Letermovir for Preventing Infection After Stem Cell Transplant in Blood Cancer

Recruiting at 18 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Must not be taking: Pimozide, Ergot alkaloids

Disqualifiers: Pregnancy, Breastfeeding, CMV end organ disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 2

Duration: 14 weeks

143 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that certain medications be stopped at least 14 days before starting the study. These include pimozide, ergot alkaloids, and specific statins if you are taking cyclosporine. Check with the trial team to see if your current medications are on this list.

Is Letermovir safe for humans?

Letermovir has been approved in several countries, including the USA, Canada, and Japan, for preventing cytomegalovirus infection in patients who have had a stem cell transplant. Studies, including a phase III trial, have shown no significant link between the drug's exposure and adverse events, supporting its safety at recommended doses. ^{1 2 3 4 5}

How is the drug Letermovir unique for preventing infection after stem cell transplant in blood cancer?

Letermovir is unique because it specifically targets and prevents infections caused by cytomegalovirus (CMV), a common and potentially serious virus in patients undergoing stem cell transplants, whereas other treatments often focus on maintaining remission or preventing relapse of the cancer itself. ^{6 7 8 9 10}

Research Team

Caitlin W Elgarten

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for children and teens (2-18 years old) who weigh at least 18 kg, are CMV sero-positive, and are planning to have a stem cell transplant. They must be healthy enough for the procedure (Lansky/Karnofsky scores > 50), not need dialysis, and have acceptable liver function tests.

Inclusion Criteria

Patient must be CMV sero-positive (i.e., recipient CMV immunoglobulin G positive)

I am between 2 and 17 years old.

My kidneys work well enough and I'm not on dialysis.

Exclusion Criteria

Hypersensitivity to letermovir or any component of the formulation

I cannot take letermovir by mouth.

All patients and/or their parents or legal guardians must sign a written informed consent

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive letermovir orally or intravenously once daily starting on day +1 post-transplant for 14 weeks

14 weeks

Weekly visits for blood sample collection

Follow-up

Participants are monitored for CMV infection and other outcomes post-treatment

48 weeks

Every 2 weeks until week 24, then at weeks 32, 40, and 52

Treatment Details

Interventions

• Letermovir

Trial Overview The study is testing if Letermovir can prevent cytomegalovirus infection in pediatric patients after a stem cell transplant. The drug aims to stop the virus from multiplying, potentially preventing or lessening the severity of infections.

Participant Groups

Group I: ARM I (Letermovir prophylaxis) Experimental Treatment 2 Interventions

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.

Group II: ARM II (No prophylaxis) Active Control 1 Intervention

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.

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?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

Findings from Research

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 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]

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 phase III trial, letermovir significantly reduced the rate of clinically significant CMV infection in adult CMV-seropositive patients after hematopoietic stem cell transplantation, demonstrating its efficacy as a prophylactic treatment.

The study found no significant relationship between letermovir exposure and the incidence of adverse events or the timing of CMV infection onset, supporting the current dosing recommendations for the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients. Prohn, M., Cho, CR., Viberg, A., et al.[2022]

In a phase 3 trial involving 202 patients with FLT3-ITD acute myeloid leukaemia, sorafenib maintenance post-transplantation significantly reduced the 1-year cumulative incidence of relapse to 7.0% compared to 24.5% in the control group, indicating its efficacy in preventing relapse after allogeneic stem-cell transplantation.

The treatment was well tolerated, with no treatment-related deaths reported, and the most common adverse events were similar between the sorafenib and control groups, suggesting that sorafenib maintenance is a safe option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Xuan, L., Wang, Y., Huang, F., et al.[2021]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Letermovir: First Global Approval. [2019]

2. Denmark pubmed.ncbi.nlm.nih.gov

Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation. [2022]

3. New Zealand 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. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Absorption, Metabolism, Distribution, and Excretion of Letermovir. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. [2021]

7. Czech Republic pubmed.ncbi.nlm.nih.gov

[Lenalidomide maintenance therapy in patients with multiple myeloma]. [2019]

8. New Zealand pubmed.ncbi.nlm.nih.gov

FLT3 Inhibitors as Maintenance Therapy after Allogeneic Stem-Cell Transplantation. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN). [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Pharmacologic maintenance strategies following allogeneic hematopoietic cell transplantation for acute myeloid leukemia. [2019]