Trabectedin + Immunotherapy for Soft Tissue Sarcoma

Overseen By Victoria Chua-Alcala, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sarcoma Oncology Research Center, LLC

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: CNS metastases, Autoimmune disease, HIV, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 6

250 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open label, dose-seeking phase 1/2 study using escalating doses of TRABECTEDIN given intravenously with defined doses of IPILIMUMAB and NIVOLUMAB based on preliminary results of the Checkmate 012 trial for NSCLC (Hellman et al., 2016). For the Phase 1 Part of Study, only previously treated patients will be enrolled. For the Phase 2 Part of Study, previously treated patients will be enrolled.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had anticancer treatments like chemotherapy or radiation within 2 weeks before joining the study.

What data supports the effectiveness of the drugs Trabectedin, Ipilimumab, Yervoy, Nivolumab, and Opdivo for treating soft tissue sarcoma?

Research shows that the combination of nivolumab and ipilimumab has been effective in prolonging overall survival in patients with advanced non-small cell lung cancer (NSCLC) and melanoma, suggesting potential benefits in other cancers. Additionally, ipilimumab has shown significant overall survival benefits in melanoma, and nivolumab is favored for its favorable toxicity profile. ^{1 2 3 4 5}

Is the combination of Trabectedin and Immunotherapy safe for humans?

The combination of nivolumab and ipilimumab, which are types of immunotherapy, has been studied in cancer patients and shown to increase the risk of side effects like colitis (inflammation of the colon), pneumonitis (lung inflammation), and diarrhea compared to using nivolumab alone. Ipilimumab can also cause skin-related side effects like rashes and itching, but these are usually manageable with proper care. ^{6 7 8 9 10}

How is the drug combination of Trabectedin, Ipilimumab, and Nivolumab unique for treating soft tissue sarcoma?

This drug combination is unique because Trabectedin, which is effective in controlling tumors resistant to other treatments, is being combined with immunotherapy drugs Ipilimumab and Nivolumab to potentially enhance the immune system's ability to fight the cancer. Trabectedin also has a favorable safety profile compared to traditional chemotherapy drugs, making it a promising option for long-term tumor control with better quality of life. ^{11 12 13 14 15}

Research Team

Erlinda M Gordon, MD

Principal Investigator

Sarcoma Oncology Research Center

Eligibility Criteria

Adults over 18 with advanced soft tissue sarcoma, either previously treated (Phase 1) or untreated (Phase 2), who understand the study and consent to participate. They must have acceptable organ function, no severe skin conditions, heart failure, bowel diseases, recent serious infections or immunosuppression. Women of childbearing age need a negative pregnancy test and all participants must agree to use effective contraception.

Inclusion Criteria

My kidney function, measured by creatinine levels, is within the normal range.

Acceptable hematologic status (without hematologic support): WBC ≥2000/µL; ANC ≥ 1500 cells/μL; Platelet count ≥ 100,000/μL; Hemoglobin ≥ 9.0 g/dL; Normal PT, PTT, INR

I am not pregnant and agree to use effective birth control during and after the study.

Exclusion Criteria

I have previously been treated with specific immunotherapy drugs.

I am not pregnant or breastfeeding.

I have received immunotherapy targeting CTLA4 or PD-1.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation Phase 1

Patients receive escalating doses of Trabectedin with Ipilimumab and Nivolumab to determine the maximum tolerated dose

Up to 54 weeks

Every 3 weeks for Trabectedin, every 12 weeks for Ipilimumab, every 2 weeks for Nivolumab

Expansion Phase 2

Patients receive the maximum tolerated dose of Trabectedin with Ipilimumab and Nivolumab to assess safety and efficacy

Up to 54 weeks

Every 3 weeks for Trabectedin, every 12 weeks for Ipilimumab, every 2 weeks for Nivolumab

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Trabectedin

Trial Overview The trial is testing combinations of Trabectedin with Ipilimumab and Nivolumab in escalating doses for first-line treatment of advanced soft tissue sarcoma. It's an open-label study where everyone knows what treatment they're getting; Phase 1 seeks safe dosages while Phase 2 tests effectiveness in untreated patients.

Participant Groups

Group I: Phase 1 Experimental Treatment 3 Interventions

Phase 1: 3-6 will be treated with escalating doses of Trabectedin every 3 weeks up to 18 doses. Dose Level 1 is 1.0 mg/m2; Dose Level 2,1.2 mg/m2; Dose Level 3,1.5 mg/m2. Beginning 2 weeks after the first dose of Trabectedin, all patients will be treated with Ipilimumab at 1 mg/kg every 12 weeks up to 5 doses, and Nivolumab at 3 mg/kg every 2 weeks up to 26 doses. Phase 2: All patients will be treated with the maximum tolerated dose of Trabectedin every 3 weeks. Beginning 2 weeks after the first dose of Trabectedin, all patients will be treated with Ipilimumab at 1 mg/kg every 12 weeks up to 5 doses, and Nivolumab at 3 mg/kg every 2 weeks up to 26 doses.

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

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Sarcoma Oncology Research Center, LLC

Lead Sponsor

Trials

9

Recruited

910+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

In a systematic review of high-risk resectable cutaneous melanoma treatments, the combination of dabrafenib and trametinib (DAB + TRAM) showed the lowest risk of relapse and metastasis compared to other therapies, indicating its strong efficacy.

DAB + TRAM demonstrated improved outcomes over traditional treatments like chemotherapy and interferons, and had comparable efficacy to other modern therapies such as nivolumab and pembrolizumab, suggesting it is a leading option for melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and safety of dabrafenib in combination with trametinib versus competing adjuvant therapies for high-risk melanoma. Sharma, R., Koruth, R., Kanters, S., et al.[2020]

In mouse models of BRAF- and NRAS-mutant melanoma, the sequence of immunotherapy (IT) followed by targeted therapy (TT) significantly improved antitumor responses compared to either treatment alone.

The IT→TT sequence enhanced the immune environment by increasing T cell and natural killer cell infiltration while reducing suppressive immune cells, leading to durable responses that depended on T-cell activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Therapy Given after Anti-PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity. Phadke, MS., Chen, Z., Li, J., et al.[2022]

After a median follow-up of nearly 55 months, the combination of nivolumab and ipilimumab significantly improved overall survival in patients with advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, with 4-year survival rates of 29% for PD-L1 ≥1% and 24% for PD-L1 <1%.

The safety profile of nivolumab plus ipilimumab remained consistent with previous studies, with immune-mediated adverse events typically occurring early in treatment and resolving quickly, indicating that discontinuation due to these events did not negatively affect long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. Paz-Ares, LG., Ramalingam, SS., Ciuleanu, TE., et al.[2022]

The combination of vibostolimab and pembrolizumab is well tolerated by patients, indicating a favorable safety profile for this treatment regimen.

This combination therapy demonstrates antitumor activity, suggesting it may be an effective option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Anti-TIGIT Antibody with a PD-1 Inhibitor Shows Promise in Solid Tumors. [2022]

High-dose interleukin-2 (HDI) therapy for high-risk melanoma has shown significant improvements in relapse-free survival (RFS) in three trials and overall survival (OS) in two trials, indicating its efficacy as an adjuvant treatment.

Recent advancements have shifted the standard of care towards immune checkpoint inhibitors like nivolumab and pembrolizumab, as well as BRAF-MEK inhibitors (dabrafenib plus trametinib), which offer better RFS benefits and lower toxicity compared to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Therapy of Melanoma. Tarhini, AA.[2022]

A systematic review of 14 randomized controlled trials found that combining nivolumab (NIVO) with ipilimumab (IPI) significantly increases the risk of treatment-related adverse events (TRAEs) compared to NIVO alone, with an overall risk ratio of 1.11 for any grade TRAEs and 1.95 for severe (grade 3 or 4) TRAEs.

Specific adverse events were notably higher with the combination therapy, including colitis (RR = 4.52), pneumonitis (RR = 3.06), and diarrhea (RR = 1.68), indicating that while the combination may be effective, it comes with increased safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. Kamat, S., Patel, J., Brown, BR., et al.[2022]

In the phase III CheckMate 238 trial, 67.7% of patients receiving nivolumab experienced treatment-related adverse events (TRAEs), with the most common being pruritus and diarrhea, primarily occurring within the first 3 months of treatment.

Despite the high incidence of TRAEs, there was no significant association found between these adverse events and recurrence-free survival (RFS), indicating that the safety profile of nivolumab remains consistent and does not negatively impact long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. Mandala, M., Larkin, J., Ascierto, PA., et al.[2022]

Ipilimumab, a monoclonal antibody that enhances T-cell responses against tumors, has shown a survival benefit in patients with metastatic melanoma, both those who have been previously treated and those who are treatment-naïve.

While ipilimumab can cause mostly mild and reversible adverse events, particularly skin-related issues like rashes, following specific treatment guidelines can help manage these side effects effectively, ensuring better patient quality of life and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab in patients with cancer and the management of dermatologic adverse events. Lacouture, ME., Wolchok, JD., Yosipovitch, G., et al.[2017]

In a study of 1255 patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with nivolumab plus ipilimumab (NIVO+IPI) showed a high incidence of treatment-related adverse events (TRAEs), with 78% experiencing any-grade TRAEs and 34% experiencing severe (grade 3 or 4) TRAEs, but the treatment was generally well tolerated.

Patients who discontinued NIVO+IPI due to TRAEs still had a favorable long-term survival rate, with a 3-year overall survival of 50%, indicating that stopping treatment because of side effects did not negatively impact their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. Paz-Ares, LG., Ciuleanu, TE., Pluzanski, A., et al.[2023]

In a study involving 74 patients with advanced melanoma, ipilimumab at a dose of 10 mg/kg showed a 13% objective response rate, with some patients achieving complete and partial responses, indicating its potential effectiveness in a real-world setting.

The median overall survival for patients treated with ipilimumab was 7.0 months, and while 60.8% experienced treatment-related adverse events, most were low-grade, suggesting that ipilimumab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with ipilimumab 10 mg/kg in patients with melanoma treated at Italian centres as part of a European expanded access programme. Altomonte, M., Di Giacomo, A., Queirolo, P., et al.[2023]

Trabectedin is a promising new treatment for soft tissue sarcomas, particularly effective against liposarcomas and leiomyosarcomas, showing measurable benefits in Phase I and II studies.

While trabectedin is approved for use in Europe, it is still awaiting FDA approval in the U.S. as Phase III trial results are pending, which will further clarify its efficacy in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trabectedin: novel insights in the treatment of advanced sarcoma. Lopez, JP., Gajdos, C., Elias, A.[2021]

Trabectedin has shown promising efficacy in treating advanced soft-tissue sarcoma, achieving tumor control in about 50% of patients in a pooled analysis of three Phase II studies involving 189 previously treated patients, with a median overall survival of 10.3 months.

Trabectedin is generally well tolerated, with manageable and reversible side effects, and it does not cause common toxicities associated with other chemotherapy drugs, such as cardiotoxicity or neurotoxicity, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trabectedin (ET-743): evaluation of its use in advanced soft-tissue sarcoma. Schöffski, P., Wolter, P., Clement, P., et al.[2018]

In a study of 147 metastatic soft tissue sarcoma patients treated with trabectedin over a mean follow-up of 5 years, it was found that higher PD-L1 expression was linked to worse patient outcomes, suggesting that tumors with an immunosuppressive environment may not respond well to trabectedin.

The research identified that patients with fewer prior chemotherapy regimens tended to stay on trabectedin longer, indicating that earlier administration of trabectedin could potentially improve treatment duration and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunologic Gene Signature Analysis Correlates Myeloid Cells and M2 Macrophages with Time to Trabectedin Failure in Sarcoma Patients. Schroeder, BA., Zhang, Y., Smythe, KS., et al.[2022]

Trabectedin (Yondelis®) is a promising treatment option for patients with advanced soft tissue sarcoma, particularly for those with refractory disease, as it aims for long-term tumor stabilization while maintaining a good quality of life.

Unlike doxorubicin-based therapies, which have high toxicity and limited overall survival benefits, trabectedin offers a novel approach that allows for long-term treatment strategies and has sparked discussions on how to better evaluate tumor response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current questions in soft tissue sarcoma: further steps with Yondelis®. Reichardt, P.[2018]

Trabectedin is a promising treatment for patients with anthracycline/ifosfamide-resistant sarcomas, showing prolonged tumor control and suggesting a need for new evaluation methods in clinical trials.

It has a more favorable safety profile compared to traditional treatments like doxorubicin and ifosfamide, particularly regarding side effects like neutropenia and hair loss, indicating it may be a better option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

13 years of trabectedin, 5 years of Yondelis®: what have we learnt? Le Cesne, A.[2018]

References

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

Comparative efficacy and safety of dabrafenib in combination with trametinib versus competing adjuvant therapies for high-risk melanoma. [2020]

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

Targeted Therapy Given after Anti-PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity. [2022]

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

First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. [2022]

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

An Anti-TIGIT Antibody with a PD-1 Inhibitor Shows Promise in Solid Tumors. [2022]

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

Adjuvant Therapy of Melanoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. [2022]

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

Ipilimumab in patients with cancer and the management of dermatologic adverse events. [2017]

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

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Clinical experience with ipilimumab 10 mg/kg in patients with melanoma treated at Italian centres as part of a European expanded access programme. [2023]

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

Trabectedin: novel insights in the treatment of advanced sarcoma. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Trabectedin (ET-743): evaluation of its use in advanced soft-tissue sarcoma. [2018]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Immunologic Gene Signature Analysis Correlates Myeloid Cells and M2 Macrophages with Time to Trabectedin Failure in Sarcoma Patients. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Current questions in soft tissue sarcoma: further steps with Yondelis®. [2018]

15. England pubmed.ncbi.nlm.nih.gov

13 years of trabectedin, 5 years of Yondelis®: what have we learnt? [2018]