary outcomes:
measure: Clinically significant cytomegalovirus (CMV) infection
timeFrame: Up to week 14 post-transplant
Secondary outcomes:
measure: Detection of CMV DNAemia
timeFrame: Up to week 14 post transplant
measure: CMV-free survival
timeFrame: Up to 24 weeks post transplant
Other outcomes:
measure: Clinically significant CMV infection in early follow up
timeFrame: Up to 24 weeks post-transplant
measure: Clinically significant CMV infection in late follow up
timeFrame: Up to 48 weeks post-transplant
measure: Overall survival (OS) in early follow up
timeFrame: Up to 24 weeks post transplant
measure: Overall survival (OS) in late follow up
timeFrame: Up to 48 weeks post-transplant
measure: Neutrophil engraftment
timeFrame: Up to 60 days post-transplant
measure: Incidence of neutropenia
timeFrame: Up to 14 weeks post-transplant
measure: Incidence of acute kidney injury
timeFrame: Up to 52 weeks post-transplant
measure: Incidence of chronic kidney disease
timeFrame: Up to 52 weeks post transplant
measure: Number of inpatient hospital days
timeFrame: Up to 14 weeks post-transplant
measure: Number of inpatient hospital days
timeFrame: Up to one-year post-transplant
measure: Incidence of resistance to antiviral medications
timeFrame: Up to 14 weeks post-transplant
measure: CD4+ lymphocyte count
timeFrame: Up to 14 weeks post-transplant
measure: CD4+ lymphocyte count
timeFrame: Up to 24 weeks post-transplant
measure: CD4+ lymphocyte count
timeFrame: Up to 48 weeks post-transplant
measure: CD8+ lymphocyte count
timeFrame: Up to 14 weeks post-transplant
measure: CD8+ lymphocyte count
timeFrame: Up to 24 weeks post-transplant
measure: CD8+ lymphocyte counts
timeFrame: Up to 48 weeks post-transplant
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mission Bay
state: California
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Jacksonville
country: United States
facility: Nemours Children's Clinic-Jacksonville
state: Florida
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: New Orleans
country: United States
facility: Children's Hospital New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
state: Michigan
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: The Children's Hospital at TriStar Centennial
state: Tennessee
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center - University Hospital
state: Wisconsin
Study officials:
affiliation: Children's Oncology Group
name: Caitlin W Elgarten
role: PRINCIPAL_INVESTIGATOR
References: