Triplex Vaccine for CMV Prevention Post-Stem Cell Transplant

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Antivirals, Alemtuzumab, Vaccines, others

Disqualifiers: Autoimmune conditions, Multiple myeloma, 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: 100

Duration: 128 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how well a new vaccine, Triplex, can prevent cytomegalovirus (CMV) infections in individuals who have undergone a stem cell transplant. While CMV usually poses little risk to healthy individuals, it can cause serious problems for those with weakened immune systems, such as transplant patients. The trial compares the effects of the Triplex vaccine with a placebo to determine which is more effective in preventing CMV. This trial is suitable for CMV-positive individuals planning to undergo a stem cell transplant for certain blood cancers, such as lymphoma or leukemia. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but certain medications are not allowed from the time of stem cell transplant to 70 days after. These include some antiviral drugs and live vaccines, so it's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the Triplex vaccine, tested to prevent CMV infection after stem cell transplants, is generally safe and well-tolerated. Previous studies indicate that this vaccine, which uses a weakened virus to help the body build immunity, has not caused serious side effects. Most people experience only mild reactions, such as soreness at the injection site or mild flu-like symptoms, similar to those from other common vaccines. Importantly, this vaccine has been safely used in other studies, further supporting its safety for people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for preventing CMV (Cytomegalovirus) after a stem cell transplant involve antiviral medications like letermovir, which work by inhibiting virus replication. But the Triplex vaccine is unique because it stimulates the immune system to recognize and fight the CMV with a multi-peptide CMV-modified vaccinia Ankara vaccine. This approach not only targets the virus more precisely but also aims to provide longer-lasting protection by training the body's immune response. Researchers are excited about this because it could significantly reduce CMV-related complications and improve patients' quality of life after a transplant.

What evidence suggests that this trial's treatments could be effective for CMV prevention post-stem cell transplant?

Research has shown that the Triplex vaccine, one of the treatments in this trial, can reduce CMV (cytomegalovirus) levels in the blood. Studies with healthy adults and transplant patients have found that the vaccine is safe and can trigger a strong immune response. This response is crucial for preventing CMV-related complications, especially in individuals with weakened immune systems after stem cell transplants. Simply put, the vaccine helps the body recognize and combat CMV infection before it can cause harm. Participants in this trial may receive either the Triplex vaccine or a placebo, both in combination with Letermovir. ^{1 2 4 5 6}

Who Is on the Research Team?

Ryotaro Nakamura, M.D.

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with certain blood cancers like leukemia and lymphoma, who are undergoing stem cell transplantation and are at risk of CMV infection. They must be CMV positive, agree to use contraception, and not have received any prior investigational CMV vaccines or treatments that could affect the immune system.

Inclusion Criteria

Participant must be willing to comply with study and/or follow-up procedures, including willingness to be followed for one year post-HCT

My leukemia is in an early or slightly advanced stage.

I have a blood cancer that is not multiple myeloma or aplastic anemia, as judged appropriate by the study's lead doctors.

Exclusion Criteria

I haven't taken immunosuppressive drugs for an autoimmune disease in the last 5 years.

My condition is advanced and includes CML in blast crisis, AML/ALL beyond 2nd remission, multiple myeloma, or aplastic anemia.

I have undergone specific treatments within 30 days before or up to 180 days after a stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive letermovir per standard of care on days 7-100 and either the Triplex vaccine or placebo on days 100 and 128 post-HCT

128 days

Multiple visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety, CMV reactivation, and other outcomes up to 365 days post-HCT

237 days

Regular monitoring visits, including qPCR tests every two weeks from Day 100 to Day 180

Long-term follow-up

Participants are followed for an additional 2 years post-HCT to assess long-term outcomes

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Letermovir
• Multi-peptide CMV-Modified Vaccinia Ankara Vaccine
• Placebo Administration

Trial Overview The study tests the Triplex vaccine's effectiveness in preventing CMV infection post-stem cell transplant. The vaccine contains three pieces of CMV DNA within a weakened virus to stimulate immunity against this potentially harmful virus in immunocompromised individuals.

How Is the Trial Designed?

Group I: Arm I (letermovir, Triplex) Experimental Treatment 2 Interventions

Patients receive letermovir per SOC on days 7-100 and multi-peptide CMV-modified vaccinia Ankara vaccine IM on days 100 and 128 post-HCT.

Group II: Arm II (letermovir, placebo) Active Control 2 Interventions

Patients receive letermovir per SOC on days 7-100 and placebo IM on days 100 and 128 post-HCT.

Multi-peptide CMV-Modified Vaccinia Ankara Vaccine is already approved in United States, European Union for the following indications:

Approved in United States as Triplex Vaccine for:

• Prevention of clinically significant CMV viremia in transplant recipients

Approved in European Union as Triplex Vaccine for:

• Prevention of clinically significant CMV viremia in transplant recipients

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The developed CMV vaccine, based on modified vaccinia Ankara (MVA), successfully expresses three key CMV antigens and shows strong immunogenicity, stimulating both primary and memory immune responses in mouse models.

In human studies, the vaccine effectively activates existing CMV-specific CD4(+) and CD8(+) T cell responses in healthy CMV-positive individuals and patients shortly after hematopoietic cell transplant, indicating its potential for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fusion protein of HCMV IE1 exon4 and IE2 exon5 stimulates potent cellular immunity in an MVA vaccine vector. Wang, Z., Zhou, W., Srivastava, T., et al.[2022]

Modified vaccinia Ankara (MVA) effectively infects human immune cells, particularly monocytes and dendritic cells, leading to strong activation and a Th-1-polarizing cytokine response, which is crucial for immunotherapy applications.

The interaction between MVA-infected leukocytes and uninfected immature dendritic cells results in the complete maturation of dendritic cells, enhancing their ability to stimulate T cells, suggesting a promising strategy for vaccine development and immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uptake of antigens from modified vaccinia Ankara virus-infected leukocytes enhances the immunostimulatory capacity of dendritic cells. Flechsig, C., Suezer, Y., Kapp, M., et al.[2020]

In a phase 2 trial involving 102 high-risk CMV-seropositive hematopoietic stem cell transplant recipients, the Triplex vaccine showed a trend towards reducing CMV reactivation, with 9.8% of Triplex recipients experiencing reactivation compared to 19.6% in the placebo group.

The Triplex vaccine was found to be safe, with no serious adverse events or deaths related to the vaccine, and it successfully increased levels of CMV-specific T cells, suggesting it effectively enhances the immune response against CMV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial. Aldoss, I., La Rosa, C., Baden, LR., et al.[2023]

The modified vaccinia Ankara (MVA) vaccine encoding the carcinoembryonic antigen (CEA) and costimulatory molecules induced strong CD4+ and CD8+ T-cell responses in mice, demonstrating its potential as an effective cancer vaccine.

A diversified vaccination regimen using MVA-CEA/TRICOM as a prime followed by rF-CEA/TRICOM as a boost resulted in significantly better antitumor responses and increased survival compared to traditional regimens, highlighting the efficacy of this approach in enhancing immune responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified vaccinia virus ankara recombinants are as potent as vaccinia recombinants in diversified prime and boost vaccine regimens to elicit therapeutic antitumor responses. Hodge, JW., Poole, DJ., Aarts, WM., et al.[2020]

The Triplex vaccine, which uses a modified vaccinia Ankara (MVA) platform to target three key cytomegalovirus (CMV) antigens, was found to be safe in a clinical trial involving 24 healthy adults, with no serious adverse events reported and only mild, transient side effects.

The vaccine successfully induced strong and lasting CMV-specific T-cell responses, even in individuals without prior immunity to CMV, suggesting its potential effectiveness for broader populations, including patients undergoing hematopoietic stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults. La Rosa, C., Longmate, J., Martinez, J., et al.[2021]

Vaccinating healthy donors with the Triplex vaccine before hematopoietic cell transplant (HCT) significantly increased levels of CMV-specific T cells in recipients, indicating enhanced immune protection against cytomegalovirus (CMV).

The Triplex vaccine was well-tolerated with minimal adverse events, and the approach shows promise for reducing the need for antiviral prophylaxis, which can hinder the development of CMV-specific immunity post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus-specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis. La Rosa, C., Aldoss, I., Park, Y., et al.[2023]

The CMVPepVax vaccine demonstrated safety in a phase 1b trial with 36 CMV-seropositive patients undergoing stem-cell transplantation, showing no adverse effects on transplant outcomes or unexpected serious adverse events.

Patients receiving the CMVPepVax vaccine had significantly better relapse-free survival compared to those under observation, suggesting potential clinical benefits that warrant further investigation in a phase 2 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Nakamura, R., La Rosa, C., Longmate, J., et al.[2022]

In a phase 2 clinical trial involving 20 patients with lymphoma or myeloma, the Triplex vaccine significantly enhanced the reconstitution of adaptive natural killer (NK) cells and CMV-specific T cells after autologous hematopoietic cell transplantation (auto-HCT), particularly in CMV-seronegative patients.

The vaccine led to a notable increase in adaptive NK cells and CMV-specific T cells, suggesting a potential for improved immune response post-transplant, although further research is needed to assess the clinical benefits of these immune enhancements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation. Rashidi, A., La Rosa, C., Curtsinger, J., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06059391

NCT06059391 | CMV-MVA Triplex Vaccination in HLA ... Giving the CMV-MVA triplex vaccine to donors may help prevent CMV infection of patients undergoing stem cell transplantation. Detailed Description. PRIMARY ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04060277

Triplex Vaccine in Preventing CMV Infection in Patients ... This phase II trial studies how well Triplex vaccine works in preventing cytomegalovirus (CMV) infection in patients undergoing a hematopoietic stem cell ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/multi-peptide-cmv-modified-vaccinia-ankara-vaccine?pn=1

Clinical Trials Using Multi-peptide CMV-Modified Vaccinia ... Review the clinical trials studying multi-peptide cmv-modified vaccinia ankara vaccine on this list and use the filters to refine the results by age and ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11215362/

Cytomegalovirus Triplex vaccine in pediatric hematopoietic ... Triplex demonstrated tolerability and immunogenicity in healthy adults, autologous and allogeneic HCT recipients, in whom it reduced CMV viremia. Based on ...

5. nature.com nature.com/articles/s41541-024-00859-3

Highly stable and immunogenic CMV T cell vaccine ... Triplex is the most advanced clinically evaluated CMV vaccine for transplant recipients and is being further tested in multiple Phase 2 clinical ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10294297/

Hematopoietic stem cell donor vaccination with CMV Triplex ... Triplex is a viral vectored recombinant vaccine expressing three immunodominant CMV antigens. The vector is modified vaccinia Ankara (MVA), an attenuated, non- ...