Letermovir + CMV-TCIP for Cytomegalovirus After Stem Cell Transplant

Overseen By University of California Irvine Medical

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, Irvine

Must not be taking: Ganciclovir, Valganciclovir, Foscarnet, others

Disqualifiers: CMV end-organ disease, Uncontrolled 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 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 14 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 2, prospective cohort clinical trial evaluating the utilization of CMV T Cell Immunity Panel (CMV-TCIP) assay to guide the duration of primary CMV prophylaxis in CMV-seropositive recipients of allogeneic stem cell transplant or recipients receiving a stem cell graft from a CMV serology positive donor.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain antiviral medications like Ganciclovir, Valganciclovir, Foscarnet, and others listed in the exclusion criteria before and during the study. If you are on these medications, you may need to stop them to participate.

What data supports the effectiveness of the drug Letermovir for cytomegalovirus after stem cell transplant?

Letermovir has been shown to significantly reduce the incidence of cytomegalovirus (CMV) infection in patients undergoing stem cell transplants, improving their overall survival. In a study, Letermovir reduced CMV infection rates and the need for CMV treatment compared to another drug, valacyclovir, in transplant patients. ^{1 2 3 4 5}

How is the drug Letermovir + CMV-TCIP different from other treatments for cytomegalovirus after stem cell transplant?

Letermovir is unique because it specifically targets the CMV-terminase complex, which is different from other antiviral drugs, and it is known for having fewer side effects. It is primarily used as a preventive measure in patients who have undergone stem cell transplants, making it a novel option for those at high risk of CMV infection. ^{2 3 6 7 8}

Research Team

Piyanuch Kongtim, MD,PhD

Principal Investigator

Chao Family Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults over 18 who've had a stem cell transplant from a CMV-positive donor or are themselves CMV-positive. They must have good organ function, no recent severe infections, and not be taking certain antiviral drugs. It's not for those with recent CMV disease or allergies to Letermovir.

Inclusion Criteria

Have undetectable CMV DNA from a plasma sample collected within 5 days prior to enrollment

I am able to care for myself but may not be able to do active work.

I had a stem cell transplant less than 28 days ago.

Exclusion Criteria

I had a CMV infection affecting my organs within the last 6 months.

Received within 7 days prior to screening or plans to receive during the study any of the following: Ganciclovir, Valganciclovir, Foscarnet, Acyclovir (> 3200 mg PO per day or > 25 mg/kg IV per day), Valacyclovir (> 3000 mg/day), Famciclovir (> 1500 mg/day), Received within 30 days prior to screening or plans to receive during the study any of the following drugs: cidofovir, CMV hyper-immune globulin, any investigational CMV antiviral agent/biologic therapy, Has suspected or known hypersensitivity to active or inactive ingredients of letermovir formulations, Has an uncontrolled infection on the day of randomization, Requires mechanical ventilation or is hemodynamically unstable at the time of randomization

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CMV-specific T cell immunity directed letermovir prophylaxis guided by CMV-TCIP assay

14 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

38 weeks

Treatment Details

Interventions

• CMV-TCIP
• Letermovir

Trial Overview The study tests if monitoring the immune response to CMV (using the CMV-TCIP assay) can guide how long patients should take Letermovir as prevention against CMV after an allogeneic stem cell transplant.

Participant Groups

Group I: AHCT recipients Experimental Treatment 3 Interventions

CMV-TCIP is already approved in United States for the following indications:

Approved in United States as Prevymis for:

• Prevention of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients undergoing allogeneic hematopoietic stem cell transplant

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Eurofins Viracor

Collaborator

Trials

1

Recruited

50+

Findings from Research

Letermovir, a new antiviral drug, has been shown to significantly suppress cytomegalovirus (CMV) infection in patients undergoing hematopoietic stem cell transplantation (HSCT), leading to improved overall survival rates in a phase III clinical trial.

Despite the effectiveness of preemptive therapy in managing CMV, it does not reduce non-relapse mortality rates, highlighting the need for continued development of vaccines and cell therapies for CMV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cytomegalovirus infections following allogeneic hematopoietic stem cell transplantation: prophylaxis and treatment]. Katayama, Y., Iwato, K.[2019]

In a phase 3 trial involving 565 CMV-seropositive transplant recipients, letermovir significantly reduced the risk of clinically significant CMV infection compared to placebo, with 37.5% of patients on letermovir experiencing infection versus 60.6% on placebo (P<0.001).

The safety profile of letermovir was comparable to placebo, with similar rates of adverse events, and it showed a lower all-cause mortality rate at 48 weeks (20.9% for letermovir vs. 25.5% for placebo).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. Marty, FM., Ljungman, P., Chemaly, RF., et al.[2022]

In a study of 6 transplant patients treated with letermovir for refractory CMV infection, 3 asymptomatic patients showed a significant decrease in viral load to below 200 IU/mL, indicating potential efficacy of the drug.

No treatment-related adverse effects were reported, suggesting that letermovir may be a safe option for treating CMV infections, although its effectiveness appears to vary and may be enhanced when used alongside other antiviral medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir as Salvage Therapy for Cytomegalovirus Infection in Transplant Recipients. Phoompoung, P., Ferreira, VH., Tikkanen, J., et al.[2023]

Letermovir is the first new drug approved for preventing cytomegalovirus (CMV) in transplant patients since 2003, but its effectiveness in treating existing CMV infections is still uncertain due to a potential low barrier to resistance.

Maribavir shows promise as a preemptive treatment for CMV, with ongoing studies needed to confirm its efficacy, particularly in patients with resistant infections, and both letermovir and maribavir have unique mechanisms that reduce the risk of cross-resistance and do not cause myelotoxicity or nephrotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir and Maribavir for the Treatment and Prevention of Cytomegalovirus Infection in Solid Organ and Stem Cell Transplant Recipients. Imlay, HN., Kaul, DR.[2021]

In a study of 38 CMV seropositive patients undergoing haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation, letermovir (LET) significantly reduced the incidence of CMV infection to 5% compared to 53% with high-dose valacyclovir (HDV).

LET also decreased the need for CMV treatment by day +100 (5% vs. 37%) and improved median CMV event-free survival, indicating its efficacy as a prophylactic treatment in this high-risk population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir vs. high-dose valacyclovir for cytomegalovirus prophylaxis following haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation receiving post-transplant cyclophosphamide. Freyer, CW., Carulli, A., Gier, S., et al.[2022]

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]

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]

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]

References

1. Japan pubmed.ncbi.nlm.nih.gov

[Cytomegalovirus infections following allogeneic hematopoietic stem cell transplantation: prophylaxis and treatment]. [2019]

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

Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. [2022]

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

Letermovir as Salvage Therapy for Cytomegalovirus Infection in Transplant Recipients. [2023]

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

Letermovir and Maribavir for the Treatment and Prevention of Cytomegalovirus Infection in Solid Organ and Stem Cell Transplant Recipients. [2021]

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

Letermovir vs. high-dose valacyclovir for cytomegalovirus prophylaxis following haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation receiving post-transplant cyclophosphamide. [2022]

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

Letermovir use to treat complex cytomegalovirus reactivations in two heart transplant recipients. [2022]

7. Japan pubmed.ncbi.nlm.nih.gov

Successful Treatment with Letermovir in a Heart Transplant Recipient with UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Colitis and Viremia. [2023]

8. United States 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. [2021]