Letermovir Treatment for Refractory or Resistant Cytomegalovirus Infection

This is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness
of an investigational drug to learn whether the drug works in treating a specific disease.
"Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved letermovir for treatment of
cytomegalovirus infection, but it has approved letermovir for the prevention of
cytomegalovirus infection in bone-marrow transplantation patients.

This is the first time that letermovir will be administered to children in a clinical trial.

Cytomegalovirus (CMV) is a common virus, which a majority of people acquire at some time in
their life. CMV remains in your body, but does not cause symptoms in the majority of people.
Patients with a weakened immune system (a system that protects you from infections) may be
more at risk for the virus becoming active and causing damage to some of your organs,
especially in the gut and lungs. If the virus becomes present above a certain quantity, the
doctor usually prescribes a drug to treat the infection at this stage to avoid damage to the
organs.

In this case, the virus is no longer responding to the prescribed drug, and other drug
options will be harmful to the participant's health. Participants are being invited to take
part in a research study for an investigational drug called letermovir. The purpose of this
study is to find out whether letermovir is as effective and as safe in treating CMV infection
in patients who cannot tolerate standard treatments such as ganciclovir or foscarnet.

Inclusion Criteria:

- 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.

Exclusion Criteria:

- 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.