Metronomic Chemotherapy for Leiomyosarcoma

(TAGGED Trial)

Overseen by Sant P Chawla, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Sarcoma Oncology Research Center, LLC

Disqualifiers: Pregnancy, Breastfeeding, Investigational treatment, others

No Placebo Group

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This is an open label phase 2 study using metronomic doses of trabectedin, gemcitabine and dacarbazine given intravenously.

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.

What data supports the effectiveness of the drug Trabectedin for treating leiomyosarcoma?

Trabectedin has shown promise in treating leiomyosarcoma, with cases reporting prolonged disease stability and partial responses in patients who had previously not responded to other treatments. It is well-tolerated over long-term use and has been associated with stable disease in patients with metastatic leiomyosarcoma. ^{1 2 3 4 5}

Is trabectedin safe for humans?

Trabectedin has been studied in people with various types of sarcomas, including leiomyosarcoma. While it can cause side effects like blood and stomach issues, adjusting the dose can make it more tolerable. Overall, it is considered a valid and generally safe treatment option for long-term use in humans. ^{2 6 7 8 9}

How is the drug Trabectedin unique in treating leiomyosarcoma?

Trabectedin is unique because it offers a treatment option for leiomyosarcoma that may allow for long-term use, even in patients who have not responded to other chemotherapies. It can be adjusted for tolerability and has shown effectiveness in stabilizing the disease, especially in metastatic cases. ^{2 3 4 10 11}

Research Team

Sant P Chawla, MD

Principal Investigator

Sarcoma Oncology Research Center, LLC

Eligibility Criteria

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

I am 18 years old or older.

My kidney function is within the required range.

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

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.

Trial Timeline

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

Treatment Details

Interventions

• Trabectedin (Alkylating agents)

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.

Participant Groups

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

Who Is Running the Clinical Trial?

Sarcoma Oncology Research Center, LLC

Lead Sponsor

Trials

9

Recruited

910+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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]

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]

References

1. United States 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. [2019]

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

Stable disease in a patient with metastatic leiomyosarcoma treated with trabectedin. [2022]

3. Switzerland 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. [2021]

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

Leiomyosarcoma: Does Location of Primary Help to Determine the Best Systemic Therapy Options? [2022]

5. England 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. [2022]

6. United States 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. [2022]

7. Netherlands 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). [2022]

8. United States 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. [2022]

9. England 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. [2022]

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

Doxorubicin combined with Trabectedin in systemic first-line M+/recurrent leiomyosarcoma patients. [2023]

11. England 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. [2022]