Letermovir for CMV Prophylaxis After Cell Therapy

Overseen By George Chen, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: High dose acyclovir, valacyclovir

Disqualifiers: Uncontrolled illness, Pregnant, CMV infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 98 days

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether Letermovir can prevent CMV, a virus, from reactivating in individuals undergoing certain cell therapies. Participants must have a lymphoma diagnosis, plan to undergo a common cell therapy, and test positive for past CMV exposure. The trial aims to find a reliable method to prevent the virus from reactivating, a significant concern after cell therapy. Participants must adhere to study rules and not receive other conflicting CMV treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot take high doses of acyclovir or valacyclovir for CMV prevention. Lower doses for other conditions are allowed.

Is there any evidence suggesting that Letermovir is likely to be safe for humans?

Research shows that Letermovir is safe for use. In earlier studies, Letermovir proved effective and safe in preventing CMV (cytomegalovirus) infections, especially in transplant patients. One study found that Letermovir worked well and caused few harmful side effects. Another study showed that using Letermovir for up to 200 days was safe and helped lower the risk of serious CMV infections. Overall, Letermovir is well-tolerated, with few reports of major problems in those who have taken it. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for CMV?

Letermovir is unique because it specifically targets the CMV virus, which can be a serious threat after cell therapy, like stem cell transplants. Unlike traditional antiviral drugs that can have broad-spectrum effects and cause significant side effects, Letermovir offers a targeted approach, potentially reducing these unwanted effects. Researchers are excited because Letermovir has a novel mechanism of action; it inhibits the CMV DNA terminase complex, which is different from how other antivirals work. This targeted mechanism could mean a safer and more effective prophylactic option for patients undergoing cell therapy.

What evidence suggests that Letermovir might be an effective treatment for CMV?

Research has shown that Letermovir effectively prevents CMV (cytomegalovirus) recurrence, particularly in transplant patients. Studies have found that a daily dose of 240 mg of Letermovir effectively stops CMV from appearing in the blood after a transplant. It is generally safe for patients due to its low toxicity. Another study found that using Letermovir for CMV prevention can also reduce overall treatment costs for high-risk patients. Additionally, Letermovir has been linked to better survival rates without disease recurrence after stem cell transplants. Participants in this trial will receive Letermovir as part of an open-label, single-arm study to evaluate its effectiveness in CMV prophylaxis after cell therapy. ^{1 4 6 7 8}

Who Is on the Research Team?

George Chen, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 who are scheduled to receive standard-of-care axicabtagene ciloleucel (AXI-CEL) therapy, have a performance status indicating they can carry out daily activities with ease or with some limitation, and are CMV seropositive. They must have adequate kidney function and liver function (if liver disease is present), and agree to use contraception if of child-bearing potential.

Inclusion Criteria

I am fully active or can carry out light work.

My liver disease is mild to moderate.

I am scheduled for standard AXI-CEL therapy.

Exclusion Criteria

I am not pregnant or breastfeeding.

I am planned to receive high-dose treatments for CMV prevention.

I tested positive for CMV recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Letermovir for CMV prophylaxis after AXI-CEL therapy

98 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Letermovir

Trial Overview

The study aims to determine the effectiveness of Letermovir in preventing Cytomegalovirus (CMV) reactivation in patients undergoing AXI-CEL therapy. It's an open-label pilot trial, meaning both researchers and participants know what treatment is being given.

How Is the Trial Designed?

Group I: Open label Single arm: Letermovir Experimental Treatment 1 Intervention

Participants will be identified/recruited/screened from the Lymphoma and Stem Cell Transplantation and Cellular Therapy services at MD Anderson Cancer Center.

Letermovir is already approved in United States, European Union for the following indications:

Approved in United States as Prevymis for:

• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
• Prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-])
• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
• Prophylaxis of cytomegalovirus (CMV) disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-])

Approved in European Union as Prevymis for:

• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
• Prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-])

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

Letermovir, an anti-CMV drug, was successfully used to treat ganciclovir-resistant CMV colitis in a heart transplant recipient, demonstrating its potential as a curative option.

In a second case, while letermovir was used as pre-emptive therapy for CMV reactivation, it did not prevent CMV esophagitis, indicating that while effective for secondary prophylaxis, it may not always prevent all forms of CMV-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir use to treat complex cytomegalovirus reactivations in two heart transplant recipients. Boignard, A., Augier, C., Kheng, M., et al.[2022]

In a retrospective analysis of patients who underwent allogeneic hematopoietic stem cell transplantation, letermovir prophylaxis significantly reduced the incidence of clinically significant CMV infections (30.2% vs. 71.6% in the control group) within 100 days, indicating its efficacy in preventing CMV reactivation.

The study also found that letermovir prophylaxis was associated with lower non-relapse mortality (4.7% vs. 19.8% at day 500), and identified that receiving a transplant from a CMV seronegative donor to a seropositive recipient increased the risk of CMV infection even with letermovir treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation. Mizuno, K., Sakurai, M., Kato, J., et al.[2022]

Letermovir, a new antiviral drug approved for preventing CMV after hematopoietic cell transplantation, was used successfully as a salvage treatment for four solid organ transplant recipients with ganciclovir-resistant CMV retinitis, leading to clinical improvement without adverse effects.

Despite initial success, three out of four patients could not maintain virologic suppression, with two developing resistance to letermovir during treatment, highlighting the need for careful monitoring and potential limitations of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Letermovir as Salvage Therapy for Drug-Resistant Cytomegalovirus Retinitis. Turner, N., Strand, A., Grewal, DS., et al.[2020]

In a study of 80 CMV-seropositive adult patients receiving letermovir as secondary prophylaxis after hematopoietic cell transplantation, the treatment was well tolerated and showed a low rate of breakthrough infections (5.5%), indicating its potential effectiveness in preventing CMV reactivation in high-risk patients.

Letermovir was administered for a median of 118 days, providing a crucial bridge between initial CMV treatment and immune recovery, although further research is needed to confirm these findings and assess long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir for Secondary Prophylaxis of Cytomegalovirus Infection and Disease after Allogeneic Hematopoietic Cell Transplantation: Results from the French Compassionate Program. Robin, C., Thiebaut, A., Alain, S., et al.[2021]

In a study of adult patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT), the use of letermovir significantly reduced the incidence of clinically significant CMV infections in high-risk patients from 51.6% to 10.5% by week 14, demonstrating its efficacy in prophylaxis.

A risk-based strategy for administering letermovir also benefited low-risk patients, where even a limited use of the drug led to a significant reduction in CMV infection rates, indicating that not all patients may need letermovir while still maintaining overall safety and survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The promising efficacy of a risk-based letermovir use strategy in CMV-positive allogeneic hematopoietic cell recipients. Sourisseau, M., Faure, E., Béhal, H., et al.[2023]

Letermovir (Prevymis™) is an effective prophylactic treatment for preventing cytomegalovirus (CMV) infection and disease in adult patients who are CMV-seropositive and have received an allogeneic hematopoietic stem cell transplant, with approvals in Canada and the USA.

The drug works by inhibiting the CMV DNA terminase complex and has received positive regulatory feedback in Europe, indicating its potential for broader international use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir: First Global Approval. Kim, ES.[2019]

In a study of 204 adult CMV-seropositive allo-SCT recipients treated with letermovir for CMV prophylaxis, the cumulative incidence of clinically significant CMV infection was low, at 5.4% by day +100 and 18.1% by day +168, indicating letermovir's efficacy in a real-world setting.

The treatment was generally safe, with low to mild adverse events reported in 40.7% of patients, primarily gastrointestinal issues and skin rashes, suggesting that letermovir is a well-tolerated option for CMV prevention in high-risk transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir Prophylaxis for Cytomegalovirus Infection in Allogeneic Stem Cell Transplantation: A Real-World Experience. Martino, M., Pitino, A., Gori, M., et al.[2021]

Letermovir, a new anti-CMV drug with fewer side effects, was successfully used off-label to treat a heart transplant recipient with ganciclovir-resistant CMV colitis, highlighting its potential as an alternative treatment.

The case suggests that monitoring CMV-pp65 antigenemia levels could be a useful additional marker for assessing the efficacy of letermovir treatment, alongside traditional CMV-DNA PCR levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment with Letermovir in a Heart Transplant Recipient with UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Colitis and Viremia. Yanase, T., Hatano, M., Bujo, C., et al.[2023]

Letermovir significantly reduces the risk of clinically significant CMV infection in CMV-seropositive patients after allogeneic hematopoietic stem cell transplantation, based on a phase 3 study with 495 participants.

Unlike traditional antiviral prophylaxis, letermovir is well tolerated and does not cause myelosuppression or nephrotoxicity, making it a promising first-line option for CMV prevention in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of letermovir for prevention of cytomegalovirus infection after allogeneic haematopoietic stem cell transplantation. Razonable, RR.[2019]

In a 6-year post-marketing surveillance study involving 461 Japanese patients who received allogenic hematopoietic stem-cell transplantation, letermovir was found to be safe, with 13.9% experiencing adverse drug reactions, primarily renal impairment and nausea.

The effectiveness of letermovir for CMV prophylaxis was confirmed, with CMV antigen positivity rates of 21.2% at Week 14 and 37.5% at Week 24 after transplantation, indicating its role in reducing CMV infection risk in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of Letermovir in Allogenic Hematopoietic Stem Cell Transplantation Recipients: Interim Report of Post-marketing Surveillance in Japan. Hiraishi, I., Ueno, R., Watanabe, A., et al.[2022]

In a study of 87 allogeneic hematopoietic cell transplant recipients, extending letermovir prophylaxis beyond 100 days resulted in a lower rate of CMV reactivation (19%) compared to the standard duration group (28%).

The study suggests that longer letermovir prophylaxis may be beneficial in reducing CMV reactivation without increasing all-cause mortality, indicating a potential strategy for improving outcomes in CMV seropositive patients post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended duration letermovir in allogeneic hematopoietic stem cell transplant. Hinman, B., Cox, J., Umoru, G., et al.[2023]

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Letermovir at a dose of 240 mg per day was highly effective in preventing CMV viremia after engraftment in transplant recipients and had little toxicity.

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In this study, LTV prophylaxis was associated with a decreased total cost of care for HR CMV patients through day+180.

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CMV prophylaxis with letermovir significantly improves ...

CMV prophylaxis with letermovir significantly improves graft and relapse free survival following allogeneic stem cell transplantation.

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The hypothesis being tested was that MK-8228 is superior to placebo in the prevention of clinically-significant CMV infection through Week 24 post-transplant.