Combination Therapy for Endometrial Cancer

Overseen By Megan P Hausler, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Checkpoint inhibitors, Lenvatinib, Anticoagulants, others

Disqualifiers: Other malignancies, Cardiac dysfunction, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: up to 1 year

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with endometrial cancer (a type of cancer affecting the uterus) that has returned or worsened, especially when the cancer exhibits high levels of a protein called HER2. The trial combines a personalized vaccine targeting HER2, known as the AdHER2DC vaccine, with drugs that enhance the immune system's ability to fight cancer, along with two already approved cancer medications. Participants must have HER2-positive endometrial cancer that has recurred or progressed after previous treatment. Eligible participants will receive a mix of oral and injected treatments over several cycles, with some receiving an additional immune-boosting drug. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on certain immune checkpoint inhibitors or therapeutic anticoagulation regimens, you may not be eligible to participate.

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

Research has shown that the AdHER2DC vaccine has been tested safely before and is generally well-tolerated. In earlier studies, the vaccine activated the immune system, a positive sign for fighting cancer.

Studies have found that the combination of pembrolizumab and lenvatinib, both FDA-approved, can help patients with endometrial cancer. However, significant side effects such as high blood pressure, diarrhea, and fatigue may occur, which can be managed with medical help.

Early results suggest that N-803, a drug that boosts immune cells, is designed to work safely with the other treatments. However, since this is an early-phase trial, researchers are still studying the complete safety details.

Participants should consult their doctors to understand the risks and benefits before joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for endometrial cancer because they utilize a combination of innovative therapies that may enhance effectiveness. The AdHER2DC vaccine is designed to stimulate the immune system to target cancer cells more effectively, which is different from standard treatments that directly attack the tumor. Pembrolizumab, a type of immunotherapy known as a checkpoint inhibitor, helps the immune system recognize and fight cancer cells. N-803 is an interleukin-15 superagonist that further boosts the immune response, offering a novel approach to cancer therapy. Together, these treatments aim to create a more robust and sustained attack on cancer cells, potentially improving outcomes compared to traditional options like surgery, radiation, and chemotherapy.

What evidence suggests that this trial's treatments could be effective for endometrial cancer?

Research shows that using pembrolizumab and lenvatinib together effectively treats endometrial cancer, with about 33.8% of patients experiencing a positive response. This means roughly one in three patients saw benefits. In this trial, participants in Arm 1 will receive the AdHER2DC vaccine combined with pembrolizumab and de-escalating doses of lenvatinib. Meanwhile, Arm 2 will test the combination of the AdHER2DC vaccine, N-803, pembrolizumab, and the recommended phase 2 dose (RP2D) of lenvatinib. Studies have also examined the AdHER2DC vaccine, which targets a protein called HER2, and N-803, which helps immune cells fight cancer. Early results suggest these treatments could help control endometrial cancer by strengthening the immune system. Importantly, the side effects of these combined treatments are manageable. This approach offers hope for treating HER2-positive endometrial cancer, which is often more aggressive. ^{1 2 3 5 6}

Who Is on the Research Team?

Hoyoung M Maeng, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults aged 18+ with HER2-positive endometrial cancer that has returned or worsened after treatment. Participants must undergo apheresis to create the AdHER2DC vaccine from their own blood and may need a special catheter for this process.

Inclusion Criteria

Evaluable (measurable or non-measurable) disease, per RECIST 1.1

- Absolute neutrophil count (ANC) > 1,000/microliter

- Platelets > 100,000/microliter

Exclusion Criteria

Radiographic evidence of major blood vessel invasion/infiltration

Human immunodeficiency virus (HIV)-positive participants

I have not received any standard or experimental immune checkpoint inhibitors.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab, lenvatinib, N-803, and AdHER2DC vaccine. The first treatment cycle is 28 days; each subsequent cycle is 21 days. Treatment may last up to 1 year.

up to 1 year

Monthly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up visits will continue up to 2 more years.

2 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• AdHER2DC vaccine
• N-803
• Pembrolizumab

Trial Overview The trial is testing a combination of two FDA-approved drugs (one pill daily, one IV) and an experimental HER2-targeting vaccine made from participants' blood, with some also receiving N-803 to boost immune cells. Treatments last up to a year with follow-up visits for two more years.

How Is the Trial Designed?

Group I: Arm 2 Experimental Treatment 5 Interventions

AdHER2DC vaccine + N-803 + pembrolizumab + RP2D of lenvatinib

Group II: Arm 1 Experimental Treatment 4 Interventions

AdHER2DC vaccine + pembrolizumab + de-escalating doses of lenvatinib

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In the KEYNOTE-158 study, pembrolizumab showed a clinically meaningful objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, with 84 out of 90 patients completing health-related quality of life (HRQoL) assessments.

Patients receiving pembrolizumab experienced significant improvements in their quality of life, with mean scores on the QLQ-C30 and EQ-5D-3L questionnaires increasing notably, especially among those who achieved a complete or partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2022]

Endometrial cancers, especially those with mismatch repair (MMR) deficiency, are highly responsive to PD-1 inhibitors like pembrolizumab, which has been approved for these tumors, marking a significant advancement in treatment options.

A case study highlighted a patient with MMR-deficient endometrial cancer and a BRCA1 mutation who achieved a rapid complete remission with pembrolizumab, suggesting that genomic testing could help identify more patients who might benefit from precision therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete Remission Following Pembrolizumab in a Woman with Mismatch Repair-Deficient Endometrial Cancer and a Germline BRCA1 Mutation. Dizon, DS., Dias-Santagata, D., Bregar, A., et al.[2019]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

In a phase II study involving 46 patients with advanced endometrial cancer, the combination of pembrolizumab with carboplatin and paclitaxel resulted in a high objective response rate (ORR) of 74.4%, significantly exceeding the historical control rate of 50%.

The treatment was generally well-tolerated, with common mild side effects like anemia and fatigue, while immune profiling indicated that responders had enriched CD8+ and CD4+ T cell populations, suggesting a potential mechanism of action related to immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium. Barber, EL., Chen, S., Pineda, MJ., et al.[2023]

In a study of 48 patients with recurrent endometrial cancer treated with pembrolizumab and lenvatinib, the best objective response rate was 23.8%, indicating a lower effectiveness compared to clinical trial results.

The treatment was associated with notable side effects, with 56.2% of patients requiring a dose reduction of lenvatinib and 16.7% discontinuing treatment due to adverse events, highlighting the importance of monitoring for safety in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. Kim, J., Noh, JJ., Lee, TK., et al.[2022]

Endometrial cancer (EC) can be effectively treated with immune checkpoint inhibitors (ICIs) like pembrolizumab and dostarlimab, especially in patients with chemoresistant tumors that have microsatellite instability (MSI-high), showing high response rates and long-lasting effects over a year.

Recent trials have also indicated that combining pembrolizumab with the angiogenesis inhibitor lenvatinib can benefit MMR proficient (MMRp) cases, leading to ongoing approvals and further studies to explore ICI combinations with chemotherapy for enhanced treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endometrial Carcinoma: Immune Microenvironment and Emerging Treatments in Immuno-Oncology. Rousset-Rouviere, S., Rochigneux, P., Chrétien, AS., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor, has been approved for treating relapsed MSI-H endometrial cancer after chemotherapy, showing promise in restoring anti-tumor immunity by blocking PD-1 interactions.

Despite encouraging response rates in MSI-H patients, over 50% do not respond to pembrolizumab, highlighting the need for better understanding of MSI status and identifying specific patient populations that may benefit from treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma. Turinetto, M., Lombardo, V., Pisano, C., et al.[2022]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

In the KEYNOTE-158 study, pembrolizumab showed a 48% objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, indicating significant antitumor activity.

The treatment was associated with manageable safety, with 76% of patients experiencing treatment-related adverse events, but no fatal events reported, highlighting its potential as a viable option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2023]

Pembrolizumab, an anti-PD-1 antibody, shows promise as a treatment for recurrent endometrial cancer, particularly due to the cancer's high rates of microsatellite instability and mismatch repair deficiency.

In a rare case, a patient achieved long-term complete remission from recurrent endometrial cancer after experiencing severe immune-related adverse events (irAEs), specifically colitis, following pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of recurrent endometrial cancer with long-term complete remission following pembrolizumab-induced severe immune-related adverse event colitis. Yamamoto, A., Nagashima, T., Imai, Y., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06253494

Study Details | NCT06253494 | Pembrolizumab, Lenvatinib ... Phase II: To preliminarily assess the efficacy of a combination of pembrolizumab, lenvatinib, N-803, and AdHER2DC vaccine in participants with HER2 positive ...

2. jitc.bmj.com jitc.bmj.com/content/12/Suppl_2/A743

647 Combination immunotherapy with pembrolizumab, ... The combination of pembrolizumab and lenvatinib in EC has shown an antitumor activity (response rate 33.8%) with manageable toxicity.

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-01526

Pembrolizumab, Lenvatinib and IL-15 Superagonist N-803 ... Objective: To test 2 study drugs-a vaccine that targets HER2 (AdHER2DC) plus a drug that supercharges immune cells that kill tumor cells (N-803)-combined with 2 ...

4. pharmacytimes.com pharmacytimes.com/view/quilt-502-trial-will-assess-n-803-with-adher2dc-vaccine-for-patients-with-endometrial-cancer

QUILT 502 Trial Will Assess N-803 With AdHER2DC ... Investigators will examine the combination with pembrolizumab and lenvatinib in patients with HER2-expressing endometrial cancer.

5. immunitybio.com immunitybio.com/immunitybio-announces-study-of-anktiva-in-combination-with-the-adher2dc-cancer-vaccine-as-a-potential-therapy-to-control-endometrial-cancer/

ANKTIVA + AdHER2DC Vaccine in Endometrial Cancer ... ImmunityBio announces study of ANKTIVA® in combination with the AdHER2DC cancer vaccine as a potential therapy to control endometrial cancer.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11341375/

Efficacy and safety of lenvatinib plus pembrolizumab in ... Lenvatinib plus pembrolizumab showed a relevant clinical benefit and significant toxicity in patients with advanced and recurrent endometrial cancer.