Combination Therapy for Endometrial Cancer
Recruiting in Palo Alto (17 mi)
Overseen byHoyoung M Maeng, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
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
Breakthrough Therapy
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.
12345Is 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.
13678What 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.
134910Eligibility 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
+19 more
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.
+18 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Arm 2Experimental Treatment5 Interventions
AdHER2DC vaccine + N-803 + pembrolizumab + RP2D of lenvatinib
Group II: Arm 1Experimental Treatment4 Interventions
AdHER2DC vaccine + pembrolizumab + de-escalating doses of lenvatinib
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Pembrolizumab as a single agent for patients with MSI-H advanced endometrial carcinoma. [2022]Endometrial cancer can be characterized by high instability of microsatellites (MSI-H), a biomarker indicative of sensibility to immune checkpoint inhibitors (ICIs). The results of the KEYNOTE-158 trial led to the approval of pembrolizumab - a monoclonal, humanized IgG4 kappa anti-PD-1 antibody able to prevent T-cell PD-1/tumor cell PD-L1/2 interaction, thus restoring T-cell-mediated anti-tumor immunity - in MSI-H endometrial cancer relapsing after at least one line of chemotherapy (CT).
Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. [2022]To investigate the effectiveness and safety of pembrolizumab and lenvatinib (PEMBRO+LEN) for recurrent endometrial cancer (EC) in a real-world setting.
New Approved Use for Keytruda. [2022]Pembrolizumab (Keytruda) is now approved as a single agent to treat advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient in those whose disease has progressed following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation.
Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. [2023]Pembrolizumab demonstrated durable antitumor activity in patients with previously treated, advanced microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) tumors, including endometrial cancer, in the nonrandomized, open-label, multicohort, phase II KEYNOTE-158 study (NCT02628067). We report efficacy and safety outcomes for patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158.
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]Pembrolizumab demonstrated a clinically meaningful objective response rate in patients with previously treated, advanced MSI-H/dMMR endometrial cancer in the multicohort phase 2 KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067). We present health-related quality of life (HRQoL) results for these patients.
Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).
A case of recurrent endometrial cancer with long-term complete remission following pembrolizumab-induced severe immune-related adverse event colitis. [2022]Endometrial cancer is generally diagnosed at an early stage and has a good prognosis, although once it recurs, the prognosis is poor because of few therapeutic options. Since endometrial cancer has a high frequency of microsatellite instability-high/mismatch repair deficiency, the anti-PD-1 antibody pembrolizumab is expected to be one of the key therapeutic agents for recurrent endometrial cancer. Immune-related adverse events (irAEs) are autoimmune-like unique and occasionally life-threatening side effects of immune checkpoint inhibitors. Here, we report a rare case of recurrent endometrial cancer that showed long-term complete remission after developing relapsing severe irAE colitis following the introduction of pembrolizumab.
Complete Remission Following Pembrolizumab in a Woman with Mismatch Repair-Deficient Endometrial Cancer and a Germline BRCA1 Mutation. [2019]Endometrial cancer is the most common gynecologic malignancy in the U.S. and, although the majority of cases present at an early stage and can be treated with curative intent, those who present with advanced disease, or develop metastatic or recurrent disease, have a poorer prognosis. A subset of endometrial cancers exhibit mismatch repair (MMR) deficiency. It is now recognized that MMR-deficient cancers are particularly susceptible to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, and in a landmark judgement in 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab for these tumors, the first tumor-agnostic approval of a drug. However, less is known about the sensitivity to PD-1 blockade among patients with known mutations in double-strand break DNA repair pathways involving homologous recombination, such as those in BRCA1 or BRCA2. Here we report a case of a patient with an aggressive somatic MMR-deficient endometrial cancer and a germline BRCA1 who experienced a rapid complete remission to pembrolizumab.
Endometrial Carcinoma: Immune Microenvironment and Emerging Treatments in Immuno-Oncology. [2021]Endometrial cancer (EC) can easily be cured when diagnosed at an early stage. However, advanced and metastatic EC is a common disease, affecting more than 15,000 patients per year in the United Sates. Only limited treatment options were available until recently, with a taxane-platinum combination as the gold standard in first-line setting and no efficient second-line chemotherapy or hormone therapy. EC can be split into four molecular subtypes, including hypermutated cases with POLE mutations and 25-30% harboring a microsatellite instability (MSI) phenotype with mismatch repair deficiency (dMMR). These tumors display a high load of frameshift mutations, leading to increased expression of neoantigens that can be targeted by the immune system, including (but not limited) to T-cell response. Recent data have demonstrated this impact of programmed death 1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors on chemo-resistant metastatic EC. The uncontrolled KEYNOTE-158 and GARNET trials have shown high response rates with pembrolizumab and dostarlimab in chemoresistant MSI-high tumors. Most responders experiment long responses that last more than one year. Similar, encouraging results were obtained for MMR proficient (MMRp) cases treated with a combination of pembrolizumab and the angiogenesis inhibitor lenvatinib. Approvals have, thus, been obtained or are underway for EC with immune checkpoint inhibitors (ICI) used as monotherapy, and in combination with antiangiogenic agents. Combinations with other targeted therapies are under evaluation and randomized studies are ongoing to explore the impact of ICI-chemotherapy triplets in first-line setting. We summarize in this review the current knowledge of the immune environment of EC, both for MMRd and MMRp tumors. We also detail the main clinical data regarding PD-1/PD-L1 inhibitors and discuss the next steps of development for immunotherapy, including various ICI-based combinations planned to limit resistance to immunotherapy.
Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium. [2023]The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC).