Everolimus + Letrozole for Endometrial Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: mTOR inhibitors, Aromatase inhibitors

Disqualifiers: Ovarian function, Severe disease, Cardiac, 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: 16

Duration: 8 weeks

42 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 RAD001 (everolimus) and Femara (letrozole) can help to control recurrent or progressive endometrial cancer. The safety of this drug combination will also be studied.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you should not have taken certain hormonal agents within the previous 4 weeks. It's best to discuss your specific medications with the trial team.

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

Research shows that the combination of Everolimus and Letrozole has been effective in reducing tumor growth in endometrial cancer cells in the lab. Additionally, a study found that this combination could help overcome resistance to hormone therapy in patients with recurrent endometrial cancer. ^{1 2 3 4 5}

Is the combination of Everolimus and Letrozole safe for humans?

The combination of Everolimus and Letrozole has been studied in clinical trials for breast cancer and endometrial cancer, showing it is generally safe for humans, though specific side effects and safety profiles should be discussed with a healthcare provider. ^{1 2 3 6 7}

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

This drug combination is unique because it targets both the mTOR pathway, which is often overactive in endometrial cancer, and estrogen production, which can drive cancer growth. By combining Everolimus, an mTOR inhibitor, with Letrozole, an aromatase inhibitor, it may overcome resistance to hormonal treatments and effectively reduce cancer cell growth. ^{1 2 5 6 8}

Research Team

Pamela T. Soliman

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced or recurrent endometrial cancer that has progressed. Participants must have tried fewer than two chemotherapy regimens, not be pregnant, and have no severe concurrent diseases. They should not have used certain cancer treatments recently and must not be of childbearing potential.

Inclusion Criteria

My liver is working well.

My cholesterol and triglyceride levels are within normal limits.

I have had no more than two chemotherapy treatments for my advanced or recurrent disease.

Exclusion Criteria

I have previously taken RAD001, mTOR inhibitors, letrozole, or aromatase inhibitors.

I have uterine sarcoma or a mixed malignant mullerian tumor.

My cancer recurrence can potentially be cured with surgery or radiation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive everolimus and letrozole daily, with study visits every 4 weeks for monitoring and assessment

8 weeks

Visits every 4 weeks (in-person)

Extended Treatment

Continued treatment with everolimus and letrozole, with assessments every 12 weeks if disease is stable or responsive

up to 2 years

Visits every 12 weeks (in-person)

End of Treatment

Final assessments and procedures within 4 weeks after the last dose of study drugs

4 weeks

Long Term Follow-up

Regular follow-up visits to monitor health status and disease progression

Treatment Details

Interventions

• Letrozole
• RAD001 (Everolimus)

Trial Overview The study tests the effectiveness and safety of combining RAD001 (Everolimus) with Letrozole in controlling recurrent or progressive endometrial cancer. It aims to find out if this drug combination can help patients whose disease has returned or worsened after treatment.

Participant Groups

Group I: Letrozole + RAD001 Experimental Treatment 2 Interventions

Letrozole and RAD001 (Everolimus)

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

Approved in United States as Femara for:

• Breast cancer in postmenopausal women
• Increasing the chance of ovulation in women with polycystic ovary syndrome

Approved in European Union as Letrozole for:

• Early breast cancer in postmenopausal women
• Advanced breast cancer in postmenopausal women

Approved in Canada as Letrozole for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• First-line treatment of postmenopausal women with hormone receptor-positive advanced breast cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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 study of 29 young women with early endometrial carcinoma (EC) and complex atypical hyperplasia (CAH), 88.2% of EC patients and 100% of CAH patients achieved complete response after treatment with gonadotropin-releasing hormone agonist (GnRHa) combined with either a levonorgestrel-releasing intrauterine system or letrozole.

Both treatment combinations were effective for fertility preservation, with a median time to complete response of around 4.5 to 5 months, suggesting they are viable options for young women with these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gonadotropin-Releasing Hormone Agonist Combined With a Levonorgestrel-Releasing Intrauterine System or Letrozole for Fertility-Preserving Treatment of Endometrial Carcinoma and Complex Atypical Hyperplasia in Young Women. Zhou, H., Cao, D., Yang, J., et al.[2018]

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

Everolimus Plus Letrozole for Treatment of Patients With HR+, HER2- Advanced Breast Cancer Progressing on Endocrine Therapy: An Open-label, Phase II Trial. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Leuprorelin combined with letrozole with/without everolimus in ovarian-suppressed premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer: The LEO study. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Gonadotropin-Releasing Hormone Agonist Combined With a Levonorgestrel-Releasing Intrauterine System or Letrozole for Fertility-Preserving Treatment of Endometrial Carcinoma and Complex Atypical Hyperplasia in Young Women. [2018]

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

Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Budget impact analysis of everolimus for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer in Kazakhstan. [2018]

8. Ireland pubmed.ncbi.nlm.nih.gov

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