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

130 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is studying a combination of targeted therapies as a possible treatment for estrogen-receptor positive (ER+) endometrial cancer and low-grade serous ovarian cancer. The drugs involved in this study are: * Abemaciclib (also known as Verzenio™) * Letrozole (also known as Femara®) * Metformin (also known as Glucophage®) * Zotatifin (also known as eFT226)

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.

What data supports the effectiveness of the drug combination Abemaciclib, Letrozole, and Metformin for endometrial cancer?

Research suggests that the combination of letrozole and abemaciclib shows promising activity in estrogen receptor-positive endometrial cancer due to their effects on pathways involved in cancer cell growth. Additionally, letrozole has been shown to be more effective than metformin in reducing endometrial thickness and improving cancer cell differentiation. ^{1 2 3 4 5}

Is the combination of Abemaciclib, Letrozole, and Metformin safe for humans?

Abemaciclib, when combined with endocrine therapy like Letrozole, has been shown to have a tolerable safety profile in breast cancer patients, with common side effects including diarrhea, infections, and low white blood cell counts. Letrozole has been studied for its hormonal effects in endometrial cancer, but specific safety data for the combination with Metformin in endometrial cancer is not available in the provided research. ^{1 2 3 6 7}

What makes the drug combination of Abemaciclib, Letrozole, and Metformin unique for endometrial cancer?

This drug combination is unique because it targets multiple pathways involved in endometrial cancer growth. Abemaciclib inhibits proteins (CDK4/6) that help cancer cells divide, Letrozole reduces estrogen levels that fuel cancer growth, and Metformin may enhance the response by affecting cancer cell metabolism. This multi-targeted approach is different from standard treatments that typically focus on a single pathway. ^{1 2 3 5 6}

Research Team

Panagiotis Konstantininopoulos, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: 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 II: 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 III: 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 IV: Cohort 2 Experimental Treatment 2 Interventions

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

Group V: Cohort 1A Experimental Treatment 2 Interventions

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

Group VI: 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+

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

Findings from Research

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 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 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]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant therapy of endometrial cancer with the aromatase inhibitor letrozole: endocrine and clinical effects. [2019]

2. France pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. [2023]

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

A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer. [2023]

4. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Effectiveness of aromatase inhibitors in comparison with metformin for neoadjuvant treatment in patients with endometrial cancer]. [2018]

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

Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study. [2020]

6. Netherlands 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. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Abemaciclib: First Global Approval. [2019]