Combination Therapy for Sarcoma

(TNT Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sarcoma Oncology Research Center, LLC

Must not be taking: Antiherpetics, Immunosuppressives

Disqualifiers: CNS metastases, Autoimmune disease, HIV, 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

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

Compensation: Varies

Number of Visits: 2

Duration: Up to 12 months

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines a combination of three treatments—talimogene laherparepvec (an oncolytic virus therapy), nivolumab (an immunotherapy drug), and trabectedin (a chemotherapy drug)—to assess their effectiveness for people with advanced sarcoma, including rare tumors like desmoid tumors and chordoma. The goal is to determine if these treatments can slow or halt the growth of these challenging cancers. This trial suits individuals with advanced sarcoma that is either locally advanced or has metastasized and cannot be surgically removed. Participants should have at least one tumor that can be directly injected with the treatment. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic immunosuppressive therapy or antiherpetic drugs, you may need to stop them before participating.

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

Research has shown that combining talimogene laherparepvec, nivolumab, and trabectedin may offer promise for treating advanced sarcomas. Earlier studies found that 34.5% of patients experienced significant side effects, including nausea, tiredness, low red blood cell count (anemia), and low potassium levels. Despite these side effects, past trials have considered the treatment safe and effective. It is important to remember that all treatments can have side effects, so discussing them with a healthcare provider is crucial to understanding what to expect. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination therapy for sarcoma because it brings together three different treatments that each have unique mechanisms of action. Nivolumab is an immune checkpoint inhibitor that boosts the body's immune response against cancer cells, while Talimogene Laherparepvec is a genetically modified virus that selectively infects and destroys cancer cells while promoting an immune response. Trabectedin, on the other hand, is a chemotherapy agent that interferes with the cancer cell's DNA, hindering its ability to multiply. By combining these therapies, the treatment aims to attack the cancer on multiple fronts, potentially leading to better outcomes than standard chemotherapy or radiotherapy alone.

What evidence suggests that this trial's treatments could be effective for advanced sarcoma?

Studies have shown that talimogene laherparepvec (T-VEC) can produce promising results in cancer treatment. In one study, about 29% of patients experienced a complete response, meaning their cancer disappeared. Nivolumab has also been effective, with about 25% of patients responding positively in a specific type of sarcoma. Trabectedin has helped control the disease in about 67% of patients with advanced soft tissue sarcoma. This trial will administer a combination of these treatments, which together may offer a strong approach against advanced sarcoma. ^{6 7 8 9 10}

Who Is on the Research Team?

Sant P Chawla, MD

Principal Investigator

Sarcoma Oncology Center

Are You a Good Fit for This Trial?

Adults with advanced sarcoma, including desmoid tumor and chordoma, who are fit (ECOG ≤ 1) and have a life expectancy of at least 3 months. They must be able to understand the study, consent to it, and agree to use effective contraception. Those with certain organ functions within specific limits can join. People with active herpes infections or recent treatments that could interfere are excluded.

Inclusion Criteria

My sarcoma cannot be surgically removed or has spread.

I understand the study's risks and have signed the consent form.

I am willing and able to follow all study rules and attend all appointments.

Exclusion Criteria

I am on medication for an autoimmune disease, not including hormone replacements.

Active herpetic skin lesions or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis).

I am allergic to TALIMOGENE LAHERPAREPVEC, NIVOLUMAB, or TRABECTEDIN.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive talimogene laherparepvec, nivolumab, and trabectedin as therapy for advanced sarcoma

Up to 12 months

Every 2-3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Talimogene Laherparepvec
• Trabectedin

Trial Overview The trial is testing talimogene laherparepvec, nivolumab, and trabectedin as potential first to third line therapies for advanced sarcoma. It's a Phase 2 study where these drugs are given in combination to see how well they work together against this type of cancer.

How Is the Trial Designed?

Group I: Talimogene laherparepvec, Nivolumab and Trabectedin Experimental Treatment 3 Interventions

This is an open label phase 2 study using known doses of TALIMOGENE LAHERPAREPVEC injected intratumorally, and NIVOLUMAB AND TRABECTEDIN given intravenously. A total of 40 previously untreated and treated patients will receive TRABECTEDIN 1.2 mg/m2 CIV over 24 hours q3 weeks, NIVOLUMAB 240 mg IV over 30 min q 2 weeks and TALIMOGENE LAHERPAREPVEC intratumorally q 2 weeks according to tumor size (see Schematic of Study Design and Imlygic product information; www.accessdata.fda.gov). Patients in this study may continue treatment until significant disease progression (see below for criteria for discontinuation of therapy) or unacceptable toxicity occurs up to one year of therapy.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Sarcoma Oncology Research Center, LLC

Lead Sponsor

Trials

9

Recruited

910+

Published Research Related to This Trial

In a phase 2 trial involving 62 patients with advanced or metastatic sarcoma, the combination of durvalumab and tremelimumab showed a promising progression-free survival rate of 49% at 12 weeks, indicating its potential efficacy as a treatment option.

While the treatment was generally active, it was associated with some serious adverse events, including one case of grade 5 pneumonitis and colitis, highlighting the need for careful monitoring of patients during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial. Somaiah, N., Conley, AP., Parra, ER., et al.[2023]

Talimogene laherparepvec (T-VEC) shows improved overall survival in patients with unresectable stage IIIB/C-IV melanoma, and when combined with CTLA-4 inhibitors like ipilimumab (T-VEC + IPI), it may offer even greater survival benefits.

An indirect comparison analysis indicated that while there was no significant difference in overall survival between T-VEC and T-VEC + IPI up to 15 months, extrapolated data suggested a substantial survival advantage for T-VEC + IPI at 48 months, with an expected survival rate of 81.1% compared to 32.0% for T-VEC alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there still a role for talimogene laherparepvec (T-VEC) in advanced melanoma? An indirect efficacy comparison of T-VEC plus ipilimumab combination therapy versus T-VEC alone as salvage therapy in unresectable metastatic melanoma. Fazel, M., AlRawashdh, N., Alamer, A., et al.[2022]

In a phase 2 trial involving 39 patients with advanced sarcomas, the combination treatment of talimogene laherparepvec, trabectedin, and nivolumab showed a 12-month progression-free survival rate of 36.7%, indicating its potential efficacy in this difficult-to-treat cancer.

The treatment was associated with a manageable safety profile, with 50% of patients experiencing grade 3 or higher adverse events, suggesting that while there are risks, the combination therapy is worth further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of TNT: a phase 2 study using talimogene laherparepvec, nivolumab and trabectedin for previously treated patients with advanced sarcomas (NCT# 03886311). Chawla, SP., Tellez, WA., Chomoyan, H., et al.[2023]

In a phase 2 trial involving 20 patients with advanced sarcoma, the combination of talimogene laherparepvec (T-VEC) and pembrolizumab achieved a 30% objective response rate at 24 weeks, indicating promising antitumor activity.

The treatment demonstrated a manageable safety profile, with only 20% of patients experiencing grade 3 treatment-related adverse events and no grade 4 events or treatment-related deaths, suggesting it is a safe option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Objective Response Rate Among Patients With Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination With Pembrolizumab: A Phase 2 Clinical Trial. Kelly, CM., Antonescu, CR., Bowler, T., et al.[2023]

The combination of pembrolizumab, an immune checkpoint inhibitor, with the oncolytic virus talimogene laherparepvec has shown effectiveness in treating sarcomas, a type of cancer.

This study suggests a promising therapeutic strategy by leveraging both immune response and direct tumor lysis to improve treatment outcomes for patients with sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talimogene Laherparepvec plus Pembrolizumab Is Effective in Sarcomas. [2020]

The combination of talimogene laherparepvec (T-VEC) and ipilimumab in patients with advanced melanoma showed a tolerable safety profile, with no dose-limiting toxicities and a manageable rate of grade 3/4 treatment-related adverse events (26.3%).

The treatment resulted in a 50% objective response rate, with 44% of patients experiencing a durable response lasting 6 months or more, indicating that this combination therapy may be more effective than using either treatment alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma. Puzanov, I., Milhem, MM., Minor, D., et al.[2022]

In a phase Ib study involving 34 patients with triple negative breast cancer (TNBC) and colorectal cancer (CRC) with liver metastases, the combination of talimogene laherparepvec (T-VEC) and atezolizumab showed a manageable safety profile, with no dose-limiting toxicities in TNBC patients and a 17% incidence in CRC patients, primarily involving serious adverse events.

Despite the safety of the combination treatment, the efficacy was limited, with only a 10% overall response rate in TNBC and no responses in CRC, indicating that while the treatment is safe, it may not provide significant antitumor benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib study of talimogene laherparepvec in combination with atezolizumab in patients with triple negative breast cancer and colorectal cancer with liver metastases. Hecht, JR., Raman, SS., Chan, A., et al.[2023]

In a phase III study involving 692 patients with advanced melanoma, the combination of talimogene laherparepvec (T-VEC) and pembrolizumab did not significantly improve progression-free survival (PFS) or overall survival (OS) compared to pembrolizumab alone.

The combination therapy showed a higher objective response rate (48.6% vs. 41.3%) and a similar safety profile to the placebo group, with grade ≥ 3 treatment-related adverse events occurring in about 20% of patients in both treatment arms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. Chesney, JA., Ribas, A., Long, GV., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39077795/

Efficacy and safety of nivolumab monotherapy in patients ... Efficacy and safety of nivolumab monotherapy in patients with unresectable clear cell sarcoma and alveolar soft part sarcoma (OSCAR Trial/ ...

2. ascopubs.org ascopubs.org/doi/10.1200/EDBK_432234

Immunotherapy in Sarcoma: Current Data and Promising ... The phase II DART trial confirmed efficacy of the nivolumab/ipilimumab combination in angiosarcoma with an ORR of 25%, and the phase II ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03190174

NCT03190174 | Nivolumab (Opdivo®) Plus ABI-009 (Nab ... This study investigates the safety/toxicity and potential anti-tumor activity of sequential administration of nivolumab and escalating doses of the ...

4. ajmc.com ajmc.com/view/first-line-combo-yields-strong-results-in-advanced-sarcoma

First-Line Combo Yields Strong Results in Advanced ... The overall response rate was 24.7% and the disease control rate was 82.5%. The most common response to the treatment was SD in 57 patients (59 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7366226/

Immunotherapy with nivolumab for the treatment of soft ... Studies have shown efficacy of this adjuvant chemotherapy in STS, with a reduction in the absolute risk of death by 6% when compared to the isolated therapy of ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e23560

Phase 2 study using talimogene laherparepvec, nivolumab ... The results indicate that the combination regimen of Talimogene laherparepvec, Nivolumab, and Trabectedin may be more effective than Trabectedin alone (Median ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)03339-8/fulltext

1728P Results of TNT: A phase II study using talimogene ... Safety: Ten of 29 (34.5%) patients experienced Grade 3/4 TRAEs that include nausea (n=2), fatigue (n=2), anemia (n=2), thrombocytopenia (n=1), hypokalemia (n=1) ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03886311

NCT03886311 | Talimogene Laherparepvec, Nivolumab ... This is a Phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin as first, second or third line therapy for advanced sarcoma, including ...

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37234994/

a phase 2 study using talimogene laherparepvec ... Conclusions: Taken together these data suggest that the TNT regimen is effective and safe for advanced previously treated sarcomas, and is worth ...

10. asco.org asco.org/abstracts-presentations/ABSTRACT403760

Interim results of a phase 2 study using talimogene ... The combination of Trabectedin (T) and Nivolumab (N) is a safe and effective therapy in soft tissue sarcoma (STS). This study aims to determine the safety and ...