Letermovir Treatment for Refractory or Resistant Cytomegalovirus Infection

NCT03728426 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 18-348
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 4

Brief Summary

The trial will evaluate the safety and efficacy of letermovir antiviral treatment of active cytomegalovirus infection or cytomegalovirus disease in patients with infections that are refractory or resistant to available treatments or who are experiencing organ dysfunction that makes unsafe the use of available antiviral treatments.

Conditions

Cytomegalovirus Infections

Keywords

Cytomegalovirus Infections; CMV

Outcome Measures

Primary Outcomes (1)

• Virological Response on Treatment Week 6

  The virologic response milestones are defined as: 1) Any decrease in CMV DNA from baseline (Week 0), measured on week 3 and 2) A ≥2 log decrease in CMV DNA from baseline, or an undetectable CMV DNA, measured on week 6. For patients with clinical CMV disease, the clinical response milestones are defined as: 1) Stabilization of clinical disease by week 3 (i.e. no worsening signs or symptoms compared to week 1) as assessed by the site investigator and 2) Improvement or resolution of clinical disease by week 6 (i.e., improvement in signs and symptoms of affected organs \[resolution of diarrhea, pneumonia, hepatitis, retinitis, etc.\]) 3) Patients with clinical CMV disease should also meet virological response milestones outlined above to support the continuation of letermovir therapy. Patients who enter the study based solely on documented CMV disease by histopathology in the absence of quantifiable CMV virus load should remain nonquantifiable (less than 137 IU/mL).

  6 weeks

Secondary Outcomes (5)

• Overall Survival

  6 months

• CMV Progression-free Survival

  6 months

• Kinetics of Viral Clearance

  6 months

• Percent of Patients With a Clinically Meaningful Treatment Response to Letermovir Treatment

  6 Weeks

• Emergence of Letermovir-resistant CMV Virus in Patients Treated in This Setting

  6 months

Study Arms (1)

Letermovir

EXPERIMENTAL

Open label letermovir will be administered daily for up to 12 weeks. The study allows an optional additional 12 weeks of treatment for secondary prophylaxis if clinically indicated.

Drug: Letermovir

Interventions

Letermovir DRUG

Patients will receive intravenous or oral letermovir at a dose of 480mg/day. Patients weighing 40 or more kilograms will receive a second, loading, dose 12 hours after the first dose of letermovir treatment. For patients receiving concomitant cyclosporine treatment, the letermovir dose will be 240mg/day.

Also known as: Prevymis

Letermovir

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥12 years
• Weight ≥30 kg
• Transplant recipient (HCT, SOT) or other immunocompromised patients including those with HIV infection that require antiviral treatment for CMV.
• Documented CMV disease or persistent CMV infection (CMV virus load above 500 IU/mL on consecutive measurements, at least one day apart).
• CMV infection is refractory to treatment (defined as ≥14 days of standard CMV treatment without clinical improvement for CMV disease, or failure to achieve \>1 log reduction in CMV VL after ≥14 days of standard treatment for CMV infection)16,17
• Current CMV infection has documented genotypic resistance to ganciclovir or foscarnet.
• For patients with any prior CMV infection episode that broke through letermovir prophylaxis, but not during the current CMV infection, documentation of letermovir susceptibility testing should demonstrate absence of letermovir mutations known to confer resistance to letermovir.
• Severe myelosuppression (ANC \<1000/µL, Hemoglobin \<8g/dL, or Platelets \<25,000/µL)17 or renal dysfunction (estimated creatinine clearance \<60 mL/min by MDRD in adults or \< 60 ml/min/1.73 m2 by bedside Schwartz equation in \< 18 years-old) at baseline or which develops during antiviral treatment.
• Patients who develop severe myelosuppression or renal dysfunction during antiviral treatment as defined above are eligible without having to meet the refractoriness/antiviral resistance criterion.
• Combinations of genotypic antiviral resistance and organ dysfunction that lead to eligibility are presented in the full protocol eligibility table.
• The effects of letermovir on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 3 months after completion of letermovir administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of letermovir administration.
• Patients of childbearing potential must have a negative serum or urine pregnancy test.
• Able to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to letermovir.
• Known history of cirrhosis with Child-Pugh Class C hepatic insufficiency at screening.
• Acute liver injury at baseline meeting Hy's law.
• Current CMV infection broke through letermovir prophylaxis.
• Patients with life expectancy of less than a week. Determination of life expectancy will be discussed with the patient's primary treatment physician.
• Patient taking strong inhibitors or inducers of hepatic CYP enzymes including rifampicin, phenytoin, clarithromycin, ritonavir, or cobicistat.
• HIV patients who are receiving antiretroviral treatment protease inhibitors (darunavir, lopinavir, etc) whether by themselves or boosted with ritonavir or cobicistat, or HIV patients receiving cyclosporine treatment due to strong drug-drug interactions.
• Combinations of genotypic antiviral resistance and organ dysfunction that do not meet eligibility criteria are described in the full protocol eligibility table.

Sponsors & Collaborators

• Amy C. Sherman, MD: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (4)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02214, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (2)

• Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-2444. doi: 10.1056/NEJMoa1706640. Epub 2017 Dec 6.

  PMID: 29211658 BACKGROUND

• Imlay HN, Kaul DR. Letermovir and Maribavir for the Treatment and Prevention of Cytomegalovirus Infection in Solid Organ and Stem Cell Transplant Recipients. Clin Infect Dis. 2021 Jul 1;73(1):156-160. doi: 10.1093/cid/ciaa1713.

  PMID: 33197929 DERIVED

MeSH Terms

Conditions

Cytomegalovirus Infections

Interventions

letermovir

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Limitations and Caveats

This study did not reach the target number of participants needed to achieve target power and statistically reliable results. The study was closed early due to difficulty in recruiting during the COVID-19 pandemic.

Results Point of Contact

• Title: Dr. Amy Sherman
• Organization: Brigham and Women's Hospital/Dana-Farber Cancer Institute

acsherman@bwh.harvard.edu

6175253575

Study Officials

• Amy C Sherman, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 31, 2018
• First Posted: November 2, 2018
• Study Start: January 11, 2019
• Primary Completion: March 28, 2022
• Study Completion: March 28, 2022
• Last Updated: March 8, 2023
• Results First Posted: March 8, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)