B-Cell Prolymphocytic Leukemia, Chronic Lymphocytic Leukemia, Peripheral T-Cell Lymphoma, Primary Cutaneous T-Cell Non-Hodgkin Lymphoma, Sezary Syndrome, T-Cell Prolymphocytic Leukemia
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGLetermovir
Given PO
Sponsors
Merck Sharp & Dohme LLC
Ohio State University Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of T-cell or B-cell prolymphocytic leukemia, chronic lymphocytic leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, or Sezary syndrome * Intent to treat with alemtuzumab. Monotherapy or combination with chemotherapy is allowed * Confirmed seropositivity for CMV IgG (\>= 0.7 U/mL) within 1 year of first letermovir dose * Confirmed lack of active CMV infection as evidenced by: * Undetectable CMV deoxyribonucleic acid (DNA) by Abbott RealTime CMV in vitro polymerase chain reaction assay (\< 50 IU/mL) within 7 days of first letermovir dose AND * Negative CMV IgM (\< 30 AU/mL) within 7 days of first letermovir dose * Able to provide informed consent * Life expectancy \> 4 months * Eastern Cooperative Oncology Group (ECOG) performance status =\< 3 * Highly unlikely to become pregnant or impregnate a partner by meeting at least one of the following: * A female subject who is not of reproductive potential is eligible without requiring the use of contraception. A female subject who is not of reproductive potential is defined as one who: * Has reached natural menopause (defined as 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone \[FSH\] levels in the postmenopausal range as determined by the local laboratory, or 12 months of spontaneous amenorrhea) OR * Is 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy OR * Has undergone bilateral tubal ligation. Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g., anorexia nervosa) * A male subject who is not of reproductive potential is eligible without requiring the use of contraception. A male subject who is not of reproductive potential is defined as one whom has undergone a successful defined as: * Microscopic documentation of azoospermia OR * A vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post-vasectomy * A male or female subject who is of reproductive potential agrees to true abstinence or to use (or have their partner use) an acceptable method of birth control starting from the time of consent through 90 days after the last dose of study therapy. True abstinence is defined as abstinence in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., abstinence only on certain calendar days, abstinence only during ovulation period, use of symptothermal method, use of post-ovulation methods) and withdrawal are not acceptable methods of contraception. Acceptable methods of birth control are: * Intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, and vasectomy OR use of appropriate double barrier contraception. Hormonal contraceptives (e.g., birth control pills, transdermal patch, or injectables) are also acceptable
Exclusion criteria
* History of confirmed CMV disease within 1 year of study entry * History of prior allogeneic hematopoietic stem cell transplant * End stage renal disease with creatinine clearance \< 10 mL/min as defined by Cockcroft-Gault equation using serum creatinine within 7 days of enrollment * Child-Pugh class C within 7 days of enrollment * Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 5 times the upper limit of normal (ULN) or serum total bilirubin \> 2.5 x ULN * Note: Subjects who meet this exclusion criterion may, at the discretion of the investigator, have one repeat testing done. If the repeat value does not meet this criterion, they may continue in the screening process. Only the specific out of range value should be repeated (not the entire panel) * Both moderate hepatic insufficiency AND moderate renal insufficiency: * Moderate hepatic insufficiency is defined as Child Pugh Class B * Moderate renal insufficiency is defined as a creatinine clearance less than 50 mL/min, as calculated by the Cockcroft-Gault equation * Cytopenias are NOT an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cytomegalovirus (CMV) Reactivation | During prophylaxis treatment (3 months after last dose of alemtuzumab) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events Grade 3 or Above | Up to 30 days post treatment, an average of 5 months | 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. |
| Development of CMV Disease | Up to 2 years | Clinically significant CMV reactivation be determined per the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. |
| Progression Free Survival (PFS) | From trial enrollment to the occurrence of progression and death, assessed up to 2 years | 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. |
| Overall Survival (OS) | From trial enrollment to the occurrence of death due to any cause, assessed up to 2 years | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Genotyping of Mutations in CMV Terminase Complex Genes | Up to 2 years | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Letermovir) 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.
Letermovir: Given PO | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Treatment (Letermovir) |
|---|---|
| Age, Continuous | 74 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Histology CTCL-Sezary Syndrome | 1 Participants |
| Histology Erythrodermic Mycosis Fungoides | 1 Participants |
| Histology T-cell Lymphoproliferative Disorder | 1 Participants |
| Histology T-cll Prolymphocytic Leukemia | 1 Participants |
| Histology Unknown | 2 Participants |
| Performance Status Ambulatory | 1 Participants |
| Performance Status Fully Active | 2 Participants |
| Performance Status Restricted | 2 Participants |
| Performance Status Unknown | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 6 |
| other Total, other adverse events | 3 / 6 |
| serious Total, serious adverse events | 2 / 6 |
Outcome results
Primary
Cytomegalovirus (CMV) Reactivation
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.
Time frame: During prophylaxis treatment (3 months after last dose of alemtuzumab)
Population: Data for this outcome was not collected
Secondary
Development of CMV Disease
Clinically significant CMV reactivation be determined per the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum.
Time frame: Up to 2 years
Population: Data for this outcome was not collected
Secondary
Number of Participants With Adverse Events Grade 3 or Above
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.
Time frame: Up to 30 days post treatment, an average of 5 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Letermovir) | Number of Participants With Adverse Events Grade 3 or Above | Platelet count decreased | 3 participants |
| Treatment (Letermovir) | Number of Participants With Adverse Events Grade 3 or Above | Anemia | 1 participants |
| Treatment (Letermovir) | Number of Participants With Adverse Events Grade 3 or Above | Diarrhea | 1 participants |
| Treatment (Letermovir) | Number of Participants With Adverse Events Grade 3 or Above | White blood cell decreased | 2 participants |
| Treatment (Letermovir) | Number of Participants With Adverse Events Grade 3 or Above | Activated partial thromboplastin time prolonged | 1 participants |
| Treatment (Letermovir) | Number of Participants With Adverse Events Grade 3 or Above | Alkaline phosphatase increased | 1 participants |
| Treatment (Letermovir) | Number of Participants With Adverse Events Grade 3 or Above | Lymphocyte count decreased | 1 participants |
| Treatment (Letermovir) | Number of Participants With Adverse Events Grade 3 or Above | Neutrophil count decreased | 1 participants |
| Treatment (Letermovir) | Number of Participants With Adverse Events Grade 3 or Above | Sinus bradycardia | 1 participants |
Secondary
Overall Survival (OS)
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.
Time frame: From trial enrollment to the occurrence of death due to any cause, assessed up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Letermovir) | Overall Survival (OS) | 8.3 months |
Secondary
Progression Free Survival (PFS)
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.
Time frame: From trial enrollment to the occurrence of progression and death, assessed up to 2 years
Population: Data for this outcome was not collected
Other Pre-specified
Genotyping of Mutations in CMV Terminase Complex Genes
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.
Time frame: Up to 2 years
Population: Data for this outcome was not collected