Nab-Sirolimus for Neuroendocrine Tumors

Recruiting in Palo Alto (17 mi)

+3 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Aadi Bioscience, Inc.

Must be taking: Somatostatin analogs

Must not be taking: mTOR inhibitors, Strong CYP3A4 drugs

Disqualifiers: Uncontrolled hypertension, Severe heart disease, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests nab-sirolimus, a drug that targets tumors, in patients with advanced neuroendocrine tumors of the GI tract, lung, or pancreas. The drug works by blocking a protein that helps tumor cells grow and survive. Nab-sirolimus is the first agent specifically approved for advanced unresectable or metastatic malignant PEComa.

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

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

What data supports the effectiveness of the drug nab-sirolimus for neuroendocrine tumors?

Research shows that everolimus, a drug similar to nab-sirolimus, has been effective in treating advanced neuroendocrine tumors, especially when combined with other treatments like octreotide. This suggests that nab-sirolimus might also be effective for these types of tumors. ^{1 2 3 4 5}

Is nab-sirolimus safe for humans?

A study on nab-rapamycin (another name for nab-sirolimus) in patients with advanced cancers found it was generally safe, but determining the maximum safe dose was a key focus. Everolimus, a similar drug, has been linked to rare lung inflammation, which suggests monitoring for similar side effects might be important with nab-sirolimus. ^{1 2 6 7 8}

What makes nab-sirolimus unique for treating neuroendocrine tumors?

Nab-sirolimus is unique because it uses albumin-bound nanoparticles to deliver sirolimus, potentially enhancing its delivery to tumors compared to other treatments like everolimus, which is also an mTOR inhibitor but does not use this nanoparticle technology. ^{2 3 6 9 10}

Research Team

Willis Navarro, MD

Principal Investigator

Aadi Bioscience

Eligibility Criteria

This trial is for adults with well-differentiated neuroendocrine tumors in the GI tract, lung, or pancreas. They should not have had prior mTOR inhibitor treatment and can have up to two other therapies (excluding somatostatin analogs). Participants need functioning major organs, controlled HIV if present, no severe medical conditions or recent surgeries, and must use effective contraception.

Inclusion Criteria

Your blood triglyceride level must be below 300 mg/dL, and your cholesterol level must be 350 mg/dL or lower after fasting.

My liver is functioning within the required limits for the trial.

I have a progressing neuroendocrine tumor despite being on a stable somatostatin analog dose for 12 weeks or more.

Exclusion Criteria

My tests show TSC1 or TSC2 gene changes.

I do not have severe health issues that could affect my participation in the study.

I am currently being treated for a severe infection or finished treatment less than a week ago.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nab-sirolimus for the treatment of well-differentiated neuroendocrine tumors

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• nab-sirolimus (mTOR Inhibitor)

Trial Overview The study tests nab-sirolimus on patients who haven't used mTOR inhibitors before. It's a Phase 2 trial where all participants receive the same drug to see how it affects their cancer. The focus is on those with specific types of NETs that are advanced and cannot be surgically removed.

Participant Groups

Group I: neuroendocrine tumors Experimental Treatment 1 Intervention

Patients with well-differentiated neuroendocrine tumors of the gastrointestinal tract, lung, or pancreas.

Who Is Running the Clinical Trial?

Aadi Bioscience, Inc.

Lead Sponsor

Trials

18

Recruited

580+

Findings from Research

The maximum-tolerated dose (MTD) of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) was established at 100 mg/m², with most side effects being mild (grade 1/2), indicating a favorable safety profile for patients with advanced nonhematologic cancers.

Preliminary results showed that nab-rapamycin effectively inhibited mTOR targets and led to a partial response in one patient, suggesting potential efficacy in treating these malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weekly nab-Rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial. Gonzalez-Angulo, AM., Meric-Bernstam, F., Chawla, S., et al.[2021]

In a phase 2 trial involving 50 patients with advanced neuroendocrine tumors (NETs), the combination of everolimus and octreotide LAR demonstrated an objective response rate of 18%, with 92% of patients achieving clinical benefit (complete response, partial response, or stable disease).

The treatment was generally well tolerated, with most adverse events being mild (grade 1 or 2), indicating that this combination therapy could be a safe and effective first-line option for patients with NETs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus in combination with octreotide long-acting repeatable in a first-line setting for patients with neuroendocrine tumors: an ITMO group study. Bajetta, E., Catena, L., Fazio, N., et al.[2015]

In a phase 3 study involving 429 patients with advanced neuroendocrine tumors, the combination of everolimus and octreotide LAR significantly improved progression-free survival, with a median of 16.4 months compared to 11.3 months for the placebo group.

Most adverse events related to the treatment were mild (grade 1 or 2), with common side effects including stomatitis, rash, fatigue, and diarrhea, indicating that the combination therapy is generally well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Pavel, ME., Hainsworth, JD., Baudin, E., et al.[2022]

The combination of everolimus (RAD001) and octreotide LAR showed promising antitumor activity in patients with advanced neuroendocrine tumors, achieving a 20% response rate and a median progression-free survival of 60 weeks across 60 enrolled patients.

The treatment was well tolerated, with the most common side effect being mild aphthous ulceration, and significant reductions in tumor proliferation markers were observed, indicating a potential mechanism of action for the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. Yao, JC., Phan, AT., Chang, DZ., et al.[2023]

In a phase 3 study involving 410 patients with advanced pancreatic neuroendocrine tumors, everolimus significantly improved progression-free survival, with a median of 11.0 months compared to 4.6 months for placebo, indicating a 65% reduction in the risk of disease progression or death.

The treatment was associated with mostly mild to moderate side effects, such as stomatitis and rash, and had a low rate of severe adverse events, suggesting that everolimus is a safe and effective option for managing this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus for advanced pancreatic neuroendocrine tumors. Yao, JC., Shah, MH., Ito, T., et al.[2022]

The novel nano-amorphous formulation of sirolimus demonstrated improved pharmacokinetic properties, achieving higher plasma concentrations compared to the standard Rapamune® formulation, suggesting it may be more effective for treating conditions like renal cancer.

This new formulation showed low-to-moderate variability in drug absorption, which could reduce the need for regular therapeutic blood monitoring in kidney transplant patients, making it a potentially safer and more convenient option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers. Basa-Dénes, O., Angi, R., Kárpáti, B., et al.[2020]

Everolimus is an effective treatment for various advanced cancers, including renal cell carcinoma and advanced breast cancer, by inhibiting the mTOR pathway, which is crucial for cell growth and survival.

While most adverse events related to everolimus are mild to moderate, proper education and monitoring of both patients and healthcare providers are essential for managing these side effects and optimizing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer. Aapro, M., Andre, F., Blackwell, K., et al.[2023]

Somatostatin analogs like octreotide and pasireotide effectively inhibit hormone secretion and alleviate symptoms of neuroendocrine tumors, with pasireotide targeting a broader range of somatostatin receptors for enhanced activity.

Everolimus, an mTOR inhibitor, shows potential in cancer therapy by blocking pathways that promote cell growth and survival, making the combination of somatostatin analogs and everolimus a promising treatment strategy for neuroendocrine tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical review: Current scientific rationale for the use of somatostatin analogs and mTOR inhibitors in neuroendocrine tumor therapy. Bousquet, C., Lasfargues, C., Chalabi, M., et al.[2022]

References

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

Weekly nab-Rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial. [2021]

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

Everolimus in combination with octreotide long-acting repeatable in a first-line setting for patients with neuroendocrine tumors: an ITMO group study. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. [2022]

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

Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. [2023]

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

Everolimus for advanced pancreatic neuroendocrine tumors. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Everolimus-induced pneumonitis in neuroendocrine neoplasms: correlation of CT findings and clinical signs. [2021]

7. France pubmed.ncbi.nlm.nih.gov

Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Budget impact of everolimus for the treatment of progressive, well-differentiated, non-functional neuroendocrine tumors of gastrointestinal or lung origin that are advanced or metastatic. [2022]

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

Clinical review: Current scientific rationale for the use of somatostatin analogs and mTOR inhibitors in neuroendocrine tumor therapy. [2022]