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

12 Participants Needed

Trial Summary

What is the purpose of this trial?

To find a recommended dose of gemcitabine and nab-sirolimus that can be given in combination to participants with advanced leiomyosarcomas or soft-tissue sarcomas.

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.

What data supports the effectiveness of the drug combination Gemcitabine and Nab-Sirolimus for treating sarcoma?

Research shows that the combination of gemcitabine and sirolimus (a type of drug that blocks a protein called mTOR) has shown significant responses in patients with certain types of sarcoma, especially those with specific genetic mutations. Preclinical studies and a Phase I study suggest that this combination may work better together than alone, and it has been effective in cases where other treatments failed. ^{1 2 3 4 5}

Is the combination of Gemcitabine and Nab-Sirolimus safe for humans?

A Phase I study showed that the combination of sirolimus (a type of mTOR inhibitor) and gemcitabine has a favorable safety profile in patients with advanced solid tumors, suggesting it is generally safe for humans. ^{1 2 3 6 7}

What makes the drug Gemcitabine + Nab-Sirolimus unique for treating sarcoma?

The combination of Gemcitabine and Nab-Sirolimus is unique because it targets sarcomas with a specific mutation (TSC mutation) that makes them sensitive to mTOR inhibitors, and it has shown enhanced antitumor activity compared to using each drug alone. This combination may offer a new option for patients with limited treatment choices, especially after other therapies have failed. ^{1 2 3 6 7}

Research Team

Elise F. Nassif

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

I am 18 years old or older.

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.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: Responses to the combination of gemcitabine with sirolimus in two patients with TSC-mutated sarcomas. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Sirolimus plus gemcitabine: a new therapeutic combination for resistant sarcomas? [2022]

3. Greece 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. [2023]

4. United States 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. [2022]

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

Ridaforolimus in advanced or metastatic soft tissue and bone sarcomas. [2021]

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

Preclinical evaluation of nanoparticle albumin-bound paclitaxel for treatment of pediatric bone sarcoma. [2015]

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

Gemcitabine/nab-paclitaxel for pediatric relapsed/refractory sarcomas. [2022]