Letrozole + Abemaciclib vs Pembrolizumab for Endometrial Cancer

Recruiting at 6 trial locations

Overseen By Panagiotis Konstantinopoulos, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CDK4/6 inhibitors, CYP3A4 inducers

Disqualifiers: Active infections, Brain metastases, Pregnancy, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

Duration: Up to 2 years

76 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a new combination of drugs, letrozole (a hormone therapy) and abemaciclib (a targeted therapy), is more effective than the standard drug, pembrolizumab (an immunotherapy), for treating endometrial cancer after chemotherapy. Researchers seek to understand if this new combination can better delay cancer progression compared to pembrolizumab alone. The trial seeks participants with estrogen receptor-positive endometrial cancer (where cancer cells grow in response to estrogen) who have completed specific cycles of chemotherapy and pembrolizumab. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that you cannot use certain medications that strongly interact with the study drugs. You may need to switch these medications before starting the trial.

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

A previous study found the combination of abemaciclib and letrozole safe for treating endometrial cancer, with patients experiencing no serious side effects. Adding metformin also demonstrated that the treatment remained safe and feasible.

Research has shown that pembrolizumab is a safe option for managing advanced endometrial cancer. Many patients have used pembrolizumab with few serious side effects. Its approval for other conditions further supports its safety.

Both treatment options are generally well-tolerated, providing confidence in their safety for those considering joining this 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 bring new strategies to the table. Abemaciclib, combined with Letrozole, offers a novel approach by targeting specific proteins that help cancer cells grow, potentially slowing down cancer progression more effectively than current hormone therapies. On the other hand, Pembrolizumab is an immunotherapy that works by boosting the body's immune system to fight cancer cells, which is a different mechanism compared to conventional chemotherapy. These treatments offer hope for more personalized and potentially more effective options for those battling advanced stages of endometrial cancer.

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

This trial will compare two treatment approaches for endometrial cancer. Research shows that combining abemaciclib and letrozole, which participants in one arm of this trial may receive, may help treat endometrial cancer. In earlier studies, more than 25% of patients responded to this combination, with some seeing their cancer shrink or disappear. Abemaciclib stops cancer cells from growing, while letrozole reduces hormone levels that can help cancer grow. Another option in this trial is pembrolizumab, which participants in another arm may receive. Previous studies have shown that when used with chemotherapy, pembrolizumab lowers the risk of cancer worsening by 70% and helps shrink tumors in nearly half of the patients with advanced endometrial cancer. Both treatments have effectively slowed down or reduced cancer growth. ^{2 5 6 7 8}

Who Is on the Research Team?

Panagiotis Konstantinopoulos, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for individuals who have experienced a recurrence of endometrial cancer and carry the TP53 gene mutation. Participants must have completed initial chemotherapy with pembrolizumab and are now considering maintenance therapy.

Inclusion Criteria

I can swallow and keep down pills.

My cancer is estrogen receptor-positive.

I am deemed suitable for maintenance therapy with pembrolizumab alone.

Exclusion Criteria

I am not pregnant or breastfeeding.

I have no stomach or bowel problems affecting medicine absorption.

I currently have an active infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either Abemaciclib + Letrozole or Pembrolizumab following chemotherapy

Up to 2 years

Every 3 or 6 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Regular imaging and assessments

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• Letrozole
• Pembrolizumab

Trial Overview The study compares two maintenance treatments after standard chemo and pembrolizumab: one group receives Letrozole with Abemaciclib, while another continues Pembrolizumab alone. The goal is to see which method is more effective in delaying cancer progression.

How Is the Trial Designed?

Group I: Arm 2B: Pembrolizumab Every 6 Weeks Experimental Treatment 1 Intervention

Participants will be stratified by Primary Stage IVb (4b) vs. Primary Measurable Stage III (3) /IVa (4a) vs. Recurrent Endometrial Cancer and will complete study procedures as follows: * Baseline visit with X-ray, CT, MRI, or PET scan. * Predetermined dose of Pembrolizumab 1x every 6 weeks for up to 2 years. * X-ray, CT, MRI, or PET scan every 9 weeks for first 9 months, then every 12 months. * End of Treatment visit with assessments and X-ray, CT, MRI, or PET scan. * Follow up for up to 3 years.

Group II: Arm 2: Pembrolizumab Every 3 Weeks Experimental Treatment 1 Intervention

Participants will be stratified by Primary Stage IVb (4b) vs. Primary Measurable Stage III (3) /IVa (4a) vs. Recurrent Endometrial Cancer and will complete study procedures as follows: * Baseline visit with X-ray, CT, MRI, or PET scan. * Predetermined dose of Pembrolizumab 1x every 3 weeks for up to 2 years. * X-ray, CT, MRI, or PET scan every 9 weeks for first 9 months, then every 12 months. * End of Treatment visit with assessments and X-ray, CT, MRI, or PET scan. * Follow up for up to 3 years.

Group III: Arm 1: Abemaciclib + Letrozole Experimental Treatment 2 Interventions

Participants will be stratified by Primary Stage IVb (4b) vs. Primary Measurable Stage III (3)/IVa (4a) vs. Recurrent Endometrial Cancer and will complete study procedures as follows: * Baseline visit with X-ray, CT, MRI, or PET scan. * Cycles 1 through 3: --Days 1 through 21 of 21 day cycle: Predetermined dose of Abemaciclib 2x per day. Predetermined dose of Letrozole 1x per day. * Cycle 4 and every 2 cycles thereafter: --Days 1 through 21 of 21 day cycle: Predetermined dose of Abemaciclib 2x per day. Predetermined dose of Letrozole 1x per day. * X-ray, CT, MRI, or PET scan every 9 weeks for first 9 months, then every 12 months. * End of Treatment visit with assessments and X-ray, CT, MRI, or PET scan. * Follow up for up to 3 years.

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

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 a study of 43 patients with recurrent endometrial cancer treated with lenvatinib and pembrolizumab, 84% experienced significant adverse events (AEs), with hypertension and weight loss being the most common.

Patients starting on a reduced dose of lenvatinib (10 mg or 14 mg) had significantly longer progression-free survival compared to those on the standard dose (20 mg), suggesting that dose optimization may improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. Zammarrelli, WA., Ma, W., Espino, K., et al.[2023]

The combination of lenvatinib and pembrolizumab shows significant clinical benefits for patients with endometrial carcinoma, with a safety profile consistent with each drug's individual use, primarily involving manageable side effects like hypertension and hypothyroidism.

Effective management of lenvatinib's common adverse events is crucial to maximize its efficacy, as most side effects can be prevented or mitigated through proactive monitoring and intervention during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. Lorusso, D., Danesi, R., Locati, LD., et al.[2023]

Checkpoint inhibitors like pembrolizumab and dostarlimab have become important treatment options for endometrial carcinoma, particularly for tumors that are mismatch repair deficient or have a high mutational load.

The review highlights the need for personalized immunotherapy approaches based on the distinct molecular subtypes of endometrial cancer, as these subtypes exhibit different characteristics that could influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Facts and Hopes in Immunotherapy of Endometrial Cancer. Marín-Jiménez, JA., García-Mulero, S., Matías-Guiu, X., 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]

The combination of lenvatinib and pembrolizumab is effective for treating advanced endometrial carcinoma, particularly in patients who have not responded to prior therapies, with manageable safety profiles similar to each drug used alone.

Common adverse reactions include hypothyroidism (51% incidence), fatigue, hypertension, and nausea, which typically occur within the first 10 weeks of treatment and can be effectively managed with dose adjustments and supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab. Makker, V., Taylor, MH., Oaknin, A., et al.[2022]

The combination of pembrolizumab and lenvatinib has shown promising efficacy in treating advanced endometrial cancer, with previous trials indicating improved objective response rates and survival outcomes compared to standard chemotherapy.

This ongoing phase 3 trial aims to determine if pembrolizumab plus lenvatinib is superior to the chemotherapy regimen of paclitaxel plus carboplatin in newly diagnosed patients, with a target enrollment of about 875 participants and results expected in 2022.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Marth, C., Tarnawski, R., Tyulyandina, A., et al.[2022]

In a study of 44 women with advanced or recurrent MMRd/MSI-H endometrial adenocarcinomas treated with pembrolizumab, obesity (BMI≥30) was linked to a higher disease control rate (85.2%) compared to those with a BMI<30 (59.8%).

Patients with obesity also experienced significantly longer progression-free survival (PFS) while overall survival (OS) rates remained similar regardless of BMI, suggesting that body weight may influence treatment outcomes with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab. Bernard, L., How, JA., Patel, S., et al.[2023]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.5513

Phase 2 study of letrozole, abemaciclib, and metformin in ... Eight pts exhibited OR: 3 complete responses (CRs) and 5 partial responses (PRs),ORR 32% (95% CI 14.9% to 53.5%). Sixteen (64%) pts had stable ...

2. dana-farber.org dana-farber.org/newsroom/news-releases/2022/drug-combination-shows-effectiveness-in-patients-with-recurrent-er-positive-endometrial-cancer

Drug combination shows effectiveness in patients with ... “Based on our findings, the letrozole/abemaciclib combination should be considered worthy of further evaluation for patients with recurrent ER- ...

3. onclive.com onclive.com/view/metformin-plus-letrozole-and-abemaciclib-induces-crs-in-er-recurrent-endometrial-cancer

Metformin Plus Letrozole and Abemaciclib Induces CRs in ... Findings from the study showed that patients who received the combination (n = 25) achieved an overall response rate (ORR) of 32%, including a ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03675893

Study Details | NCT03675893 | RESOLVE: Abemaciclib + ... Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor. CDK inhibitors work to stop cancer cell growth. Letrozole is a hormonal therapy that works by lowering ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10982620/

A phase II, multicenter, open-label study of abemaciclib and ... The combination therapy of abemaciclib and letrozole will provide a clinically meaningful therapeutic benefit, with an overall response rate of >25%.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04393285

Abemaciclib and Letrozole to Treat Endometrial Cancer This is a phase II single arm trial to determine the percentage of patients without evidence of disease progression on abemaciclib and letrozole in advanced ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11431580/

Therapeutic Prospects of Abemaciclib for Patients with ... We highlight abemaciclib's properties and potential clinical usefulness in patients with EC, particularly in recurrent estrogen-receptor-positive cases.

8. physicianresources.dana-farber.org physicianresources.dana-farber.org/news/treatment-of-recurrent-endometrial-cancer-with-metformin-letrozole-and-abemaciclib-is-safe-and-promising-dana-farber-research-shows

Treatment of Recurrent Endometrial Cancer with Metformin ... Treatment with metformin, letrozole, and abemaciclib for recurrent estrogen receptor-positive endometrial cancer is safe and appears to induce deeper and more ...