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

Trial Summary

What is the purpose of this trial?

A Phase 2 Multi-center Open-label Trial of nab-Sirolimus in Combination with Letrozole in Advanced or Recurrent Endometrioid Endometrial Cancer

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.

What data supports the effectiveness of the drug nab-Sirolimus + Letrozole for endometrial cancer?

Research shows that targeting the mTOR pathway, which is often active in endometrial cancer, can help overcome resistance to hormone treatments. Everolimus, a drug similar to nab-Sirolimus, has shown benefits in treating advanced endometrial cancer, especially when combined with letrozole, suggesting potential effectiveness for nab-Sirolimus + Letrozole. ^{1 2 3 4 5}

Is the combination of nab-Sirolimus and Letrozole generally safe for humans?

There is limited safety data specifically for nab-Sirolimus and Letrozole in endometrial cancer, but a similar drug, everolimus, has shown clinical benefits with some severe side effects in other studies. In one case, sirolimus, a related drug, was used with minimal toxicity for over two years in a patient with a different type of cancer. ^{1 2 3 4 6}

What makes the drug nab-Sirolimus + Letrozole unique for treating endometrial cancer?

Nab-Sirolimus + Letrozole is unique because it combines a targeted therapy (nab-Sirolimus) with a hormone therapy (Letrozole) to potentially overcome resistance in endometrial cancer by targeting the PI3K/AKT/mTOR pathway, which is often active in these cancers. This combination aims to enhance treatment effectiveness by addressing both hormonal and molecular pathways involved in the disease. ^{1 2 3 4 5}

Research Team

Willis Navarro, MD

Principal Investigator

Aadi Bioscience

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Novel polymer-based system for intrauterine delivery of everolimus for anti-cancer applications. [2022]

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. Italy pubmed.ncbi.nlm.nih.gov

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

5. England 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. [2021]

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

Reversion of Hormone Treatment Resistance with the Addition of an mTOR Inhibitor in Endometrial Stromal Sarcoma. [2021]