Nab-Sirolimus for Cancer

Recruiting at 1 trial location

Overseen By Aadi Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Aadi Bioscience, Inc.

Must not be taking: mTOR inhibitors, Antiretrovirals, Corticosteroids

Disqualifiers: Uncontrolled hypertension, Severe infection, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 2

Duration: 2 weeks

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores nab-sirolimus, an experimental treatment for individuals with advanced or spreading solid tumors. Researchers aim to assess the safety and effectiveness of this drug, particularly in those with normal liver function or moderate liver issues. The trial targets individuals with confirmed solid tumors who manage daily life without severe medical problems. It offers a chance for those who haven't recently used similar treatments to try something new. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, providing participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have taken an mTOR inhibitor within 4 weeks before the first dose, and high-dose systemic corticosteroids are not allowed within 2 weeks of the first dose.

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

Research has shown that nab-sirolimus has been tested in people before. In these studies, researchers used it to treat certain types of tumors, and most participants tolerated the treatment well. Some experienced side effects, usually mild, such as nausea or fatigue. Importantly, the FDA has already approved nab-sirolimus for treating a specific tumor type called PEComa, indicating an acceptable safety level for that condition. While this new trial is just beginning, existing research provides some reassurance about the treatment's safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about nab-sirolimus because it offers a new approach to treating cancer. Unlike traditional therapies that often target cancer cells directly, nab-sirolimus is a form of sirolimus bound to nanoparticles, which may enhance its delivery and effectiveness. This unique delivery method allows the drug to target tumors more precisely, potentially reducing side effects and improving outcomes. By focusing on inhibiting a protein called mTOR, nab-sirolimus disrupts the growth and spread of cancer cells in a way that current treatments may not.

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

Research has shown that nab-sirolimus, the treatment under study in this trial, holds potential for treating certain cancers. In earlier studies, nab-sirolimus led to partial improvements in patients with tumors such as leiomyosarcoma and solitary fibrous tumor. Specifically, for patients with malignant PEComa, nab-sirolimus proved effective, resulting in significant response rates and disease control. This treatment delivers more of the drug directly to the tumor, potentially increasing its effectiveness. Overall, nab-sirolimus offers a new approach to targeting tumors, which may lead to better outcomes. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

Adults with advanced or metastatic solid tumors and moderate liver issues (or normal liver function) can join this trial. They must be able to consent, have an ECOG score of 0-2, not be pregnant or breastfeeding, use effective birth control, and have recovered from previous treatments. People with severe lung problems, uncontrolled illnesses, recent heart attacks or infections requiring IV antibiotics cannot participate.

Inclusion Criteria

Creatinine clearance ≥30 mL/min as assessed by the Cockcroft-Gault equation

Willing and able to provide informed consent and comply with protocol requirements for the duration of the study

Fasting serum triglyceride must be ≤300 mg/dL; fasting serum cholesterol must be ≤350 mg/dL

Exclusion Criteria

I have taken an mTOR inhibitor within the last 4 weeks.

I do not have severe medical or psychiatric conditions that could affect my participation in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nab-sirolimus by intravenous infusion over 30 minutes on Days 1 and 8

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• nab-sirolimus

Trial Overview The study is testing different doses of nab-sirolimus to find a safe amount for patients with solid tumors who also have moderate liver impairment. It's an early-phase trial where everyone gets the drug; there are no comparison groups.

How Is the Trial Designed?

Group I: Experimental Experimental Treatment 1 Intervention

nab-Sirolimus

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

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 II trial involving 45 patients with advanced gastric cancer, the combination of nab-paclitaxel and ramucirumab achieved an overall response rate of 54.8%, indicating significant efficacy as a second-line treatment.

The treatment was associated with manageable side effects, primarily decreased neutrophil and white blood cell counts, but no treatment-related deaths occurred, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer. Bando, H., Shimodaira, H., Fujitani, K., et al.[2023]

Sirolimus, an mTOR inhibitor, when conjugated to albumin nanoparticles and combined with paclitaxel, significantly reduced cell viability in breast cancer cell lines, indicating enhanced anticancer effects compared to non-conjugated nanoparticles.

The study found that sirolimus-conjugated nanoparticles with lower concentrations of paclitaxel (0.01 μg/mL) resulted in a 44% cell viability in MDA-MB-468 cells, compared to 53% for non-conjugated nanoparticles, suggesting that the timing and method of drug release can optimize treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced Cytotoxicity to Cancer Cells by Codelivery and Controlled Release of Paclitaxel-loaded Sirolimus-conjugated Albumin Nanoparticles. Behrouz, H., Esfandyari-Manesh, M., Khoeeniha, MK., et al.[2021]

Nab-paclitaxel, a formulation of paclitaxel bound to nanoparticles, shows reduced risk of hypersensitivity reactions and allows for potential dose escalation, making it a safer option for patients.

In Phase III studies, nab-paclitaxel demonstrated better efficacy and tolerability compared to conventional treatments like docetaxel and paclitaxel in patients with metastatic breast cancer, suggesting its potential for broader use in other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[nab-Paclitaxel. Clinical value of an innovative taxane-containing formulation]. Lipp, HP.[2015]

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]

The developed micelles of PEG-rapamycin conjugates can effectively co-deliver paclitaxel and rapamycin, enhancing their combined therapeutic effects against cancer.

This novel nanomedicine demonstrated a 20-fold increase in potency compared to free paclitaxel when tested on multidrug-resistant human breast cancer cells, suggesting it can overcome common drug resistance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Self-assembled micelles of amphiphilic PEGylated rapamycin for loading paclitaxel and resisting multidrug resistant cancer cells†Electronic supplementary information (ESI) available: Chemicals and reagents, detailed experimental procedures for materials synthesis, characterization, cellular evaluations and supporting figures and tables. See DOI: 10.1039/c4tb01633eClick here for additional data file. Tian, W., Liu, J., Guo, Y., et al.[2019]

Nab-paclitaxel, a nanoparticle albumin-bound form of paclitaxel, is the first nanotechnology-based drug approved for cancer treatment, showing significant promise in breast and pancreatic cancers.

This innovative drug not only enhances the effectiveness and reduces the toxicity of traditional treatments but also demonstrates activity in cancers that typically do not respond to standard taxane therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanoparticle albumin bound Paclitaxel in the treatment of human cancer: nanodelivery reaches prime-time? Cucinotto, I., Fiorillo, L., Gualtieri, S., et al.[2022]

Sirolimus has become a foundational therapy for immunosuppression in transplant patients, significantly reducing the risk of acute allograft rejection by allowing over 80% reduction in calcineurin inhibitor exposure, which leads to better long-term renal function despite some increased risks of lymphoceles and impaired wound healing.

The drug also has anti-cancer properties by inhibiting mTOR, reducing tumor incidence in patients, and is relatively non-nephrotoxic, allowing for the withdrawal of steroid therapy and lower rates of viral infections, making it a promising option in immunosuppressive regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fifteen years of clinical studies and clinical practice in renal transplantation: reviewing outcomes with de novo use of sirolimus in combination with cyclosporine. Kahan, BD.[2014]

The layer-by-layer (LbL) coating of liquid crystalline nanoparticles (Rap-LbL-LCNPs) significantly improved the water solubility and bioavailability of rapamycin, showing a 3.35-fold increase compared to the free drug.

In tests on CD44-overexpressed MDA-MB-231 cancer cells, Rap-LbL-LCNPs exhibited superior cytotoxicity, inhibited tumor growth, enhanced survival in animal models, and reduced side effects like nephrotoxicity and hyperglycemia associated with rapamycin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Layer-by-layer-coated lyotropic liquid crystalline nanoparticles for active tumor targeting of rapamycin. Freag, MS., Elnaggar, YS., Abdelmonsif, DA., et al.[2022]

Sirolimus, an mTOR inhibitor with multiple therapeutic properties, faces challenges in clinical use due to poor solubility and low bioavailability, but recent advancements in pharmaceutical nanotechnology show promise for improving its delivery.

Various nanostructured carriers, including liposomes and polymeric nanoparticles, are being explored to enhance sirolimus delivery for conditions like organ transplantation and cancer, with the FDA-approved Rapamune® tablet being the first nanoparticle-based formulation available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanomedicine approaches for sirolimus delivery: a review of pharmaceutical properties and preclinical studies. Haeri, A., Osouli, M., Bayat, F., et al.[2019]

Sirolimus is rapidly absorbed and slowly eliminated from the body, with a half-life of about 60 hours, indicating that it remains in the system for an extended period, which is important for its use in preventing organ rejection after transplantation.

The metabolites of sirolimus, while present in the blood, do not significantly contribute to its immunosuppressive effects, as they have low activity compared to the parent drug, suggesting that sirolimus itself is the primary agent responsible for its therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose. Leung, LY., Lim, HK., Abell, MW., et al.[2022]

In a phase 1b study involving 23 patients with advanced solid tumors, sirolimus at a weekly dose of 40 mg combined with nab-paclitaxel showed an acceptable safety profile, with manageable dose-limiting toxicities.

The study found that changes in AKT expression and FDG activity after treatment could serve as early predictors of response to sirolimus, indicating potential biomarkers for treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel in patients with advanced solid tumors. Abu-Khalaf, MM., Baumgart, MA., Gettinger, SN., et al.[2021]

Citations

1. 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 ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.11521

A phase I study of nanoparticle albumin-bound sirolimus ... Four (21%) remain on study as of 2/2023. 18 were evaluable for best response: 3 partial responses (PR; leiomyosarcoma, solitary fibrous tumor, ...

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

FYARRO (SIROLIMUS ALBUMIN-BOUND NANOPARTICLES ... The efficacy results are summarized in Table 6. Table 6. Efficacy Results in AMPECT. Efficacy Endpoints. FYARRO. (N=31). Overall Response Rate (95% CI)*. 39% ( ...

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/30/NCT03670030/Prot_SAP_002.pdf

A pilot phase 2 study of albumin-bound sirolimus ... The novel nanoparticle albumin-bound sirolimus (formerly nab-rapamycin, ABI-009) is freely dispersible in saline and is suitable for IV administration, and has ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8601264/

nab-Sirolimus for Patients With Malignant Perivascular ... nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support

6. aadibio.com aadibio.com/aadi-bioscience-announces-publication-of-its-phase-2-registrational-ampect-trial-of-nab-sirolimus-in-patients-with-malignant-perivascular-epithelioid-cell-tumors-in-the-journal-of-clinical-oncology/

Aadi Bioscience Announces Publication of its Phase 2 ... The authors concluded that investigational nab-sirolimus (ABI-009, formerly known as nab-rapamycin), if approved, may represent an important new ...