A Study of the Drug Letermovir (LTV) as Prevention for Recurrent of Cytomegalovirus (CMV) Infection

An Open-label, Single-arm Study of Letermovir (LTV) for Prevention of Recurrent CMV Infection in High-risk Hematopoietic Cell Transplant (HCT) Recipients

The purpose of this study is to determine of letermovir (LTC) is effective at preventing Cytomegalovirus (CMV) infection from returning in people who have already had CMV infection after a bone marrow transplant.

Study Overview

• Status: Recruiting
• Conditions: CMV; CMV Infection; Hematopoietic Cell Transplant
• Intervention / Treatment: Drug: Letermovir Pill; Other: blood draw

• Study Type: Interventional
• Enrollment (Estimated): 106
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Genovefa Papanicolaou, MD; Phone Number: 347-501-0044; Email: papanicg@mskcc.org
• Study Contact Backup: Name: Yeon Joo Lee, MD; Phone Number: 212-639-8180; Email: leey3@mskcc.org

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • University of Minnesota
      • Contact: Jo-Anne Young, MD; Phone Number: 612-624-9996
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Genovefa Papanicolaou, MD; Phone Number: 347-501-0044

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >/= 12 years (any weight)
• Have received allogenic 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 prior to enrollment (see also exclusion criteria below).

• Have one or more risk factors for recurrent CMV infection:

  1. 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 -DRC1gene loci, or
     • Cord blood as stem cell source
  2. Acute or chronic GVHD requiring either topical steroids for gastrointestinal GVHD and/or systemic steroid treatment (>/= 1mg/kg/day of prednisone or equivalent dose of another corticosteroid) within 14 days prior to enrollment
  3. 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.

Subject eligibility criteria for the observational cohort:

• Age 18 years or older
• First allogenic peripheral blood or marrow HCT
• 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) </= mL/min/1.73m^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 > 500mg twice daily), or famciclovir (doses > 500mg/day) for varicella zoster virus (VZV)/herpes simplex virus prophylaxis; limited treatment courses at higher doses for VZV infections are permissible if treatment duration dose not exceed 14 days total. Short courses of IV cidofovir for adeno virus (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 ontraindicated 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 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 of 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/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)

Exclusion criteria for 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)
• Grade 3-4 GVHD
• Cord blood as cell source for HCT
• Treatment with systemic steroids (>0.5mg/kg for 2 weeks or longer) within 3 weeks prior to enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Hematopoietic cell transplantation/HCT; Participants will be hematopoietic cell transplantation (HCT) recipients with a history of CMV infection. INTERVENTIONAL COHORT: Patients receive letermovir PO QD (or 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.

Drug: Letermovir Pill; Patients enrolled on the study will receive oral LTV 480 mg daily (240 mg daily for patients receiving cyclosporine A). The maximum duration of LTV administration will be 14 weeks. Patients receiving oral medication will be administered a pill diary for drug compliance purposes. This will be administered and reconciled in clinic.; Other Names: LTV; Other: blood draw; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The rate of breakthrough clinically significant Cytomegalovirus (CMV) infection by week 14	up to 24 weeks from time of study treatment

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Genovefa Papanicolaou, Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2019
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: July 10, 2019
• First Submitted That Met QC Criteria: July 10, 2019
• First Posted (Actual): July 12, 2019

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Memorial Sloan Kettering Cancer Center; HCT; Letermovir; CMV infection; LTV; 19-174
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Cytomegalovirus Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Letermovir
• Other Study ID Numbers: 19-174

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No