Abemaciclib + Letrozole +/- Metformin for Endometrial Cancer

Recruiting at 2 trial locations

Overseen By Panagiotis Konstantinopoulos, MD, PhD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Metformin, CDK4/6 inhibitors

Disqualifiers: Brain metastases, Cardiovascular risk, 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: 1

Duration: 6 months

180 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new medication combinations to treat certain types of endometrial and ovarian cancers that respond to estrogen. It includes drugs like Abemaciclib (a cancer treatment), Letrozole, and others, administered either orally or through an IV. This study suits individuals with estrogen-receptor positive endometrial cancer or low-grade serous ovarian cancer resistant to standard treatments. Participants must have a confirmed diagnosis of these cancers and, for certain groups, should not have any remaining ovarian function. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot take certain drugs that interact with the study medications, like moderate or strong CYP3A4 inducers or inhibitors. If you're on these, you'll need to switch to a different medication before starting the trial.

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

Research has shown that using abemaciclib and letrozole together in patients with endometrial cancer is generally safe. Studies also indicate that adding metformin to this combination is safe and might enhance the treatment's effectiveness. Patients have tolerated these combinations well, with no major safety issues reported.

For combinations involving zotatifin and gedatolisib, less direct information about their safety exists. However, the early phase of this study suggests these treatments have demonstrated sufficient safety for further investigation.

Overall, each of these combinations has undergone enough research to advance to this trial phase, indicating they have not shown serious safety problems in earlier studies. ^{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 explore novel combinations and targets. Abemaciclib and Letrozole, both taken orally, are combined with various agents like Gedatolisib, Zotatifin, LY3023414, and Metformin, each adding unique mechanisms to the mix. For instance, Gedatolisib and Zotatifin are administered intravenously and act on different cellular pathways, potentially enhancing treatment effectiveness. Metformin, traditionally used for diabetes, is included to explore its additional benefits in cancer therapy. These combinations aim to offer more comprehensive cancer control and possibly better outcomes than standard hormone therapies alone.

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

Research shows that combining abemaciclib and letrozole may help treat a type of endometrial cancer that relies on estrogen to grow. In studies, over 25% of patients responded well, with some experiencing tumor shrinkage or disappearance. Abemaciclib inhibits proteins that promote cancer cell growth, while letrozole reduces estrogen levels, which many cancers require for growth. In this trial, some participants will receive abemaciclib and letrozole, while others will receive this combination with metformin. Adding metformin increased the response rate to 32%, with some patients achieving complete responses. These findings suggest that these treatments are effective and warrant further study for this type of cancer. ^{2 5 6 7 8}

Who Is on the Research Team?

Panagiotis Konstantininopoulos, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with measurable, estrogen-receptor positive endometrial cancer that's recurrent or resistant to standard treatments. They must have good organ and bone marrow function, no history of certain heart conditions or uncontrolled illnesses, and not be on conflicting medications. Women must use contraception and can't be pregnant or breastfeeding.

Inclusion Criteria

My cancer is estrogen receptor-positive.

I am fully active or can carry out light work.

Participants must have normal organ and bone marrow function as defined below: Absolute neutrophil count ≥ 1,500/mcL, Platelets ≥ 100,000/mcL, Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN). Patients with Gilbert's syndrome with a total bilirubin </= 2.0 times ULN and direct bilirubin within normal limits are permitted, AST(SGOT)/ALT(SGPT) ≤ 3× institutional ULN, Creatinine ≤ 1.5 × institutional ULN, OR Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal

Exclusion Criteria

I do not have any serious illnesses or social situations that would stop me from following the study's requirements.

I have had heart problems or treatments within the last 6 months.

I am not taking any strong medication that affects liver enzymes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of Abemaciclib, Letrozole, and either Metformin or Zotatifin, depending on the cohort

6 months

Zotatifin administered intravenously on days 1 and 8 of a 21-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• Letrozole
• Metformin

Trial Overview The study tests a combination of targeted therapies: Abemaciclib (Verzenio™), Letrozole (Femara®), with or without Metformin (Glucophage®) as potential treatments for ER+ endometrial cancer. It aims to see how well these drugs work together in treating this type of cancer.

How Is the Trial Designed?

Group I: Cohort 7 Experimental Treatment 3 Interventions

* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Gedatolisib is administered intravenously on days 1, 8 and 15 of a 28-day cycle

Group II: Cohort 6 Experimental Treatment 3 Interventions

* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Gedatolisib is administered intravenously on days 1, 8 and 15 of a 28-day cycle

Group III: Cohort 5 Experimental Treatment 3 Interventions

* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Zotatifin is administered intravenously on days 1 and 8 of a 21-day cycle

Group IV: Cohort 4 Experimental Treatment 3 Interventions

* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Zotatifin is administered intravenously on days 1 and 8 of a 21-day cycle

Group V: Cohort 3 Experimental Treatment 3 Interventions

* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily * Metformin is administered by mouth once daily

Group VI: Cohort 2 Experimental Treatment 2 Interventions

* Abemaciclib is administered by mouth twice daily * LY3023414 is administered by mouth twice daily

Group VII: Cohort 1A Experimental Treatment 2 Interventions

* Abemaciclib is administered by mouth twice daily * Letrozole is administered by mouth once daily

Group VIII: Cohort 1 Experimental Treatment 3 Interventions

* Abemaciclib is administered by mouth twice daily * LY3023414 is administered by mouth twice daily * Letrozole is administered by mouth once daily

Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Effector Therapeutics

Industry Sponsor

Trials

11

Recruited

600+

Celcuity Inc

Industry Sponsor

Trials

9

Recruited

1,600+

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

In a phase III trial, abemaciclib combined with endocrine therapy significantly reduced the risk of breast cancer recurrence in patients with hormone receptor positive (HR+), HER2-negative, node-positive early breast cancer, regardless of prior chemotherapy or tumor characteristics.

The combination treatment was generally well-tolerated, with manageable side effects such as diarrhea, infections, and neutropenia, making it a valuable option for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. Fung, S., Blair, HA.[2023]

In a phase II study involving 30 patients with recurrent ER-positive endometrial cancer, the combination of letrozole and abemaciclib showed a 30% objective response rate, indicating promising efficacy in treating this type of cancer.

The treatment resulted in a median progression-free survival of 9.1 months, with 55.6% of patients remaining progression-free at 6 months, while the most common serious side effects were neutropenia and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer. Konstantinopoulos, PA., Lee, EK., Xiong, N., et al.[2023]

In a study of 10 post-menopausal patients with endometrial cancer, short-term treatment with letrozole was well-tolerated and led to a significant 37.8% reduction in blood estradiol levels, indicating its effectiveness in lowering estrogen levels.

The treatment also resulted in notable clinical improvements, such as pain relief and a 31.1% decrease in endometrial ultrasound signal, suggesting potential benefits in managing endometrial cancer before surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant therapy of endometrial cancer with the aromatase inhibitor letrozole: endocrine and clinical effects. Berstein, L., Maximov, S., Gershfeld, E., et al.[2019]

In a pooled analysis of 1152 patients from the MONARCH 2 and MONARCH 3 studies, abemaciclib combined with endocrine therapy showed a consistent improvement in progression-free survival (PFS) across all age groups, indicating its efficacy in treating HR+, HER2- advanced breast cancer regardless of age.

Older patients experienced higher rates of clinically relevant side effects, such as diarrhea and nausea, but these were manageable with dose adjustments, suggesting that while safety concerns exist, the treatment remains effective for older populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials. Goetz, MP., Okera, M., Wildiers, H., et al.[2022]

Abemaciclib is an oral medication that inhibits cyclin-dependent kinases 4 and 6, specifically approved in the USA for treating advanced or metastatic breast cancer that is hormone receptor-positive and HER2-negative.

It is effective both as a combination therapy with fulvestrant for patients who have progressed after endocrine therapy and as a standalone treatment for those who have also undergone chemotherapy, highlighting its role in advanced cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: First Global Approval. Kim, ES.[2019]

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. 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 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10901901/

Combined aromatase, CDK4/6 and PI3K blockade using ... We evaluated the combination of abemaciclib, letrozole and LY3023414 (an orally available, selective inhibitor of the class I PI3K isoforms and mTORC1/2) in ...