Nab-Sirolimus for Neuroendocrine Tumors

Recruiting at 3 trial locations

Overseen By Aadi Bioscience Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 2

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 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 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

21 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called nab-sirolimus (an mTOR inhibitor) to evaluate its effectiveness for people with certain types of neuroendocrine tumors (NETs) not previously treated with mTOR inhibitors. These tumors affect areas like the gastrointestinal tract, lungs, or pancreas and can be either functional or non-functional, meaning they may or may not cause symptoms from hormone secretion. The trial seeks participants who have experienced disease progression despite having had two or fewer previous treatments and have measurable tumors. The goal is to determine if nab-sirolimus can manage these tumors more effectively. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that nab-sirolimus has undergone safety testing in humans. One study found nab-sirolimus to be tolerable for patients, though some participants experienced side effects like mouth sores and fatigue. These side effects were generally manageable.

Nab-sirolimus already has FDA approval for treating another type of tumor, indicating its general safety. However, individual reactions to treatments can vary. Prospective trial participants should discuss any concerns with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for neuroendocrine tumors?

Unlike the standard treatments for neuroendocrine tumors, which typically include options like surgery, somatostatin analogs, and targeted therapies, nab-sirolimus offers a novel approach. Nab-sirolimus is a nanoparticle albumin-bound form of sirolimus, which allows for better delivery of the drug directly to the tumor cells. This innovative formulation enhances the drug's ability to inhibit the mTOR pathway, a key driver in the growth of neuroendocrine tumors. Researchers are excited because this method of delivery could potentially increase the treatment's effectiveness while reducing side effects compared to existing therapies.

What evidence suggests that nab-sirolimus might be an effective treatment for neuroendocrine tumors?

Research shows that nab-sirolimus, the investigational treatment in this trial, could be a promising option for neuroendocrine tumors. Studies have found that its special formulation delivers the drug more effectively to tumors. This treatment targets a protein called mTOR, which aids cancer cell growth. By blocking mTOR, nab-sirolimus can slow or stop tumor growth. Similar drugs, like rapamycin, have successfully treated various solid tumors, suggesting nab-sirolimus might work similarly. Early research indicates that nab-sirolimus could be effective, with some studies showing high response rates in certain tumor types. Overall, these findings support nab-sirolimus as a hopeful treatment option for neuroendocrine tumors. ^{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 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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• nab-sirolimus

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.

How Is the Trial Designed?

Group I: neuroendocrine tumors Experimental Treatment 1 Intervention

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

nab-sirolimus is already approved in United States for the following indications:

Approved in United States as Fyarro for:

• Advanced malignant perivascular epithelioid cell tumors (PEComa)

Who Is Running the Clinical Trial?

Aadi Bioscience, Inc.

Lead Sponsor

Trials

18

Recruited

580+

Published Research Related to This Trial

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]

Everolimus, an mTOR inhibitor approved for advanced neuroendocrine tumors (NETs), shows significant clinical benefits, including longer progression-free survival for patients with gastrointestinal and lung NETs.

The budget impact of everolimus on a typical US health plan is minimal, estimated at $0.0568-$0.1443 per member per month for GI NETs and $0.0181-$0.0355 for lung NETs, largely due to the low prevalence of these rare diseases.

NCBI (Pubmed)

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. Rose, DB., Nellesen, D., Neary, MP., et al.[2022]

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]

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]

In a study of 90 patients with neuroendocrine neoplasms treated with everolimus, 20% developed drug-induced pneumonitis, highlighting a significant adverse effect of this treatment.

CT scans can detect pneumonitis even before symptoms appear, but there is no clear correlation between clinical symptoms, pulmonary function tests, and CT findings, suggesting that monitoring asymptomatic patients is crucial for timely intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus-induced pneumonitis in neuroendocrine neoplasms: correlation of CT findings and clinical signs. Fehrenbach, U., Rodríguez-Laval, V., Jann, H., et al.[2021]

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]

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 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]

Citations

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A pilot phase 2 study of albumin-bound sirolimus ... Recently the FDA has approved radionuclide therapy with Lu-177 in patients with gastroenteropancreatic neuroendocrine tumors (GEPNETs) based off a study ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11533328/

A Phase 1 Study of ABI‐009 (Nab‐sirolimus) in ... This enhances the accumulation of albumin‐bound drug in solid tumors, and may improve drug delivery, efficacy, and reduce the risk of ...

3. 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 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3935482/

Weekly nab-Rapamycin in Patients with Advanced ... mTOR inhibition with rapamycin and rapalogs (everolimus, temsirolimus) has proven to be effective in various solid tumors including renal cell carcinoma, ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05997056?term=AREA%5BInterventionSearch%5D(FYARRO)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=2

Trial of Nab-sirolimus in Patients With Well-differentiated ... This is a prospective phase 2 single arm, open-label, multi-institutional study to determine the efficacy and safety prospective of nab-sirolimus and ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39487711/

A Phase 1 Study of ABI-009 (Nab-sirolimus) in Combination ... This phase I trial was conducted to define dose-limiting toxicities (DLT), maximum tolerated or recommended phase II dose (MTD/RP2D), and pharmacokinetics of ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/213312lbl.pdf

FYARRO (SIROLIMUS ALBUMIN-BOUND NANOPARTICLES ... FYARRO is contraindicated in patients with a history of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin [see Warnings and ...

8. cancernetwork.com cancernetwork.com/view/fda-approves-nab-sirolimus-for-locally-advanced-unresectable-or-metastatic-pecoma

FDA Approves Nab-Sirolimus for Locally Advanced ... The FDA approved nab-sirolimus as the first drug specifically indicated for the treatment of patients with malignant perivascular epithelioid cell tumors.