A Study of the Drug Letermovir as Prevention for Recurrence of Cytomegalovirus Infection
This phase II trial studies how well letermovir works in preventing cytomegalovirus infection from coming back (recurring) in high-risk stem cell transplant patients. Letermovir is an antiviral drug that stops cytomegalovirus from multiplying and may prevent cytomegalovirus infection and make the disease less severe.
Inclusion Criteria
- Age >= 12 years (any weight)
- Have received allogeneic hematopoietic cell transplant (HCT)
- Have received preemptive therapy for clinically significant CMV infection post-HCT and have completed preemptive therapy no longer than 7 days prior to enrollment. Preemptive treatment includes ganciclovir, valganciclovir, foscarnet or cidofovir. Clinically significant CMV infection is defined as CMV viremia requiring preemptive therapy or CMV EOD. Patients who have received LTV prophylaxis prior to onset of clinically significant CMV infection are eligible as long as they also received preemptive therapy for clinically significant CMV infection prior to enrollment
- Have one or more risk factors for recurrent CMV infection: * Human leukocyte antigen (HLA) mismatch ** HLA-related (sibling) donor with at least one mismatch at the HLA-A, -B or -DR gene loci ** Haploidentical donor ** Unrelated donor with at least one mismatch at the HLA-A, -B, -C or -DRB1 gene loci, or ** Cord blood as stem cell source * Acute or chronic graft versus host disease (GVHD) requiring either topical steroids for gastrointestinal GVHD and/or systemic steroid treatment (>= 1 mg/kg/day of prednisone or equivalent dose of another corticosteroid) within 14 days prior to enrollment * T-cell-depleted allograft ex-vivo or in-vivo T-cell depleting agents including but not limited to ATG, alemtuzimab and post HCT cyclophosphamide
- For adult patients, able to provide written consent and complete the informed consent. For patients under 18 years, the patient’s parent(s) or legal guardian(s) must provide informed consent and the patient must provide written assent to participation in the study
- Willing and able to comply with trial instructions and requirements
- Male and female patients of childbearing potential must be willing to use a highly effective method of contraception for the course of the study. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient
- OBSERVATIONAL COHORT: Age 18 years or older
- OBSERVATIONAL COHORT: First allogeneic peripheral blood or marrow HCT
- OBSERVATIONAL COHORT: LTV prophylaxis starting < 30 days post HCT and given for at least 6 weeks
Exclusion Criteria
- Clinically significant CMV infection present at enrollment
- Breakthrough CMV infection while on primary LTV prophylaxis (unless patient non-adherent or unable to adequately absorb letermovir) or documented resistance to LTV
- Glomerular filtration rate (GFR) =< 10 mL/min/1.73 m^2 (equivalent to creatinine clearance =< 10 mL/min)
- Severe hepatic impairment
- Routine use of high-dose acyclovir (doses of > 800 mg twice daily), valacyclovir (doses of > 500 mg twice daily), or famciclovir (doses > 500 mg/day) for varicella zoster virus (VZV)/herpes simplex virus prophylaxis; limited treatment courses at higher doses for VZV infections are permissible if treatment duration does not exceed 14 days total. Short courses of IV cidofovir for adenovirus (ADV) are permissible
- Suspected or known hypersensitivity to active or inactive ingredients of LTV formulations
- Patients treated with a medication whose administration with LTV is contraindicated and whose discontinuation is not possible. Contraindicated medications include pimozide, ergot alkaloids and pitavastatin or simvastatin when co-administered with cyclosporine
- Imminent demise (expected survival < 6 weeks)
- Documented positive result for human immunodeficiency virus antibody (HIV-Ab) or for hepatitis C virus antibody (HCV-Ab) with detectable HCV ribonucleic acid (RNA), or hepatitis B surface antigen (HBsAg) at any time prior to HCT
- Need for mechanical ventilation and/or vasopressor support at the time of enrollment
- Pregnancy or breastfeeding
- Plans to conceive or father children within the projected duration of the trial
- History or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or would place the subject at undue risk as judged by the investigator, such that it is not in the best interest of the subject to participate in this study
- The following antivirals are allowed up to the listed dose limits: * Acyclovir up to 800 mg twice daily * Valacyclovir up to 500 mg twice daily * Famciclovir up to 500 mg/day for VZV/herpes simplex virus (HSV) prophylaxis; limited treatment courses at higher doses for VZV infections are permissible if treatment duration does not exceed 14 days total * Short courses of IV cidofovir for ADV (up to two doses)
- OBSERVATIONAL COHORT: Clinically significant CMV infection during the 100 days following HCT. Clinically significant CMV infection defined as either CMV viremia requiring preemptive therapy with CMV antivirals or CMV end organ disease (EOD)
- OBSERVATIONAL COHORT: Grade 3-4 graft versus host disease (GVHD)
- OBSERVATIONAL COHORT: Cord blood as cell source for HCT
- OBSERVATIONAL COHORT: Treatment with systemic steroids (> 0.5 mg/kg for 2 weeks or longer) within 3 weeks prior to enrollment
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04017962.
PRIMARY OBJECTIVE:
I. To evaluate the efficacy of letermovir (LTV) in preventing cytomegalovirus (CMV) infection among patients receiving allogeneic hematopoietic cell transplant with history of CMV infection and who are at high risk of recurrent CMV infection, as assessed by the rate of breakthrough clinically significant CMV infection by week 14.
SECONDARY OBJECTIVES:
I. The cumulative incidence of clinically significant CMV infection at 14 weeks will be estimated separately for patients who have undetectable CMV and detectable CMV at baseline.
II. To estimate the extended efficacy of LTV by the cumulative incidence of clinically significant CMV infection through week 24.
III. To assess the efficacy of LTV via additional endpoints:
IIIa. Time to onset of clinically significant CMV infection among patients treated with LTV.
IIIb. Number of days free of CMV viremia, CMV end organ disease (EOD), CMV antivirals, alive, and out of hospital through week 14.
IIIc. Utilization of CMV antivirals (type and duration) through week 24.
IIId. Number and reason(s) for readmissions and hospital length of stay (LOS) through week 24.
IIIe. Invasive procedures (endoscopy, bronchoscopy, etc.) through week 24.
IIIf. All-cause and non-relapse mortality at week 24.
IV. To determine the proportion of patients who develop LTV resistance (determined using CMV isolates from patients with CMV viremia during the study).
V. To assess the occurrence of serious adverse events (SAEs) and toxicity leading to LTV discontinuation.
VI. To assess CMV-cell mediated immunity (CMI) at day (D) +100 in a secondary observational cohort of hematopoietic cell transplantation (HCT) recipients that received LTV prophylaxis and did not have clinically significant infection.
OUTLINE:
INTERVENTIONAL COHORT: Patients receive letermovir orally (PO) once daily (QD) (or intravenously [IV] over 1 hour for patients unable to receive PO) for 14 weeks in the absence of disease progression or unacceptable toxicity.
OBSERVATIONAL COHORT: Patients undergo collection of blood samples for CMV-CMI analysis via CMV immunity T cell panel assay on day 100. Patients with negative CMI on day 100 undergo collection of blood samples for retesting on day 180.
After completion of study treatment, patients are followed up at 16, 20, and 24 weeks.
Trial PhasePhase II
Trial Typeprevention
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorGenovefa A. Papanicolaou
- Primary ID19-174
- Secondary IDsNCI-2019-05122
- ClinicalTrials.gov IDNCT04017962