Nab-Sirolimus + Endocrine Therapy for Ovarian Cancer

Overseen By Lead Nurse

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: University of Oklahoma

Must not be taking: Steroids, Immunosuppressants, CYP3A4 drugs

Disqualifiers: Infections, Lung disease, Cardiac 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

Compensation: Varies

Number of Visits: 1

Duration: 21-day cycles, ongoing as long as effective

37 Participants Needed

Trial Summary

What is the purpose of this trial?

This single arm phase II study proposes to evaluate the efficacy and safety of nab-sirolimus + endocrine therapy (Fulvestrant) in patients with recurrent low grade serous ovarian cancer (LGSOC).

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically those that are strong inducers or substrates of CYP3A4, at least 5 half-lives before starting the trial. If you are taking any of these medications, you will need approval from the Medical Monitor to participate.

What data supports the effectiveness of the drug Nab-Sirolimus + Endocrine Therapy for Ovarian Cancer?

Research suggests that mTOR inhibitors, like sirolimus, can play a role in treating ovarian cancer by blocking pathways that help cancer cells grow. Although mTOR inhibitors alone have shown limited effectiveness, combining them with other treatments, such as chemotherapy, may enhance their impact. ^{1 2 3 4 5}

Is Nab-Sirolimus generally safe for human use?

Sirolimus, used in various forms including Nab-Sirolimus, has been studied for safety in humans, particularly in kidney transplant patients. It can cause side effects like impaired wound healing, infections, and blood-related issues, but these are often manageable with additional treatments. It is considered relatively safe compared to some other drugs, though it can have specific side effects like lung issues and swelling. ^{4 5 6 7 8}

What makes the drug Nab-Sirolimus + Endocrine Therapy unique for ovarian cancer?

Nab-Sirolimus (a form of sirolimus bound to albumin nanoparticles) is unique because it uses nanotechnology to potentially enhance the drug's effectiveness and reduce side effects, which is a novel approach compared to traditional treatments for ovarian cancer. ^{9 10 11 12 13}

Research Team

Christina Washington, MD

Principal Investigator

OU Health Stephenson Cancer Center

Eligibility Criteria

This trial is for adults with recurrent low-grade serous ovarian cancer. Participants must be in good physical condition (ECOG 0-1), have measurable disease, and adequate organ function. They should not have had major surgery or radiation within the last 4 weeks and 2 weeks respectively, and must agree to effective contraception if of childbearing potential.

Inclusion Criteria

My ovarian cancer is low-grade and has come back.

I am fully active and can carry on all my pre-disease activities without restriction.

It has been over 2 weeks since my last radiation therapy session.

Exclusion Criteria

I have not taken drugs targeting the mTOR pathway, except possibly one chemotherapy or a MEK inhibitor.

I have severe lung issues and need oxygen sometimes.

I have not had a stroke or mini-stroke in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nab-sirolimus on days 1 and 8 and fulvestrant on days 1 and 15 of cycle 1, then every 21-day cycle

21-day cycles, ongoing as long as effective

Visits on days 1, 8, and 15 of cycle 1, then every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 2 years

Long-term monitoring

Participants are monitored for disease progression and adverse events

Up to 3 years

Treatment Details

Interventions

• Fulvestrant
• nab-Sirolimus

Trial Overview The study is testing the combination of nab-Sirolimus, a targeted therapy drug, with Fulvestrant, an endocrine therapy. It aims to assess how safe and effective this combo is for patients who've seen their ovarian cancer return after previous treatments.

Participant Groups

Group I: nab-sirolimus + Fulvestrant Experimental Treatment 2 Interventions

Patients will be treated with the combination nab-sirolimus (100 mg/m2 intravenous injection on day 1 and 8 of each 21-day cycle) and fulvestrant (500mg intramuscular injection on days 1 and 15 of cycle 1 and then every 21 days).

Fulvestrant is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in United States as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Canada as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Japan as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Who Is Running the Clinical Trial?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

Aadi Bioscience, Inc.

Industry Sponsor

Trials

18

Recruited

580+

Findings from Research

New targeted therapies for epithelial ovarian cancer are being developed, focusing on overcoming drug resistance and targeting specific receptors like HER, with combinations of drugs like erlotinib and cetuximab showing feasibility and good tolerance alongside standard chemotherapy.

Emerging treatments include proteasome inhibitors, mTOR inhibitors, and angiogenesis inhibitors, with ongoing trials exploring their effectiveness, indicating a shift towards personalized medicine based on genetic and molecular profiles of tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel targeted therapies in epithelial ovarian cancer: from basic research to the clinic. Gadducci, A., Cosio, S., Genazzani, AR.[2019]

Tyrosine kinase inhibitors (TKIs) combined with chemotherapy show promise in improving progression-free survival (PFS) in ovarian cancer patients, based on emerging data from phase I and II trials.

mTOR inhibitors appear to be less effective in treating ovarian cancer, highlighting the need for further research into targeting multiple signaling pathways and advancing promising treatments to phase III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinase Inhibitors and Ovarian Cancer. Katopodis, P., Chudasama, D., Wander, G., et al.[2023]

Sirolimus, an mTOR inhibitor, effectively reduced the expression of HIF-1alpha protein and decreased tumor growth in an ovarian carcinoma model using athymic mice, indicating its potential as a therapeutic agent.

The combination of sirolimus with paclitaxel showed the most significant reduction in tumor burden (51.0%) and increased apoptosis in cancer cells, suggesting that sirolimus enhances the effectiveness of standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Inhibition of hypoxia-inducible factor 1alpha expression and tumor growth in SKOV3 ovarian cancer model by sirolimus]. Jiang, HY., Feng, YJ.[2015]

In a study involving 44 women with platinum-refractory ovarian cancer or advanced endometrial carcinoma, the mTOR inhibitor temsirolimus was found to be well tolerated with mild toxicity, but it did not meet the predefined efficacy criteria for progression-free survival.

Despite the overall lack of efficacy, some patients experienced long-lasting disease stabilization, indicating that temsirolimus may still have potential benefits for a subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8). Emons, G., Kurzeder, C., Schmalfeldt, B., et al.[2016]

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]

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]

Sirolimus is an immunosuppressive drug that, while having a range of organ and tissue toxicities, offers significant benefits for renal transplant recipients, such as reducing the need for calcineurin inhibitors like cyclosporine and tacrolimus.

It also lowers the risk of certain post-transplant cancers, including lymphomas and Kaposi sarcomas, and has less nephrotoxicity compared to traditional calcineurin inhibitors, making it a valuable option in managing transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current approaches to the use of sirolimus in renal transplantation. Kahan, BD.[2014]

In a study of 24 renal transplant recipients who switched from tacrolimus to sirolimus, there was a significant increase in regulatory T cell frequencies and improved renal function after 3 and 6 months, suggesting enhanced immune regulation.

Conversion to sirolimus also led to decreased levels of inflammatory cytokines and changes in STAT protein activation, indicating a potential for reduced toxicity and promotion of immune tolerance in transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential regulation of Tregs and Th17/Th1 cells by a sirolimus-based regimen might be dependent on STAT-signaling in renal transplant recipients. Li, Y., Shi, Y., Liao, Y., et al.[2015]

In a phase II study of 85 patients with metastatic breast cancer, the combination of nab-paclitaxel and gemcitabine showed a significant objective response rate of 52.4%, with a median progression-free survival of 7.9 months and overall survival of 25.8 months.

The treatment was generally well tolerated, with common side effects including neutropenia and peripheral neuropathy, and tumor/stromal Caveolin-1 levels were identified as potential predictive biomarkers for treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caveolin-1 expression predicts efficacy of weekly nab-paclitaxel plus gemcitabine for metastatic breast cancer in the phase II clinical trial. Zhao, Y., Lv, F., Chen, 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]

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 study of 47 patients with recurrent ovarian, peritoneal, or fallopian tube cancer, nab-paclitaxel demonstrated a significant objective response rate of 64%, indicating its efficacy in this patient population.

The treatment was associated with manageable toxicities, primarily neutropenia (24%) and neuropathy (9%), suggesting that nab-paclitaxel could be a viable option for patients with limited therapeutic choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II evaluation of nanoparticle albumin-bound paclitaxel in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer. Teneriello, MG., Tseng, PC., Crozier, M., et al.[2015]

A phase 3 study (J-AXEL) is underway to compare the efficacy and safety of nab-paclitaxel to docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC), involving randomization of patients to receive either treatment until disease progression or unacceptable toxicity.

The primary goal of the study is to demonstrate that nab-paclitaxel is noninferior to docetaxel in terms of overall survival, which could establish nab-paclitaxel as a new treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Rationale and Design for J-AXEL: A Randomized Phase 3 Study Comparing Nab-Paclitaxel With Docetaxel in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. Yoneshima, Y., Morita, S., Ando, M., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Novel targeted therapies in epithelial ovarian cancer: from basic research to the clinic. [2019]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Kinase Inhibitors and Ovarian Cancer. [2023]

3. China pubmed.ncbi.nlm.nih.gov

[Inhibition of hypoxia-inducible factor 1alpha expression and tumor growth in SKOV3 ovarian cancer model by sirolimus]. [2015]

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

Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8). [2016]

5. England pubmed.ncbi.nlm.nih.gov

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

6. 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]

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

Current approaches to the use of sirolimus in renal transplantation. [2014]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Differential regulation of Tregs and Th17/Th1 cells by a sirolimus-based regimen might be dependent on STAT-signaling in renal transplant recipients. [2015]

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

Caveolin-1 expression predicts efficacy of weekly nab-paclitaxel plus gemcitabine for metastatic breast cancer in the phase II clinical trial. [2022]

10. 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]

11. Egypt pubmed.ncbi.nlm.nih.gov

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

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

Phase II evaluation of nanoparticle albumin-bound paclitaxel in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer. [2015]

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

Treatment Rationale and Design for J-AXEL: A Randomized Phase 3 Study Comparing Nab-Paclitaxel With Docetaxel in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. [2018]