Everolimus + Letrozole for Endometrial Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of two drugs, everolimus (RAD001) and letrozole (Femara), can control endometrial cancer that has recurred or progressed. Researchers are also assessing the safety of this drug combination for patients. It suits those with endometrial cancer who have undergone up to two prior chemotherapy treatments and have experienced disease spread or recurrence. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that the combination of everolimus and letrozole is generally well-tolerated by patients. In studies, about half of the women experienced benefits, with their cancer either stopping growth or shrinking. This combination has effectively controlled cancer growth, with success rates between 28% and 45%.

While everolimus and letrozole work well together, some patients have reported side effects such as mouth sores, tiredness, and nausea. These side effects are usually manageable. Both everolimus and letrozole have been studied in other types of cancer, providing doctors with insights into potential patient reactions.

Overall, evidence suggests that this treatment combination is safe for many patients. However, individual experiences can vary, so discussing any concerns with a doctor is advisable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for endometrial cancer?

Researchers are excited about Everolimus combined with Letrozole for endometrial cancer because it introduces a novel approach to treatment. Most current therapies, like surgery, radiation, and hormonal therapies, focus on directly attacking cancer cells or managing hormone levels. Everolimus, however, works by inhibiting a pathway called mTOR, which is crucial for cancer cell growth and proliferation. This unique mechanism could potentially slow down or stop the progression of cancer in ways that existing treatments might not. Additionally, the combination with Letrozole, a well-known aromatase inhibitor, may enhance the treatment's effectiveness by further disrupting the cancer's growth signals.

What evidence suggests that the combination of everolimus and letrozole could be effective for endometrial cancer?

Research has shown that using everolimus and letrozole together, as studied in this trial, may help treat endometrial cancer that has returned or is worsening. Studies have found that this combination benefited 37% to 50% of patients by either shrinking their cancer or stopping its growth. Specifically, about 28% to 32% of patients in some studies experienced tumor reduction. These findings suggest that everolimus and letrozole might control this cancer by inhibiting cancer cell growth and preventing new blood vessels from nourishing the tumor. Further research is underway to confirm the effectiveness and safety of this combination. ^{1 3 6 7 8}

Who Is on the Research Team?

Pamela T. Soliman

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7002216/

Everolimus, letrozole, and metformin in women with ... The combination of everolimus, letrozole and metformin resulted in CB for 50% of women with advanced or recurrent endometrial cancer, with an overall RR of 28%.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01068249

Letrozole and RAD001 With Advanced or Recurrent ... The Study Drugs: Everolimus is designed to stop cancer cells from multiplying. It may also stop the growth of new blood vessels that help tumor growth, ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.5567

Everolimus plus letrozole treatment of recurrent ... Results: There were no complete responders, but 7 of 19 (37%) patients treated had clinical benefit, with 1 PR and 6 with stable disease. In ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0090825821016991

A randomized phase II trial of everolimus and letrozole or ... Endometrial cancer​​ Citation Excerpt : The doublet of everolimus and letrozole gave encouraging response rates of 28–32%, which rose to 45% in patients with PR- ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35063278/

A randomized phase II trial of everolimus and letrozole or ... Median follow-up was 37 months. Eight (22%; 95% CI 11% to 37%) patients responded on EL (one CR) and nine (25%; 95% CI 14% to 41%) patients ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4348638/

Phase II Study of Everolimus and Letrozole in Patients With ... Letrozole in combination with everolimus showed a high CBR, high RR, and overall better than expected activity in a phase II clinical trial in ...

7. aacrjournals.org aacrjournals.org/clincancerres/article/26/3/581/83017/Everolimus-Letrozole-and-Metformin-in-Women-with

Everolimus, Letrozole, and Metformin in Women with ... In this phase II study, the combination of everolimus, letrozole, and metformin was well tolerated and 50% of women had clinical benefit (CB), with a 28% ORR ...

8. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2014.58.3401

Phase II Study of Everolimus and Letrozole in Patients With ... Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented.