Infections

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Cytomegalovirus Infections

Disease Attributes

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Cyclosporine

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Letermovir

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Enzyme Inhibitors

Antiviral Agents

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.

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.

Letermovir Pill

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.

blood draw

Genovefa Papanicolaou, MD

Yeon Joo Lee, MD

Jo-Anne Young, MD

Genovefa Papanicolaou

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.

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

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.

Merck Sharp & Dohme LLC

Memorial Sloan Kettering Cancer Center

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Syndrome

Lymphoma

Lymphoma, T-Cell

Lymphoma, T-Cell, Peripheral

Lymphoma, T-Cell, Cutaneous

Leukemia

Leukemia, Lymphoid

Hematologic Neoplasms

Leukemia, Lymphocytic, Chronic, B-Cell

Leukemia, Prolymphocytic

Leukemia, Prolymphocytic, T-Cell

Sezary Syndrome

Leukemia, Prolymphocytic, B-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Lymphoma, Non-Hodgkin

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B Cell Prolymphocytic Leukemia

Vitamins

Acetic Acid

Piperazine

Mebendazole

Piperazine citrate

DMP 777

Alemtuzumab

Retinol acetate

Anti-Bacterial Agents

Beginning within 7 days of the first administration of standard alemtuzumab, patients receive letermovir PO (or IV over 1 hour if patient is unable to take PO for an extended period of time) daily on days 1-28. Cycles repeat every 28 days for up to 3 months after the last dose of alemtuzumab in the absence of unacceptable toxicity.

John C Reneau, MD

This phase II trial studies how well letermovir works for the prevention of cytomegalovirus reactivation in patients with hematological malignancies treated with alemtuzumab. Patients receiving treatment with alemtuzumab may experience cytomegalovirus reactivation. Letermovir may block cytomegalovirus replication and prevent infection.

PRIMARY OBJECTIVE:

I. To estimate the rate of cytomegalovirus (CMV) reactivation in patients treated with letermovir at 3 months after completion of alemtuzumab therapy.

SECONDARY OBJECTIVES:

I. To evaluate the tolerability of letermovir in combination with alemtuzumab.

II. To evaluate the efficacy of letermovir for the prevention of clinically significant CMV disease.

III. To estimate the progression free survival of patients in the study population.

IV. To estimate the overall survival of patients in the study population.

EXPLORATORY OBJECTIVE:

I. To evaluate mechanisms of antiviral resistance in letermovir prophylaxis failures.

OUTLINE:

Beginning within 7 days of the first administration of standard alemtuzumab, patients receive letermovir orally (PO) (or intravenously \[IV\] over 1 hour if patient is unable to take PO for an extended period of time) daily on days 1-28. Cycles repeat every 28 days for up to 3 months after the last dose of alemtuzumab in the absence of unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Letermovir for the Prevention of Cytomegalovirus Reactivation in Patients With Hematological Malignancies Treated With Alemtuzumab

Letermovir for Cytomegalovirus Prophylaxis in Patients With Hematological Malignancies Treated With Alemtuzumab

CMV DNA sequence analysis to be performed only in subjects with CMV reactivation. Resistance to letermovir will be monitored by retrospective genotypic analysis of the CMV terminase genes in CMV DNA extracts from selected plasma samples collected at the time of diagnosed CMV reactivation. Samples will be analyzed by standard population sequencing technology through an established contract laboratory with validated protocols in place.

Defined as the proportion of patients who experience CMV reactivation (CMV deoxyribonucleic acid \[DNA\] by real time polymerase chain reaction \> 500 IU/mL) during prophylaxis period among all patients who receive \>= 90% of planned letermovir doses. The rate will be provided with 95% binomial confidence interval.

Adverse event data will be described and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 guidelines. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns, especially for grade 3 or above adverse events. To assess tolerability, will also capture the proportion of patients who go off treatment due to adverse events.

Clinically significant CMV reactivation be determined per the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum.

PFS will be estimated with the method of Kaplan-Meier (KM), where KM curves will be drawn to aid with visualization and estimates provided with 95% confidence intervals.

OS will be estimated with the method of KM, where KM curves will be drawn to aid with visualization and estimates provided with 95% confidence intervals.

Ohio State University Comprehensive Cancer Center

Principal Investigator

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.

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.

Biospecimen Collection

Caitlin W Elgarten

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.

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.

A Study of the Drug Letermovir as Prevention of Cytomegalovirus Infection After Stem Cell Transplant in Pediatric Patients

Letermovir Prophylaxis for Cytomegalovirus in Pediatric Hematopoietic Cell Transplantation

Will be assessed using a competing risks analysis (stratified by CMV risk) using Gray's test will compare time from transplant to onset of clinically significant CMV infection between arms. A Fine and Gray model will estimate the HR and one-sided upper bound of the 95% CI. Death and relapse occurring prior to CMV infection will be considered as competing events.

Will be assessed using a standard survival analysis and log-rank test will be used to evaluate time from transplant to death between arms. A cox proportional hazard model will estimate the HR and 2-sided 95%CI.

Will be assessed using competing risks analysis using Gray's test. A Fine and Gray model will estimate the HR and 2-sided 95% CI.

Neutropenia will be defined as an absolute neutrophil count \< 500 cells/uL. Poisson regression will be used to compare the number of weeks neutropenia was detected across the two study arms accounting for observation weeks as the offset.

Acute kidney injury will be defined as grade 3 or higher creatinine elevation using the common terminology criteria for adverse events (CTCAE) v5 definitions. Competing risks analysis using Gray's test will compare time from transplant to acute kidney injury between arms. Death will be considered a competing event. A Fine and Gray model will estimate the HR and 2-sided 95% CI.

Chronic kidney disease outcome will be defined as grade 2 or higher using the CTCAE v5 definitions. Competing risks analysis using Gray's test will compare time from transplant to chronic kidney disease between arms. Death will be considered a competing event. A Fine and Gray model will estimate the HR and 2-sided 95% CI.

Will be assessed using poisson regression accounting for observation days as the offset. Observation days will be defined as the total days from the transplant date to the earliest of relapse, death, or end of Week 14- or one-year-post transplant for the two respective analyses.

Will be assessed by quantifying the total number or resistant isolates and then describe the incidence of resistance to antiviral medications among the patients who develop clinically significant CMV infection on letermovir and those on no prophylaxis. This analysis will be restricted to patients with viral loads \> 1000 IU/mL.

Will be assessed by the median CD4+ and CD8+ lymphocyte counts obtained as a part of standard-of-care separately, between patients who received letermovir versus those who received no prophylaxis using the Mann-Whitney U test.

Will be assessed using a standard Kaplan Meier survival analysis.

Will be 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 be determined based on central review of data collected by clinical research associates (CRAs) and submitted by participating centers. Competing risks analysis (stratified by CMV risk) using Gray's test will be used to evaluate time from transplant to onset of clinically significant CMV infection between arms. The final observed Gray's test statistic will be compared against 1.6997 rather than 1.65 to account for an efficacy interim analysis. A Fine and Gray model, adjusted for baseline CMV risk, will estimate the hazard ratio (HR) and one-sided upper bound of the 95% confidence interval (CI).

Will be assessed using competing risks analysis (stratified by CMV risk) using Gray's test will compare time from transplant to first detection of CMV DNAemia, defined as any detectable CMV by plasma PCR. A Fine and Gray model, adjusted for baseline CMV risk, will estimate the HR and one-sided upper bound of the 97.5% CI. Death and relapse occurring prior to CMV DNAemia will be considered as competing events.

Will be assessed using a competing risks analysis (stratified by CMV risk) using Gray's test will compare the 24 week CMV-free survival rate between the study arms. CMV DNAemiaand death will be considered events of interest. A Fine and Gray model, adjusted for baseline CMV risk, will estimate the HR and one-sided upper bound 97.5% CI.

Children's Oncology Group

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Leukemia, Myeloid, Chronic-Phase

Hodgkin Disease

Myeloproliferative Disorders

Primary Myelofibrosis

Leukemia, Myeloid, Accelerated Phase

Bone Marrow Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Myeloid Leukemia

Hodgkin Lymphoma

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

Vaccines

Immunologic Factors

Patients receive letermovir per SOC on days 7-100 and multi-peptide CMV-modified vaccinia Ankara vaccine IM on days 100 and 128 post-HCT.

Patients receive letermovir per SOC on days 7-100 and placebo IM on days 100 and 128 post-HCT.

Multi-peptide CMV-Modified Vaccinia Ankara Vaccine

Placebo Administration

Ryotaro Nakamura

This phase II trial studies how well Triplex vaccine works in preventing cytomegalovirus (CMV) infection in patients undergoing a hematopoietic stem cell transplantation. CMV is a virus that may be carried for life and does not cause illness in most healthy individuals. However, in people whose immune systems are lowered (such as those undergoing stem cell transplantation), CMV can reproduce and cause disease and even death. The Triplex vaccine is made up of 3 small pieces of CMV deoxyribonucleic acid (DNA) (the chemical form of genes) placed into a weakened virus called modified vaccinia Ankara (MVA) that may help produce immunity (the ability to recognize and respond to an infection) and reduce the risk of developing complications related to CMV infection.

PRIMARY OBJECTIVE:

I. To determine if CMV-MVA multi-peptide CMV-modified vaccinia Ankara vaccine (Triplex) reduces the frequency of clinically significant CMV reactivation in CMV positive (+) haploidentical hematopoietic cell transplantation (haploHCT) adult recipients from when letermovir (Prevymis) prophylaxis is stopped at day (d)100 until d180 post HCT.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of Triplex in vaccinated, haploHCT recipients by assessing the following: non-relapse mortality (NRM) at d180 post-HCT, severe (grade 3-4) acute graft versus host disease (GVHD), and grade 3-4 adverse events (AEs) (Common Terminology Criteria for Adverse Events \[CTCAE\] 5.0) probably or definitely related to the vaccination within 2 weeks from each vaccination at d180 post-HCT.

II. To characterize CMV related events in recipients of Triplex compared to placebo, by assessing time-to viremia (number of days from d100 to the date of \>= 625 IU/mL), duration of viremia, recurrence of viremia, incidence of late CMV viremia/disease (\>= 625 IU/mL, \> 200 and =\< 365 days post-HCT), use of antiviral drugs (triggered by clinically significant viremia), cumulative number of CMV specific antiviral treatment days.

III. To evaluate the impact of Triplex on transplant related outcomes up to d365 post-HCT by assessing the incidence of acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, non-relapse mortality, all-cause mortality, infections.

IV. To determine if Triplex increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated compared to placebo treated, CMV seropositive HCT-recipients.

V. To determine whether vaccination induces adaptive natural killer (NK) cell population changes, and increase in the highly cytotoxic memory NKG2C+ NK cells.

VI. To compare GVHD biomarkers between the vaccine and placebo groups up to d365 post-HCT.

VII. To determine if immunity to 3 CMV antigens contained in the Triplex vaccine correlates with protection against CMV events, and if T-cell increases reflect vaccine response and exceed placebo immune response levels up to d365 post-HCT.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive letermovir per standard of care (SOC) on days 7-100 and multi-peptide CMV-modified vaccinia Ankara vaccine intramuscularly (IM) on days 100 and 128 post-HCT.

ARM II: Patients receive letermovir per SOC on days 7-100 and placebo IM on days 100 and 128 post-HCT.

After completion of study treatment, patients are followed up to 365 days post-HCT and then for an additional 2 years post-HCT.

Triplex Vaccine in Preventing CMV Infection in Patients Undergoing Hematopoietic Stem Cell Transplantation

A Phase II Randomized, Placebo-Controlled, Multicenter Trial to Evaluate the Protective Function of CMV-MVA Triplex Vaccine in Adult Recipients of Haploidentical Hematopoietic Stem Cell Transplant

Will be defined by histology. Will compare vaccine and placebo regarding cumulative incidence of CMV events from first injection to day 180 post HCT using Gray's test.

Cumulative incidence curves and Gray's test will be used.

Adverse events probably or definitely related to the vaccination and modified vaccinia Ankara vector persistence will be evaluated. Final analysis of HCT-recipients safety will be based on comparison of vaccine and placebo regarding severe GVHD, immune reconstitution, and survival. Comparisons will be made using standard methods for right-censored data with interim analysis using standard group-sequential testing. Will plan a 2\^0 analysis comparing event-free survival in both arms.

Will be compared using Kaplan-Meier curves and log-rank test.

Levels and kinetics of CMV-specific T cell immunity combined with immunophenotyping and functional studies will be evaluated.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of the Drug Letermovir (LTV) as Prevention for Recurrent of Cytomegalovirus (CMV) Infection	NCT04017962	CMV CMV Infection Hematopoietic C...	Letermovir Pill blood draw	12 Years -	Memorial Sloan Kettering Cancer Center
Letermovir for the Prevention of Cytomegalovirus Reactivation in Patients With Hematological Malignancies Treated With Alemtuzumab	NCT04312841	B-Cell Prolymph... Chronic Lymphoc... Peripheral T-Ce... Primary Cutaneo... Sezary Syndrome T-Cell Prolymph...	Letermovir	18 Years -	Ohio State University Comprehensive Cancer Center
A Study of the Drug Letermovir as Prevention of Cytomegalovirus Infection After Stem Cell Transplant in Pediatric Patients	NCT05711667	Hematopoietic a... Malignant Solid...	Biospecimen Col... Letermovir	2 Years - 18 Years	Children's Oncology Group
A Study of the Drug Letermovir (LTV) as Prevention for Recurrent of Cytomegalovirus (CMV) Infection	NCT04017962	CMV CMV Infection Hematopoietic C...	Letermovir Pill blood draw	12 Years -	Memorial Sloan Kettering Cancer Center
Letermovir for the Prevention of Cytomegalovirus Reactivation in Patients With Hematological Malignancies Treated With Alemtuzumab	NCT04312841	B-Cell Prolymph... Chronic Lymphoc... Peripheral T-Ce... Primary Cutaneo... Sezary Syndrome T-Cell Prolymph...	Letermovir	18 Years -	Ohio State University Comprehensive Cancer Center
A Study of the Drug Letermovir as Prevention of Cytomegalovirus Infection After Stem Cell Transplant in Pediatric Patients	NCT05711667	Hematopoietic a... Malignant Solid...	Biospecimen Col... Letermovir	2 Years - 18 Years	Children's Oncology Group
A Study of the Drug Letermovir as Prevention of Cytomegalovirus Infection After Stem Cell Transplant in Pediatric Patients	NCT05711667	Hematopoietic a... Malignant Solid...	Biospecimen Col... Letermovir	2 Years - 18 Years	Children's Oncology Group
Triplex Vaccine in Preventing CMV Infection in Patients Undergoing Hematopoietic Stem Cell Transplantation	NCT04060277	Accelerated Pha... Acute Lymphobla... Acute Myeloid L... Chronic Lymphoc... Chronic Phase C... Hematopoietic a... Hodgkin Lymphom... Lymphoblastic L... Myelodysplastic... Myelofibrosis Myeloproliferat... Non-Hodgkin Lym...	Letermovir Multi-peptide C... Placebo Adminis...	18 Years -	City of Hope Medical Center

Spots Global Cancer Trial Database for letermovir

Every month we try and update this database with for letermovir cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for letermovir

Every month we try and update this database with for letermovir cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for letermovir cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.