Nivolumab + Chemotherapy for Soft Tissue Sarcoma

Recruiting at 187 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: PD-1 inhibitors, PD-L1 inhibitors, VEGF TKIs, others

Disqualifiers: Autoimmune diseases, CNS metastases, 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: Unknown

Duration: Up to 24 months

90 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well paclitaxel with and without nivolumab works in treating patients with soft tissue sarcoma that have not received taxane drugs, and how well nivolumab and cabozantinib work in treating taxane pretreated patients with soft tissue sarcoma. Nivolumab works through the body's immune system to help the immune system act against tumor cells. Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This trial is being done to see if the combination of nivolumab and paclitaxel or cabozantinib can shrink soft tissue sarcoma and possibly prevent it from coming back.

Will I have to stop taking my current medications?

The trial requires that you stop taking strong inhibitors and inducers of CYP3A4 at least 7 to 14 days before starting the study. If you are on systemic steroid therapy, you must reduce the dose to 10 mg of prednisone or less per day at least 7 days before registration. Please consult with the study team for specific guidance on your medications.

What data supports the effectiveness of the drug Nivolumab combined with chemotherapy for soft tissue sarcoma?

Research shows that combining Nivolumab with another drug, Ipilimumab, has been effective in some patients with soft tissue sarcoma, leading to partial or complete responses in a few cases. Additionally, chemotherapy drugs like Paclitaxel have shown activity in treating certain types of sarcomas, suggesting potential benefits when used together. ^{1 2 3 4 5}

Is the combination of Nivolumab and chemotherapy safe for humans?

Nivolumab, also known as Opdivo, has been used in combination with other drugs like ipilimumab and has shown to be generally well-tolerated, though some patients experienced fatigue and cough. Paclitaxel, also known as Taxol or Abraxane, is associated with skin reactions when exposed to sunlight. Overall, these treatments have been used safely in humans, but they can have side effects like fatigue, cough, and skin sensitivity. ^{1 2 6 7 8}

How does the drug combination of Nivolumab and Paclitaxel differ from other treatments for soft tissue sarcoma?

The combination of Nivolumab, an immune checkpoint inhibitor, and Paclitaxel, a chemotherapy drug, is unique for soft tissue sarcoma as it combines immunotherapy with chemotherapy, potentially enhancing the immune system's ability to fight cancer while directly targeting cancer cells. This approach is different from traditional treatments like surgery and standard chemotherapy, which do not typically involve immune system modulation. ^{1 2 9 10 11}

Research Team

Juneko E Grilley-Olson

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

Adults with certain types of soft tissue sarcoma who haven't had taxane drugs or are pre-treated with them. They must be in good health, not pregnant or nursing, and without serious heart issues or recent thromboembolic events. No history of severe autoimmune diseases, uncontrolled illnesses, or hypersensitivity to the trial drugs is allowed.

Inclusion Criteria

I am fully active or can carry out light work.

Your platelet count is at least 100,000 per cubic millimeter.

Your bilirubin levels must be within a certain range, unless you have Gilbert's disease, in which case a higher level is allowed.

Exclusion Criteria

I am not currently taking aspirin (more than 81 mg/day) or any blood thinners.

I haven't had any cancer except for skin cancer in the last 5 years.

I haven't needed systemic treatment for an autoimmune disease in the last 2 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treatment based on their assigned arm: nivolumab and paclitaxel, paclitaxel alone, or nivolumab and cabozantinib. Treatment cycles repeat every 4 weeks for up to 2 years.

Up to 24 months

Multiple visits per cycle for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes imaging and clinical assessments.

Every 3 months for 3 years

Treatment Details

Interventions

• Nivolumab
• Paclitaxel

Trial Overview The effectiveness of adding Nivolumab to chemotherapy (Paclitaxel) for patients new to taxane treatment and its combination with Cabozantinib for those previously treated. The study aims to see if these combinations can shrink tumors and prevent recurrence.

Participant Groups

Group I: Arm III (nivolumab, cabozantinib S-malate) Experimental Treatment 8 Interventions

Patients receive nivolumab IV over 30 minutes on day 1 and cabozantinib S-malate PO daily. Cycles repeat every 4 weeks for up to 2 years (24 months) for patients who achieve CR, PR or SD on immunotherapy/nivolumab, or in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood at baseline and on study, CT scan, spiral CT, or MRI, or FDG-PET scan throughout the trial.

Group II: Arm II (paclitaxel) Experimental Treatment 7 Interventions

Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles repeat every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood at baseline and on study, CT scan, spiral CT, or MRI, or FDG-PET scan throughout the trial.

Group III: Arm I (nivolumab, paclitaxel) Experimental Treatment 8 Interventions

Patients receive nivolumab IV over 30 minutes on day 1 and paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles repeat every 4 weeks for up to 2 years (24 months) for patients who achieve CR, PR or SD on immunotherapy/nivolumab, or in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood at baseline and on study, CT scan, spiral CT, or MRI, or FDG-PET scan throughout the trial.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of treatment-naive patients with PD-L1 positive metastatic soft tissue sarcomas, the combination of nivolumab and ipilimumab (NPI) significantly improved overall survival (12.2 months) and progression-free survival (4.1 months) compared to nivolumab alone (NIV), which had overall survival of 9.2 months and progression-free survival of 2.2 months.

While NPI showed greater efficacy in extending survival, it was associated with a higher incidence of severe adverse events (72.9% in NPI vs. 27.1% in NIV), indicating that while it may be more effective, it is also less tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab versus nivolumab in individuals with treatment-naive programmed death-ligand 1 positive metastatic soft tissue sarcomas: a multicentre retrospective study. Chen, Y., Liu, X., Liu, J., et al.[2023]

In a study of patients with advanced soft tissue sarcoma treated with the combination of ipilimumab and nivolumab, the objective response rate was 15%, with one complete response and five partial responses, indicating some level of efficacy.

The treatment was generally well tolerated, with a clinical benefit rate of 34% and a median overall survival of 12 months, although 58% of patients experienced adverse events, primarily mild, with a small percentage facing more severe complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab for soft tissue sarcoma: a single institution retrospective review. Zhou, M., Bui, N., Bolleddu, S., et al.[2021]

Checkpoint inhibitor therapy, specifically ipilimumab and nivolumab, can lead to long-term remission in patients with advanced soft tissue sarcoma, even in cases with zero percent PD-L1 expression, suggesting efficacy regardless of this biomarker.

The combination of checkpoint inhibitors with treatments like cryoablation may enhance the effectiveness of immunotherapy, indicating a potential strategy for improving outcomes in soft tissue sarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Remission with Ipilimumab/Nivolumab in Two Patients with Different Soft Tissue Sarcoma Subtypes and No PD-L1 Expression. Zhou, M., Bui, N., Lohman, M., et al.[2021]

In a phase II trial involving 38 patients with advanced metastatic soft tissue sarcoma (STS) who had failed previous treatments, the combination of sintilimab (a PD-1 inhibitor) and doxorubicin showed a promising overall objective response rate of 39.5% and a disease control rate of 71.1%.

The treatment was found to be safe and well-tolerated, with manageable adverse events primarily being hematologic, and patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma experienced significantly longer progression-free survival compared to other subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sintilimab plus doxorubicin in advanced soft tissue sarcoma: A single-arm, phase II trial. Tian, Z., Dong, S., Zuo, W., et al.[2023]

A woman with non-small cell lung cancer developed a photodistributed dermatitis as a side effect of nab-paclitaxel therapy, which worsened with each treatment cycle, highlighting the potential for skin reactions in patients receiving taxane chemotherapy.

The patient's condition improved with topical corticosteroids and strict sun avoidance, indicating that while photodermatoses can occur with taxane treatments, they can be managed effectively without necessarily stopping chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nab-paclitaxel-associated photosensitivity: report in a woman with non-small cell lung cancer and review of taxane-related photodermatoses. Beutler, BD., Cohen, PR.[2020]

In a phase 2 study involving 85 patients with metastatic sarcoma, the combination of nivolumab and ipilimumab showed a higher confirmed response rate (16%) compared to nivolumab alone (5%), indicating that the combination therapy may be more effective for certain sarcoma subtypes.

While both treatments had manageable safety profiles, serious treatment-related adverse events occurred in 19% of patients receiving nivolumab and 26% in those receiving the combination therapy, suggesting that while the combination is promising, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. D'Angelo, SP., Mahoney, MR., Van Tine, BA., et al.[2021]

References

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

Nivolumab plus ipilimumab versus nivolumab in individuals with treatment-naive programmed death-ligand 1 positive metastatic soft tissue sarcomas: a multicentre retrospective study. [2023]

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

Nivolumab plus ipilimumab for soft tissue sarcoma: a single institution retrospective review. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Role of chemotherapy in patients with soft tissue sarcomas. [2007]

4. France pubmed.ncbi.nlm.nih.gov

[Docetaxel and gemcitabine combination in soft-tissue sarcomas treatment]. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Long-Term Remission with Ipilimumab/Nivolumab in Two Patients with Different Soft Tissue Sarcoma Subtypes and No PD-L1 Expression. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sintilimab plus doxorubicin in advanced soft tissue sarcoma: A single-arm, phase II trial. [2023]

7. Austria pubmed.ncbi.nlm.nih.gov

Nab-paclitaxel-associated photosensitivity: report in a woman with non-small cell lung cancer and review of taxane-related photodermatoses. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Phase II trial of paclitaxel in patients with soft-tissue sarcoma. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. [2021]

10. Ireland pubmed.ncbi.nlm.nih.gov

The treatment of soft tissue sarcomas with focus on chemotherapy: a review. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Emerging therapies for adult soft tissue sarcoma. [2022]