Nab-Sirolimus + Letrozole for Endometrial Cancer

Recruiting at 9 trial locations

Overseen By Aadi Bioscience Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Aadi Bioscience, Inc.

Must not be taking: Strong CYP3A4 drugs

Disqualifiers: Brain metastases, Severe heart 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

29 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments, nab-Sirolimus (an experimental treatment) and Letrozole, to determine their effectiveness for patients with advanced or recurring endometrial cancer, which affects the lining of the uterus. Researchers aim to discover if these drugs can work together to shrink tumors or halt their growth. Suitable candidates include those with advanced endometrial cancer that cannot be surgically removed and who have undergone certain treatments in the past, but not more than one round of chemotherapy. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications that strongly interact with CYP3A4 enzymes, such as certain antibiotics and antifungals, before starting the study treatment. If you're on any of these, you'll need to discontinue them before your first dose of nab-sirolimus.

Is there any evidence suggesting that nab-Sirolimus + Letrozole is likely to be safe for humans?

Research has shown that nab-Sirolimus is generally safe for people. It is already approved in the U.S. to treat a rare cancer called PEComa. Studies indicate that nab-Sirolimus can provide long-term benefits. Safety data suggest its side effects resemble those of sirolimus, the main ingredient. Common side effects include mouth sores, tiredness, and nausea, but these are usually manageable. While specific safety data for nab-Sirolimus combined with letrozole is lacking, nab-Sirolimus alone has a consistent safety record. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about nab-sirolimus for endometrial cancer because it offers a fresh approach to treatment. Unlike traditional therapies that often focus on hormone receptors or chemotherapy, nab-sirolimus is a targeted therapy that inhibits a specific protein called mTOR, which plays a key role in cancer cell growth and survival. This mechanism can potentially lead to fewer side effects and improved effectiveness, especially for patients with advanced or recurrent endometrioid endometrial carcinoma. Additionally, its formulation as a nanoparticle allows for better delivery to cancer cells, which may enhance its efficacy compared to standard treatments.

What evidence suggests that nab-Sirolimus + Letrozole might be an effective treatment for endometrial cancer?

Research shows that nab-Sirolimus, one of the treatments studied in this trial, may help treat advanced or returning endometrial cancer when combined with letrozole. Earlier studies found that nab-Sirolimus had a strong effect on certain cancers, especially those with specific genetic changes. This drug blocks mTOR, a protein that helps cancer cells grow, potentially slowing or stopping cancer progression. Lab tests suggest that nab-Sirolimus can accumulate well in tumors, enhancing its effectiveness. Letrozole, often used for hormone-related cancers, might boost this effect by lowering estrogen levels, which can drive some cancers. Together, these drugs could offer a new treatment option for patients with endometrial cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Willis Navarro, MD

Principal Investigator

Aadi Bioscience

Are You a Good Fit for This Trial?

This trial is for adults with advanced or recurrent endometrioid endometrial cancer that can't be removed by surgery. Participants must have measurable cancer, acceptable organ function, and no severe infections or heart disease. They should not be pregnant, agree to use contraception, and cannot have certain other cancers or HIV/AIDS complications.

Inclusion Criteria

My endometrial cancer cannot be removed by surgery without severe risk.

I have a tumor that can be measured by CT or MRI.

My cancer is advanced or has come back and is a type called endometrioid endometrial carcinoma.

Exclusion Criteria

Patients with the following are excluded: Known or suspected brain metastases. Severe heart disease defined as unstable angina pectoris, New York Heart Association (NYHA) Class III or IV congestive heart failure, myocardial infarction ≤6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease. Severe lung disease defined as a diffusing capacity for carbon monoxide (DLCO) that is ≤50% of normal predicted value and/or an O2 saturation ≤88% at rest on room air (Note: spirometry and pulmonary function tests [PFTs] are not required to be performed unless clinically indicated). Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy. A history of malignancies other than the one under treatment unless the patient is disease-free for more than 5 years from completion of therapy administered with curative intent. Controlled non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer, certain low grade hematologic malignancies (eg, chronic lymphocytic leukemia [CLL], follicular lymphoma, etc), or other adequately treated carcinoma in situ may be eligible, after discussion with the Medical Monitor. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. Active hepatitis B and/or hepatitis C infection and detectable viral load despite antiviral therapy. Required use of concomitant medications with strong CYP3A4 interactions (induction or inhibition) should be discontinued (strong inhibitors include ketoconazole, itraconazole, voriconazole, erythromycin, clarithromycin, telithromycin; strong inducers include rifampin and rifabutin). These agents must be discontinued prior to first dose of nab-sirolimus.

I have been treated with an mTOR inhibitor before.

My condition improved with previous treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nab-sirolimus (IV on Days 1 and 8 in a 21-day cycle) combined with letrozole (orally, daily) until unacceptable toxicity, disease progression, or at patient discretion

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• nab-Sirolimus

Trial Overview The study tests nab-Sirolimus combined with Letrozole in patients with a specific type of uterine cancer. It's an open-label Phase 2 trial where everyone gets the same treatment to see how effective it is at controlling the disease.

How Is the Trial Designed?

Group I: Endometrioid Endometrial Cancer Experimental Treatment 1 Intervention

Patients with advanced or recurrent endometrioid endometrial carcinoma

nab-Sirolimus is already approved in United States, Canada for the following indications:

Approved in United States as FYARRO for:

• Locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa)

Approved in Canada as Sirolimus NAB for:

• Malignant perivascular epithelioid cell tumor (PEComa)

Who Is Running the Clinical Trial?

Aadi Bioscience, Inc.

Lead Sponsor

Trials

18

Recruited

580+

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]

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]

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]

A case study of a patient with low-grade metastatic endometrial stromal sarcoma (ESS) showed that combining the hormone treatment medroxyprogesterone acetate with the mTOR inhibitor sirolimus led to a partial response and maintained improvement for over 2 years.

This suggests that the addition of an mTOR inhibitor may help overcome hormone resistance in ESS, indicating a potential new treatment strategy that warrants further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversion of Hormone Treatment Resistance with the Addition of an mTOR Inhibitor in Endometrial Stromal Sarcoma. Martin-Liberal, J., Benson, C., Messiou, C., et al.[2021]

The combination of oral topotecan and everolimus in patients with advanced endometrial cancer showed dose-limiting toxicity primarily due to myelosuppression, specifically neutropenia and thrombocytopenia.

The maximum tolerated dose was determined to be 1.9 mg/m of topotecan on days 1 to 5 combined with 5 mg of everolimus every other day, indicating a need for careful dose management to avoid severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of the mammalian target of rapamycin inhibitor everolimus in combination with oral topotecan for recurrent and advanced endometrial cancer. Acevedo-Gadea, C., Santin, AD., Higgins, SA., et al.[2021]

Citations

1. aadibio.com aadibio.com/aadi-bioscience-recieves-fda-orphan-product-development-grant-for-treatment-of-advanced-pecoma-2-2-2-2/

Aadi Bioscience Breakthrough Therapy nab-Sirolimus (ABI ... Exploratory mutational analysis shows an 89% confirmed response rate in TSC2 mutated tumors; US FDA New Drug Application expected to be ...

2. prnewswire.com prnewswire.com/news-releases/aadi-bioscience-to-present-new-non-clinical-data-highlighting-combinability-of-nab-sirolimus-at-the-american-association-for-cancer-research-aacr-annual-meeting-302111705.html

Aadi Bioscience to Present New Non-clinical Data ... It will present new non-clinical data that highlight the combinability of nab-sirolimus and its potential for synergy to enhance anti-cancer effects and ...

3. firstwordpharma.com firstwordpharma.com/story/5860169

Aadi Bioscience Presents New Nonclinical Data ... nab-Sirolimus demonstrated significantly greater intratumoral drug concentration, stronger inhibition of mTOR targets and greater antitumor ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.02266

Phase II Trial of nab-Sirolimus in Patients With Advanced ... These results highlight the long-term clinical benefit of nab-sirolimus in patients with advanced malignant PEComa, with a DOR of >3 years.

5. targetedonc.com targetedonc.com/view/study-investigates-nab-sirolimus-plus-letrozole-in-advanced-endometrial-cancer

Study Investigates Nab-Sirolimus Plus Letrozole in ... Nonclinical data showed that nab-Sirolimus, an intravenous (IV) nanoparticle albumin-bound mTOR inhibitor, had improved tumor accumulation ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1048891X24163530

TP004/#1561 A phase 2, open-label, single-arm, ... nab-Sirolimus, an intravenous nanoparticle albumin-bound mTOR inhibitor (mTORi), is approved in the US for adults with advanced malignant perivascular ...

7. aadibio.com aadibio.com/update-aadi-bioscience-presents-two-abstracts-on-fyarro-nab-sirolimus-at-the-annual-meeting-of-the-connective-tissue-oncology-society-ctos/

Aadi Bioscience Presents Two Abstracts on FYARRO (nab- ... In this study, the safety profile of nab-sirolimus was ... Aadi's lead product candidate is FYARRO™ (sirolimus albumin-bound nanoparticles ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2022/213312Orig1s000IntegratedR.pdf

213312Orig1s000 INTEGRATED REVIEW - accessdata.fda.gov ABI-009) is sirolimus formulated as albumin-bound nanoparticles. ABI ... safety data are consistent with the known safety profile of sirolimus ...