Everolimus + Letrozole + Metformin for Endometrial Cancer

Recruiting at 5 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Immunosuppressants, mTOR inhibitors, others

Disqualifiers: Uterine sarcomas, Brain metastases, Cardiac disease, 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

Compensation: Varies

Number of Visits: 3

Duration: Ongoing

62 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to learn if the combination of everolimus, letrozole, and metformin can help to control recurrent or progressive endometrial cancer. The safety of this drug combination will also be studied. Everolimus is designed to block a protein inside cancer cells that is involved in cancer growth. Letrozole is designed to block a protein from making estrogen. This may interfere with the growth of cancer cells. Metformin is commonly used to control blood sugar levels in patients with diabetes. It is designed to lower insulin levels, which may slow or stop the growth of endometrial cancer cells.

Do I have to stop taking my current medications to join the trial?

The trial requires that you stop all other anti-tumor therapies for at least four weeks before joining. If you are on chronic systemic corticosteroids or other immunosuppressive agents, you cannot participate. Metformin must be paused for 24 hours before and 48 hours after imaging with IV contrast.

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

Research shows that combining Everolimus and Letrozole can help treat endometrial cancer by targeting specific pathways in cancer cells, and adding Metformin might improve the response. Studies have found that this combination can be beneficial for patients with advanced or recurrent endometrial cancer. ^{1 2 3 4 5}

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

The combination of Everolimus, Letrozole, and Metformin has been studied in women with advanced or recurrent endometrial cancer, and while the studies focus on effectiveness, they imply that the treatment is generally safe for use in humans. However, specific safety data is not detailed in the available research abstracts. ^{1 2 3 4 5}

How is the drug combination of Everolimus, Letrozole, and Metformin unique for treating endometrial cancer?

This drug combination is unique because it targets the PIK3/mTOR pathway, which is often altered in endometrial cancer, and combines it with hormonal therapy to potentially overcome resistance. The addition of metformin may enhance the response, offering a novel approach compared to the limited existing treatments for advanced or recurrent endometrial cancer. ^{1 2 3 4 6}

Research Team

Pamela T. Soliman

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced or recurrent endometrial carcinoma that's resistant to standard treatments. Participants can have had no more than two prior chemo regimens, must not be pregnant or of child-bearing potential, and should have adequate organ function. They cannot join if they've had other cancers (except certain skin cancers) in the past 3 years, known hypersensitivity to everolimus, uncontrolled brain metastases, severe liver impairment, active infections, or are on immunosuppressants.

Inclusion Criteria

I have had 2 or fewer chemotherapy treatments for recurrent endometrial cancer.

GOG performance status </= 2

Adequate liver function as shown by: a. serum bilirubin </= 1.5 x ULN b. ALT and AST </= 2.5x ULN (</= 5x ULN in patients with liver metastases); Adequate renal function:serum creatinine < 1.4mg/dL (per manufacturer, metformin is contraindicated in the presence of renal dysfunction defined as a serum creatinine> 1.4 mg/dL in females and in patients with abnormal clearance) ; Fasting serum cholesterol </= 240 mg/dL OR </=7.75 mmol/L AND fasting triglycerides </= 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication

Exclusion Criteria

I am allergic to everolimus or similar medications.

My cancer has returned in a specific area and can be treated with surgery or radiation.

Prior treatment with any investigational drug within the preceding 4 weeks

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in Period

Participants take Metformin alone for 7-10 days before starting Cycle 1

1-2 weeks

1 visit (in-person)

Treatment

Participants receive Everolimus, Letrozole, and Metformin in 4-week cycles

Ongoing

1 visit per cycle (in-person)

End-of-Treatment

Final assessments after the last dose of study drugs

Within 4 weeks after last dose

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

As needed

Visits as needed (in-person)

Treatment Details

Interventions

• Everolimus
• Letrozole
• Metformin

Trial Overview The study tests a combination of three drugs: Everolimus (blocks cancer growth proteins), Letrozole (interferes with estrogen production affecting cancer cell growth), and Metformin (commonly used for diabetes but may slow cancer by lowering insulin levels). The aim is to see if this combo controls endometrial cancer better and understand its safety profile.

Participant Groups

Group I: Letrozole + Metformin + RAD001 Experimental Treatment 3 Interventions

Patients have a 7-10 day lead in period where they take Metformin alone. The starting dose of Metformin 500 mg by mouth daily for 4 days and then increased to 500 mg by mouth twice a day. Everolimus and Letrozole added and considered the start of Cycle #1. Everolimus administered by mouth as once daily dose of 10 mg. Letrozole 2.5 mg tablet by mouth once daily. The oral dose of Everolimus should be taken together with the daily dose of Letrozole 2.5mg.

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

Approved in United States as Afinitor for:

• Advanced renal cell carcinoma
• Subependymal giant cell astrocytoma
• Progressive neuroendocrine tumors of pancreatic origin
• Advanced hormone receptor-positive, HER2-negative breast cancer
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Findings from Research

Letrozole alone effectively reduces the viability and invasiveness of Ishikawa endometrial carcinoma cells, indicating its potential as a treatment option.

The combination of letrozole and everolimus enhances the anti-tumor effects by further inhibiting cell proliferation and inducing apoptosis through the PI3K/Akt/mTOR signaling pathway, suggesting a synergistic therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic in vitro anti-tumor effect of letrozole and everolimus on human endometrial carcinoma Ishikawa cells. Lu, XY., Yang, Y., Xu, H., et al.[2021]

In a phase II trial involving 38 women with recurrent endometrial cancer, the combination of everolimus and letrozole showed a clinical benefit rate of 40%, indicating that this treatment can effectively stabilize or reduce tumor size in some patients.

The study found that patients with endometrioid histology and specific CTNNB1 mutations had better responses to the treatment, suggesting that genetic factors may help predict which patients will benefit most from this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. Slomovitz, BM., Jiang, Y., Yates, MS., et al.[2021]

In a phase 2 study involving 44 patients with advanced or metastatic endometrial cancer who had limited treatment options, everolimus showed a 36% non-progressive disease rate at 3 months, indicating some efficacy in this difficult-to-treat population.

The most common side effects included anemia, fatigue, and hypercholesterolemia, but overall, everolimus was considered to have acceptable tolerability, supporting further research into targeted therapies for endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO. Ray-Coquard, I., Favier, L., Weber, B., et al.[2022]

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]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Synergistic in vitro anti-tumor effect of letrozole and everolimus on human endometrial carcinoma Ishikawa cells. [2021]

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

Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO. [2022]

4. 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]

5. Ireland pubmed.ncbi.nlm.nih.gov

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

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

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