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

Trial Summary

What is the purpose of this trial?

This is a Phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin as first, second or third line therapy for advanced sarcoma, including desmoid tumor and chordoma.

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.

What data supports the effectiveness of the treatment combination of Nivolumab, Opdivo, Talimogene Laherparepvec, Imlygic, T-VEC, Oncovex, Trabectedin, Yondelis for sarcoma?

Research shows that Talimogene Laherparepvec (T-VEC) can boost the immune system's response to tumors, and when combined with other drugs like Pembrolizumab, it has been effective in treating sarcomas. Additionally, the combination of T-VEC with Trabectedin and Nivolumab may work together to enhance treatment effects in advanced sarcomas. ^{1 2 3 4 5}

Is the combination therapy for sarcoma generally safe for humans?

The combination of talimogene laherparepvec (T-VEC) with other drugs like pembrolizumab and ipilimumab has shown an acceptable safety profile in patients with advanced melanoma, suggesting it is generally safe for humans. ^{1 2 3 6 7}

How is the combination therapy for sarcoma different from other treatments?

This treatment is unique because it combines talimogene laherparepvec (an oncolytic virus that helps the immune system attack cancer cells) with nivolumab and trabectedin, potentially creating a stronger immune response against advanced sarcomas compared to using each drug alone. ^{1 2 3 6 8}

Research Team

Sant P Chawla, MD

Principal Investigator

Sarcoma Oncology Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

References

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

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

2. Switzerland 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). [2023]

3. United States 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. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial. [2023]

5. England 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. [2022]

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

Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma. [2022]

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

Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. [2023]

8. England 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. [2023]