Levonorgestrel IUS + Everolimus for Endometrial Cancer

(LEVER Trial)

Not currently recruiting at 24 trial locations

Overseen By Shannon Westin, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Lipid lowering

Must not be taking: Corticosteroids, Immunosuppressive, others

Disqualifiers: Diabetes, Cardiac disease, Infections, 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: 9 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a hormone-releasing device, the levonorgestrel-releasing intrauterine system (LIUD), used alone or with everolimus (an immunosuppressant and cancer treatment) for certain early-stage uterine conditions, such as atypical hyperplasia (a pre-cancerous condition) or stage IA grade 1 endometrial cancer. The device releases a hormone that may slow or stop tumor growth, while everolimus could block enzymes necessary for tumor cell growth. Individuals with confirmed diagnoses of these conditions, who have experienced stable or persistent disease with the device in place for at least three months, may be suitable candidates for this study. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial requires a 28-day period without prior progesterone treatment before starting the study, unless you have tissue samples from before any progesterone treatment. If you are on medications that are contraindicated with everolimus, you must confirm with your doctor that you can change or stop them if you are assigned to the LIUD + everolimus group.

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

Research has shown that the levonorgestrel-releasing intrauterine system (IUS) is generally safe. Commonly used for birth control, it reduces the risk of endometrial cancer by 50 to 78% in the general population, indicating it is usually well-tolerated for its intended purpose.

Studies have demonstrated that everolimus is effective and has an acceptable safety profile for patients with advanced or spreading endometrial cancer. It blocks proteins in cancer cells that aid their growth. Although patients have generally tolerated it well in other situations, like any medication, it can cause side effects.

Both treatments have a history of safe use, but individual experiences may vary. It is important to consult a healthcare provider about potential risks and benefits before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of the Levonorgestrel-Releasing Intrauterine System (LIUD) and everolimus for endometrial cancer because it introduces a novel approach by combining targeted drug delivery with systemic therapy. Unlike standard treatments like surgery, radiation, or chemotherapy, this method uses the LIUD to deliver levonorgestrel directly to the uterine lining, potentially reducing side effects. Additionally, everolimus, taken orally, targets specific pathways involved in cancer cell growth, offering a more focused attack on the cancer cells. This dual-action strategy could lead to improved outcomes with fewer side effects compared to conventional therapies.

What evidence suggests that this trial's treatments could be effective for atypical hyperplasia or stage IA grade 1 endometrial cancer?

Research has shown that the levonorgestrel-releasing intrauterine system (LNG-IUS) can lower the risk of endometrial cancer. It completely reverses abnormal cell growth in about 85% of patients with atypical hyperplasia and can reduce the risk of endometrial cancer by up to 78%. In this trial, some participants will receive the LNG-IUS alone. Meanwhile, everolimus has demonstrated potential in treating advanced or spreading endometrial cancer, with studies indicating it helps in 21% to 45% of cases. Everolimus blocks certain enzymes that cancer cells need to grow, potentially stopping them from multiplying. Other participants in this trial will receive both LNG-IUS and everolimus together to evaluate their effectiveness for early-stage endometrial cancer and pre-cancerous conditions. ^{1 5 6 7 8}

Who Is on the Research Team?

Shannon Westin, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with atypical hyperplasia or stage IA grade 1 endometrial cancer. Eligible participants must have proper liver function, not be pregnant or nursing, and cannot have HIV or other recent malignancies. They should not be on certain medications that can't be combined with everolimus and must agree to use additional contraception if of childbearing potential.

Inclusion Criteria

You have enough infection-fighting white blood cells in your body.

Your platelet count is at least 100 billion per liter.

Your levels of ALT and AST in the blood should be less than 2.5 times the upper limit of normal.

Exclusion Criteria

I haven't had cancer in the last 3 years, except for skin cancer.

You have been diagnosed with HIV.

I am not currently on cancer treatments or have had a break for at least 28 days or 7 days, depending on the treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the levonorgestrel-releasing intrauterine system alone or in combination with everolimus. Treatment is assessed every 3 months.

9 months

Visits every 3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with evaluations every 6 months if complete response is confirmed.

Up to 11 years

What Are the Treatments Tested in This Trial?

Interventions

• Everolimus
• Levonorgestrel-Releasing Intrauterine System

Trial Overview The study is testing the effectiveness of a levonorgestrel-releasing intrauterine device (LIUD), alone or with the drug everolimus, in preventing tumor growth in patients with early-stage endometrial cancer or pre-cancerous uterine growths. It's unclear if adding everolimus improves outcomes compared to LIUD alone.

How Is the Trial Designed?

Group I: Arm II (LIUD, everolimus) Experimental Treatment 3 Interventions

Patients continue treatment with the LIUD and receive everolimus PO QD on days 1-28. Treatment repeats every 28 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (LIUD) Experimental Treatment 2 Interventions

Patients continue treatment with the LIUD for up to 9 months in the absence of disease progression or unacceptable toxicity.

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+

Published Research Related to This Trial

A new polymer-based intrauterine delivery system for everolimus allows for localized treatment of low-grade endometrial cancer, achieving effective drug levels similar to oral administration while minimizing systemic exposure.

In vivo studies in a rat model demonstrated that this delivery system can release everolimus for up to 84 days, effectively reducing cancer-related biomarkers and suggesting a promising non-surgical option for women wishing to preserve fertility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel polymer-based system for intrauterine delivery of everolimus for anti-cancer applications. Melendez, B., Shah, S., Jiang, Y., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3658508/

Everolimus as second- or third-line treatment of advanced ... Everolimus demonstrated efficacy and acceptable tolerability in patients with chemotherapy-refractory advanced or metastatic endometrial cancer.

2. 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- ...

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

Everolimus, Letrozole, and Metformin in Women with ... Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor–positive tumors may have better response.

4. asco.org asco.org/abstracts-presentations/ABSTRACT80682

A phase II study of everolimus and letrozole in patients with ... We previously documented a clinical benefit response (CBR) rate of 21% at 20 weeks with single agent everolimus in this population.

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23238879/

Predicting Everolimus Treatment Efficacy in Patients With ... Median progression-free survival (PFS) and overall survival (OS) were longer in patients without K-RAS mutations (PFS 3.12 ± 1.7 months versus 1.05 ± 0.4 months ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1040842824002981

First-line treatments for advanced or recurrent endometrial ... Median progression-free survival was reported in 28 trials (range, 1.9–18.8 months), median overall survival in 26 trials with mature data (range, 6.9–41 months) ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01797523

NCT01797523 | A Phase II, Single-Arm Study of RAD001 ... 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.

8. onco-hema.healthbooktimes.org onco-hema.healthbooktimes.org/article/120914-evolving-treatment-landscape-in-endometrial-cancer

Evolving Treatment Landscape in Endometrial Cancer The safety profile for atezolizumab plus chemotherapy was manageable and consistent with previously reported data.52 An exploratory subgroup ...