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

Trial Summary

What is the purpose of this trial?

Background: Endometrial cancer (EC) of the uterus is becoming more common in the US. Sometimes EC often has increased levels of a protein called HER2. Cancers with HER2 tend to be more aggressive and have poorer outcomes. 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 FDA-approved cancer treatment drugs in people with EC. Eligibility: Adults aged 18 and older with HER2-positive EC that returned or got worse after treatment. Design: AdHER2DC vaccine is made from each participant s own blood. Participants will undergo apheresis: Blood is removed from the body through a tube attached to a needle. The blood passes through a machine that separates out the target cells. The remaining blood is returned to the body through a second needle. A special catheter may be needed. The first treatment cycle is 28 days; each cycle after that will be 21 days. All participants will get the 2 approved drugs and the vaccine. One drug is a tablet taken by mouth once a day, every day. The other drug is given through a tube attached to a needle inserted into a vein. The vaccine is injected under the skin. Participants will receive the vaccine on day 1 of cycles 1, 2, and 3. Additional doses up to 3 doses will be give if possible. Some participants will receive N-803. This drug is injected under the skin of the abdomen on day 1 of each cycle. Treatment may last up to 1 year. Follow-up visits will continue up to 2 more years.

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.

What data supports the effectiveness of the drug combination therapy for endometrial cancer?

Pembrolizumab, a part of the combination therapy, has shown effectiveness in treating advanced endometrial cancer with high microsatellite instability (MSI-H), as demonstrated in the KEYNOTE-158 study. This study found that pembrolizumab can help the immune system attack cancer cells in patients whose cancer has progressed after other treatments. ^{1 2 3 4 5}

Is the combination therapy for endometrial cancer safe for humans?

Pembrolizumab (Keytruda), part of the combination therapy, has been associated with some serious side effects like pneumonitis (lung inflammation) and colitis (inflammation of the colon), which are rare but can be life-threatening. These side effects are related to its role as an immune checkpoint inhibitor, which can sometimes cause the immune system to attack healthy tissues. ^{1 3 6 7 8}

What makes the combination therapy for endometrial cancer unique?

This combination therapy is unique because it includes the AdHER2DC vaccine, which is designed to target specific cancer cells, along with N-803, an IL-15 superagonist that boosts the immune system, and pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells. This multi-faceted approach aims to enhance the body's immune response against endometrial cancer, which is different from traditional chemotherapy or single-agent treatments. ^{1 3 4 9 10}

Research Team

Hoyoung M Maeng, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma. [2022]

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

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. [2022]

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

New Approved Use for Keytruda. [2022]

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

Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. [2023]

5. United States 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. [2022]

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

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

7. Australia 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Complete Remission Following Pembrolizumab in a Woman with Mismatch Repair-Deficient Endometrial Cancer and a Germline BRCA1 Mutation. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Endometrial Carcinoma: Immune Microenvironment and Emerging Treatments in Immuno-Oncology. [2021]

10. United States 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. [2023]