Nab-sirolimus for Cancer

Recruiting at 185 trial locations

Overseen By Aadi Bioscience Medical Information

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Aadi, LLC

Must not be taking: mTOR inhibitors, CYP3A4 drugs

Disqualifiers: Brain tumors, Severe infections, 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: 9 months

120 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug on adults and adolescents with certain genetic changes in their tumors. These changes make their cancer hard to treat with standard methods. The drug works by blocking a pathway that helps the cancer grow, aiming to slow down or stop tumor growth. The drug has been studied for its effectiveness and safety in various types of cancer.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications that interact with CYP3A4 and P-gp enzymes, such as some antibiotics and antifungals, at least 5 half-lives before starting the trial drug. If you're on these medications, you'll need to discuss alternatives with your doctor.

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

Research shows that sirolimus, a component of nab-sirolimus, can enhance anticancer effects by inhibiting the mTOR pathway, which is important in many cancers. Additionally, similar nanoparticle formulations like nab-paclitaxel have shown increased drug accumulation in tumors and improved effectiveness in treating breast cancer, suggesting potential benefits for nab-sirolimus. ^{1 2 3 4 5}

Is nab-sirolimus generally safe for human use?

Sirolimus, including its nanoparticle forms like nab-sirolimus, has been used in humans primarily for organ transplantation and cancer treatment. It is generally considered safe, but it can cause side effects like impaired wound healing, infections, and blood-related issues, which are usually manageable with additional treatments. ^{6 7 8 9 10}

What makes the drug nab-sirolimus unique for cancer treatment?

Nab-sirolimus is unique because it uses nanotechnology to bind sirolimus (a drug that inhibits a protein involved in cell growth) to albumin, which helps deliver the drug more effectively to tumors and potentially reduces side effects compared to traditional formulations. ^{1 5 11 12 13}

Eligibility Criteria

Adults and adolescents (12+) with malignant solid tumors that can't be surgically removed or have spread, and have specific genetic changes in TSC1/TSC2 genes. They should have tried all standard treatments without success or not be suitable for them. Participants need to meet certain health criteria like good organ function, stable vital signs, and agree to use contraception.

Inclusion Criteria

Patients will be enrolled after the central evaluation of NGS report confirms eligibility

Adequate hematologic parameters: ANC ≥1.0 × 10^9/L, Platelet count ≥100,000/mm^3, Hemoglobin ≥8.0 g/dL

My liver is functioning within the required limits.

Exclusion Criteria

I stopped taking medications that affect drug processing in my body 5 half-lives ago.

I have a primary brain tumor or PEComa.

Active Hepatitis B or Hepatitis C with detectable viral load

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive single agent IV nab-sirolimus until disease progression, unacceptable toxicity, or at patient discretion

9 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• nab-sirolimus

Trial Overview The trial is testing nab-sirolimus on patients with advanced cancer who carry certain genetic alterations. It's an open-label study where everyone knows what treatment they're getting, aiming to see how effective this drug is against various types of solid tumors.

Participant Groups

Group I: Arm B: Pathogenic inactivating TSC2 alterations Experimental Treatment 1 Intervention

Patients with pathogenic inactivating TSC2 alterations.

Group II: Arm A: Pathogenic inactivating TSC1 alterations Experimental Treatment 1 Intervention

Patients with pathogenic inactivating TSC1 alterations.

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, LLC

Lead Sponsor

Trials

8

Recruited

310+

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]

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]

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]

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]

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]

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]

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 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]

A new preanalytical procedure for measuring sirolimus in whole blood using LC/ESI-MS/MS has been developed, which minimizes matrix effects and allows for accurate quantification within a detection range of 0.5-50 ng/mL, suitable for therapeutic drug monitoring (TDM).

This method showed better accuracy compared to commercially available immunoassays, which tended to overestimate sirolimus levels due to potential cross-reactivity with metabolites, making the new procedure a reliable reference for future analytical methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An accurate quantitative LC/ESI-MS/MS method for sirolimus in human whole blood. Mano, N., Sato, M., Nozawa, M., et al.[2013]

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]

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]

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]

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. England 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. [2019]

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

Enhanced Cytotoxicity to Cancer Cells by Codelivery and Controlled Release of Paclitaxel-loaded Sirolimus-conjugated Albumin Nanoparticles. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Layer-by-layer-coated lyotropic liquid crystalline nanoparticles for active tumor targeting of rapamycin. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

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

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

Nanomedicine approaches for sirolimus delivery: a review of pharmaceutical properties and preclinical studies. [2019]

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

Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose. [2022]

8. United States 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. [2014]

9. 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]

10. Netherlands pubmed.ncbi.nlm.nih.gov

An accurate quantitative LC/ESI-MS/MS method for sirolimus in human whole blood. [2013]

11. England pubmed.ncbi.nlm.nih.gov

A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer. [2023]

12. Egypt pubmed.ncbi.nlm.nih.gov

Nanoparticle albumin bound Paclitaxel in the treatment of human cancer: nanodelivery reaches prime-time? [2022]

13. United States 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. [2021]