Gemcitabine + Nab-Sirolimus for Sarcoma

Overseen By Gracy Zacharian, BSN,MSN,RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Active malignancy, Uncontrolled diabetes, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of two drugs, gemcitabine and nab-sirolimus (also known as Fyarro), for treating advanced sarcoma. Participants will receive these drugs in combination to evaluate their effectiveness together. The trial seeks individuals with sarcomas that are difficult to remove surgically or have metastasized, and who have specific gene changes identified through standard genetic tests. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use strong inhibitors or inducers of CYP3A4 within 7 days before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Previous studies indicate that patients taking gemcitabine and nab-sirolimus have generally tolerated the treatment well. Research shows that while side effects can occur, they are often manageable. For instance, a study on nab-sirolimus combined with another drug found that patients experienced side effects like tiredness and nausea, but these were usually mild or moderate.

Other studies have shown that the combination of gemcitabine and sirolimus can lead to positive outcomes in some patients with certain types of sarcomas. This suggests that the treatment can be effective while maintaining an acceptable level of safety.

Overall, this combination is still being tested to determine the best dose, so new side effects might be discovered. However, current evidence suggests that the combination is relatively safe, with known side effects that can be managed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Gemcitabine and Nab-Sirolimus for treating sarcoma because of its novel approach. Unlike standard treatments, which often focus on chemotherapy alone, this combination uses Nab-Sirolimus, an mTOR inhibitor that helps block cancer cell growth and survival pathways, alongside Gemcitabine, a chemotherapy drug. This dual approach targets the cancer more precisely, potentially leading to more effective treatment outcomes and minimizing the growth of resistant cancer cells.

What evidence suggests that this treatment might be an effective treatment for sarcoma?

Research has shown that nab-sirolimus, part of the treatment in this trial, delivers medicine more effectively to tumors due to its special tiny particle design, which targets solid tumors better. Studies have found that nab-sirolimus offers long-term benefits, particularly for some rare tumors. Gemcitabine, also included in this trial, is a chemotherapy drug known for successfully treating various cancers, including sarcomas. This trial examines whether combining these two drugs enhances their effectiveness against advanced sarcomas. Although early results are promising, further research is needed to confirm their combined effects. ^{1 5 6 7 8}

Who Is on the Research Team?

Elise F. Nassif

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for people with advanced leiomyosarcomas or soft-tissue sarcomas, specifically those with TSC2 or TSC1 loss-of-function mutations or deletions. The full eligibility criteria are not provided, but typically participants must meet certain health standards and may be required to have tried other treatments first.

Inclusion Criteria

Life expectancy of >3 months, as determined by the investigator

I can take care of myself but might not be able to do active work.

Women of child-bearing potential and men must agree to use adequate contraception from the time of study entry and for the duration of study participation. Negative serum HCG will be required before study drug administration. Approved methods of birth control are specified

Exclusion Criteria

Participants who are eligible for the PRECISION 1 trial, NCT05103358

I haven't taken strong CYP3A4 affecting drugs in the last week.

I have been treated for sarcoma with mTOR inhibitors before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of gemcitabine and nab-sirolimus to determine the Maximum Tolerated Dose (MTD) and assess safety and anti-tumor activity

Approximately 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and survival outcomes

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Gemcitabine
• Nab-Sirolimus

Trial Overview The trial is testing the combination of two drugs: Gemcitabine and Nab-Sirolimus. It aims to find a safe dosage that can be given together to treat patients with specific types of advanced sarcomas.

How Is the Trial Designed?

Group I: Gemcitabine + Nab-sirolimus Experimental Treatment 2 Interventions

Participants found to be eligible to take part in this study, participants will be assigned to a dose level of gemcitabine and nab-sirolimus based on when participants join this study.

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

Approved in European Union as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Aadi Bioscience

Collaborator

Trials

1

Recruited

10+

Published Research Related to This Trial

The combination of the mTOR inhibitor nab-sirolimus and the immune checkpoint inhibitor nivolumab was found to be safe for patients with advanced sarcoma, with a maximum-tolerated dose established at 100 mg/m2 and no unexpected adverse events reported.

While the treatment did not improve overall outcomes compared to nivolumab alone, the best responses were observed in patients with specific genetic mutations, such as PTEN loss and TSC2 mutation, indicating potential for biomarker-driven approaches in future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I/II Investigation of Safety and Efficacy of Nivolumab and nab-Sirolimus in Patients With a Variety of Tumors With Genetic Mutations in the mTOR Pathway. Gordon, EM., Angel, NL., Omelchenko, N., et al.[2023]

Ridaforolimus, an mTOR inhibitor, shows promising clinical activity against advanced soft tissue and bone sarcomas, with early trials indicating a strong pharmacokinetic profile and effective target inhibition.

The drug has demonstrated an acceptable safety and tolerability profile, making it a potential treatment option for patients with poor outcomes from existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ridaforolimus in advanced or metastatic soft tissue and bone sarcomas. Mita, MM., Gong, J., Chawla, SP.[2021]

The combination of the mTOR inhibitor sirolimus and the cytotoxic drug gemcitabine has shown enhanced antitumor activity in preclinical models of sarcoma, suggesting a promising new treatment approach.

A Phase I study indicated that this combination therapy has a favorable toxicity profile in patients with advanced solid tumors, warranting further investigation specifically for sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus plus gemcitabine: a new therapeutic combination for resistant sarcomas? Martin-Liberal, J., Tirado, OM., García del Muro, X.[2022]

TSC-mutated sarcomas are rare but sensitive to mTOR inhibitors, with nab-sirolimus being the only FDA-approved treatment for these tumors.

In two reported cases, patients with TSC-mutated sarcomas showed significant responses to a combination of gemcitabine and sirolimus after not responding to previous treatments, suggesting this combination could be a promising option when standard treatments fail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report: Responses to the combination of gemcitabine with sirolimus in two patients with TSC-mutated sarcomas. Nassif, EF., Joseph, CP., Lazcano, R., et al.[2023]

In a study of 16 pediatric patients with relapsed/refractory sarcomas, the combination of gemcitabine and nab-paclitaxel was found to be relatively safe, with 55% of treatment cycles resulting in Grade 3 or higher toxicity, primarily hematologic in nature.

The treatment provided clinical benefit to 31% of patients, with a median duration of stable disease of 4.5 months, indicating it may be a viable palliative option for some children with difficult-to-treat cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine/nab-paclitaxel for pediatric relapsed/refractory sarcomas. Metts, JL., Alazraki, AL., Clark, D., et al.[2022]

In a phase II trial involving 212 patients with advanced sarcomas, ridaforolimus demonstrated a clinical benefit response rate of 28.8%, indicating its potential effectiveness in this heavily pretreated population.

The treatment was associated with manageable side effects, primarily mild to moderate, such as stomatitis and fatigue, suggesting that ridaforolimus is a relatively safe option for patients with advanced sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. Chawla, SP., Staddon, AP., Baker, LH., et al.[2022]

Nab-paclitaxel, a less toxic and more effective drug than docetaxel, showed significant growth inhibition and improved survival in Ewing sarcoma models, suggesting its potential as a treatment option.

The combination of nab-paclitaxel and gemcitabine demonstrated additive effects in osteosarcoma models, supporting further research into this combination for treating bone sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of nanoparticle albumin-bound paclitaxel for treatment of pediatric bone sarcoma. Wagner, LM., Yin, H., Eaves, D., et al.[2015]

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.23.02266

Phase II Trial of nab-Sirolimus in Patients With Advanced ... These results highlight the long-term clinical benefit of nab-sirolimus in patients with advanced malignant PEComa, with a DOR of >3 years.

3. prnewswire.com prnewswire.com/news-releases/fyarro-sets-new-standard-in-rare-oncology-market-with-strong-growth-prospects--delveinsight-302431214.html

FYARRO Sets New Standard in Rare Oncology Market with ... FYARRO, the only FDA-approved treatment for advanced malignant PEComas, utilizes nanoparticle albumin-bound technology to deliver targeted ...

4. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2022/213312Orig1s000IntegratedR.pdf

213312Orig1s000 INTEGRATED REVIEW - accessdata.fda.gov ABI-009) is sirolimus formulated as albumin-bound nanoparticles. ABI ... Based on these results, ABI-009 did not result in any cardiac effects.

5. digitalcommons.library.tmc.edu digitalcommons.library.tmc.edu/cgi/viewcontent.cgi?article=2227&context=baylor_docs

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

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

A phase I study of nanoparticle albumin-bound sirolimus ... A phase I study of nanoparticle albumin-bound sirolimus (NAB-S) combined with pazopanib (PAZO) in patients with advanced soft tissue sarcoma (STS).

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9947835/

Case report: Responses to the combination of gemcitabine ... We report on two cases of patients with TSC-mutated sarcomas who experienced significant responses to the combination of gemcitabine and sirolimus.

8. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/sirolimus-albumin-bound-nanoparticles?pn=1

Clinical Trials Using Sirolimus Albumin-bound Nanoparticles Review the clinical trials studying sirolimus albumin-bound nanoparticles on this list and use the filters to refine the results by age and location.