Metronomic Chemotherapy for Leiomyosarcoma

(TAGGED Trial)

Overseen By Victoria Chua-Alcala, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sarcoma Oncology Research Center, LLC

Disqualifiers: Pregnancy, Breastfeeding, Investigational treatment, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: up to 12 months

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new chemotherapy approach for individuals with leiomyosarcoma, a cancer affecting smooth muscle tissue. Researchers aim to test the effectiveness and safety of a combination of three drugs—trabectedin (Yondelis), gemcitabine, and dacarbazine—administered in small, regular doses. This trial suits those previously treated for advanced leiomyosarcoma that cannot be surgically removed and who are willing to undergo intravenous treatment. Participants should be able to manage daily activities with some effort and have had their disease measured by doctors. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are currently in another investigational drug study, you must wait at least 14 days after ending that treatment before joining this trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that trabectedin treatment is generally well-tolerated by patients with certain sarcomas, such as leiomyosarcoma. Studies have found that combining trabectedin with other drugs does not lead to unexpected side effects. Patients with leiomyosarcoma who received trabectedin showed better results compared to those with other sarcoma types.

The FDA has already approved trabectedin for treating specific cancers, indicating that its safety is well-understood. However, like all treatments, it can have side effects. Potential participants should discuss with the medical team to understand how the treatment might affect them personally. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about trabectedin for treating leiomyosarcoma because it works differently than traditional chemotherapy options like doxorubicin or ifosfamide. Trabectedin targets the DNA of cancer cells to disrupt their ability to multiply, which is a unique approach. Additionally, the combination with gemcitabine and dacarbazine in a metronomic schedule—meaning it's given in smaller, more frequent doses—may enhance its effectiveness while potentially reducing side effects. This innovative approach offers hope for a more effective and tolerable treatment for patients with this challenging cancer.

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

Research shows that trabectedin effectively treats leiomyosarcoma, a type of soft tissue cancer. Studies have found that trabectedin can help patients live longer without their cancer worsening, compared to dacarbazine, another cancer drug. Specifically, trabectedin lowered the risk of disease progression by 45% in patients with advanced soft tissue sarcoma. Additionally, it benefits those with recurring or spreading uterine leiomyosarcoma. These findings suggest that trabectedin could be a promising option for managing leiomyosarcoma. Participants in this trial will receive trabectedin as part of a single-arm study, alongside gemcitabine and dacarbazine. ^{1 4 5 6 7}

Who Is on the Research Team?

Sant P Chawla, MD

Principal Investigator

Sarcoma Oncology Research Center, LLC

Are You a Good Fit for This Trial?

Adults with advanced leiomyosarcoma, previously treated and measurable by certain criteria, can join this trial. They must have a life expectancy of at least 3 months, be able to perform daily activities (ECOG ≤ 2), and have proper liver, kidney, and blood function. Participants must agree to use effective contraception during the study.

Inclusion Criteria

My kidney function is within the required range.

My liver functions within normal limits, or close to it, even if I have liver metastases.

My cancer is a type called leiomyosarcoma and cannot be removed by surgery.

Exclusion Criteria

I am a woman able to have children and agree to use birth control during and for 3 months after treatment.

I am not currently in another drug study and it's been over 14 days since my last one.

I am allergic to trabectedin, gemcitabine, or dacarbazine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trabectedin, gemcitabine, and dacarbazine intravenously in 3-week cycles

up to 12 months

Visits on Day 1 and Day 8 of each 3-week cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Trabectedin

Trial Overview

The trial is testing metronomic doses of trabectedin combined with gemcitabine and dacarbazine in patients with leiomyosarcoma. It's an open-label phase 2 study where all participants receive the drugs intravenously to evaluate their effectiveness.

How Is the Trial Designed?

Group I: Single arm Experimental Treatment 1 Intervention

Trabectedin 24 h CIV 0.5 mg/m2 D1 and D8 Gemcitabine i.v. 250 mg/m2 D1 and D8 Dacarbazine i.v. 250 mg/m2 D1 and D8

Trabectedin is already approved in European Union, United States for the following indications:

Approved in European Union as Yondelis for:

• Metastatic or unresectable liposarcoma
• Metastatic or unresectable leiomyosarcoma

Approved in United States as Yondelis for:

• Metastatic or unresectable liposarcoma
• Metastatic or unresectable leiomyosarcoma

Who Is Running the Clinical Trial?

Sarcoma Oncology Research Center, LLC

Lead Sponsor

Trials

9

Recruited

910+

Published Research Related to This Trial

The combination of Doxorubicin and Trabectedin has been shown to improve progression-free survival (PFS) and disease control rate (DCR) in patients with advanced leiomyosarcoma compared to Doxorubicin alone, marking a significant advancement in treatment options.

Previous combination therapies for advanced leiomyosarcoma had failed to show improved outcomes, making the LMS-04 trial results pivotal as they demonstrate that Doxorubicin-Trabectedin is the first effective combination therapy in this setting, despite higher but manageable toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin combined with Trabectedin in systemic first-line M+/recurrent leiomyosarcoma patients. Turinetto, M., Meeus, P., Ray-Coquard, I.[2023]

In a phase 2 trial involving 109 patients with metastatic uterine or soft-tissue leiomyosarcoma, the combination of doxorubicin and trabectedin demonstrated significant disease control, with 87.2% of uterine leiomyosarcoma patients and 91.8% of soft-tissue leiomyosarcoma patients achieving disease control.

While the treatment was associated with manageable side effects, including neutropenia and fatigue, the results indicate that this combination therapy is a promising first-line option and warrants further investigation in a phase 3 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial. Pautier, P., Floquet, A., Chevreau, C., et al.[2022]

In a study of 36 women with advanced uterine leiomyosarcoma treated with trabectedin, the median progression-free survival was 5.4 months and overall survival was 18.5 months, indicating that trabectedin can provide significant clinical benefits after anthracycline treatment.

The study found that patients receiving trabectedin earlier in their treatment (≤ 2nd line) had a significantly better overall survival (25.3 months) compared to those receiving it later (≥ 3rd line, 15.1 months), highlighting the importance of treatment timing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of trabectedin in metastatic uterine leiomyosarcoma: A retrospective multicenter study of the Spanish ovarian cancer research group (GEICO). Rubio, MJ., Lecumberri, MJ., Varela, S., et al.[2022]

Trabectedin has shown promise as a long-term treatment option for patients with uterine leiomyosarcoma, achieving a very good partial response in a patient who had previously failed multiple chemotherapy regimens.

Despite initial severe side effects, dose adjustments allowed for acceptable tolerability, and the patient has maintained stable disease for 2 years on trabectedin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stable disease in a patient with metastatic leiomyosarcoma treated with trabectedin. Tavella, K., Villanucci, A., Vannini, L., et al.[2022]

Management of leiomyosarcoma (LMS) is highly individualized, depending on factors like tumor location, whether the disease is localized or metastatic, and the resectability of the tumor.

For patients with recurrent or metastatic LMS, systemic chemotherapy is typically the first-line treatment, with options including anthracycline or gemcitabine regimens, and emerging therapies may be guided by tumor genomics for more personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leiomyosarcoma: Does Location of Primary Help to Determine the Best Systemic Therapy Options? Novotny, JP., George, S.[2022]

In a phase II study involving 270 patients with advanced liposarcoma or leiomyosarcoma, the trabectedin regimen administered every 3 weeks via a 24-hour infusion showed a significantly longer median time to progression (3.7 months) compared to the weekly 3-hour infusion regimen (2.3 months).

The 3-week regimen also demonstrated better progression-free survival (3.3 months vs. 2.3 months) and was generally well tolerated, with rare occurrences of severe side effects like febrile neutropenia, suggesting trabectedin is a promising treatment option for patients who have not responded to standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. Demetri, GD., Chawla, SP., von Mehren, M., et al.[2022]

In a phase 3 trial involving 150 patients with metastatic or unresectable leiomyosarcomas, the combination of doxorubicin and trabectedin significantly improved progression-free survival compared to doxorubicin alone, with median survival times of 12.2 months versus 6.2 months, respectively.

While the combination treatment showed increased efficacy, it also resulted in higher rates of severe side effects, such as neutropenia and thrombocytopenia, indicating that while more effective, the treatment requires careful management of its toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): a randomised, multicentre, open-label phase 3 trial. Pautier, P., Italiano, A., Piperno-Neumann, S., et al.[2022]

ET-743 (trabectedin) shows a clinical benefit in women with leiomyosarcoma and undifferentiated uterine sarcoma, with a response rate of 38% across 13 patients and a clinical benefit in 54%.

In a more focused analysis of uterine leiomyosarcomas, the response rate was 45% and clinical benefit was observed in 64% of 11 patients, suggesting promising efficacy that warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcome of ET-743 (Trabectedin; Yondelis) in high-grade uterine sarcomas: report on five patients and a review of the literature. Amant, F., Coosemans, A., Renard, V., et al.[2022]

Trabectedin, a new DNA-damaging agent, was well tolerated and led to 17 months of disease stability in a 76-year-old patient with progressive metastatic leiomyosarcoma, demonstrating its potential as a treatment option for advanced cases.

The treatment with trabectedin did not result in cumulative toxicity over 22 cycles, suggesting it may be a safer alternative compared to traditional chemotherapy regimens for patients who have limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged disease stability with trabectedin in a heavily pretreated elderly patient with metastatic leiomyosarcoma of the thigh and renal failure: a case report and review of the literature. Galizia, D., Palesandro, E., Nuzzo, AM., et al.[2019]

Chemotherapy options such as doxorubicin, gemcitabine, and gemcitabine plus docetaxel may be effective for women with inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma, based on a systematic review of several studies.

Hematologic toxicity is a common side effect of these treatments, necessitating careful monitoring, and the use of granulocyte colony-stimulating factor may be beneficial when using gemcitabine plus docetaxel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy (gemcitabine, docetaxel plus gemcitabine, doxorubicin, or trabectedin) in inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma: a clinical practice guideline. Gupta, AA., Yao, X., Verma, S., et al.[2021]

In a study of 20 patients with advanced uterine leiomyosarcoma, trabectedin showed a partial response rate of 10%, with some patients experiencing response durations of up to 5.7 months.

The treatment was well tolerated, with manageable side effects such as neutropenia and thrombocytopenia, and no treatment-related deaths, indicating a favorable safety profile despite the low response rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II evaluation of trabectedin in the treatment of advanced, persistent, or recurrent uterine leiomyosarcoma: a gynecologic oncology group study. Monk, BJ., Blessing, JA., Street, DG., et al.[2022]

Citations

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Trabectedin and Doxorubicin Effective for Leiomyosarcoma

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tandfonline.com/doi/full/10.2217/fon-2022-0517

A review of the Efficacy of Trabectedin as Second-Line ...

This article summarizes data on the efficacy and effectiveness of trabectedin in the management of patients with aSTS.

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HCP Efficacy Information

YONDELIS® significantly improved progression-free survival (PFS) · YONDELIS® improved median PFS* vs dacarbazine · In a subgroup analysis of PFS, YONDELIS® ...

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sciencedirect.com/science/article/pii/S0923753419372928

Clinical outcomes and safety with trabectedin therapy in ...

L-sarcoma patients exhibited longer, OS compared with other histologies [16.2 months (95% confidence interval (CI) 14.1–19.5) versus 8.4 months (95% CI 7.1–10.7)] ...

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SON-1010 Plus Trabectedin Completes First Safety ...

SON-1010 combined with trabectedin showed positive results in advanced leiomyosarcoma and liposarcoma, with no unexpected toxicities at the ...