Immunotherapy + Chemotherapy for Soft Tissue Sarcoma

Recruiting in Palo Alto (17 mi)

+27 other locations

Overseen by A P Chen

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute LAO

Must not be taking: CYP3A4 inducers

Disqualifiers: Pregnancy, Uncontrolled illness, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 8 Jurisdictions

Trial Summary

What is the purpose of this trial?

This phase II trial compares the effect of immunotherapy with ipilimumab and nivolumab alone to their combination with cabozantinib in treating patients with soft tissue sarcoma that has spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply and may also prevent the growth of new blood vessels that tumors need to grow. By these actions it may help slow or stop the spread of cancer cells. Adding cabozantinib to the combination of ipilimumab and nivolumab may be better in stopping or slowing the growth of tumor compared to ipilimumab and nivolumab alone in patients with advanced soft tissue sarcoma.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take certain medications that affect cabozantinib, like strong CYP3A4 inhibitors or inducers. If you are on these, you may need a washout period (time without taking these medications) before starting the trial.

What data supports the effectiveness of the drug combination of Cabozantinib, Cabometyx, Ipilimumab, Nivolumab, Yervoy, and Opdivo for treating soft tissue sarcoma?

Research shows that the combination of ipilimumab and nivolumab, which are part of this drug regimen, has shown effectiveness in treating soft tissue sarcoma, with some patients experiencing partial or complete responses. Additionally, these drugs have been effective in other cancers, suggesting potential benefits for soft tissue sarcoma. ^{1 2 3 4 5}

Is the combination of immunotherapy and chemotherapy safe for treating soft tissue sarcoma?

The combination of ipilimumab and nivolumab has been shown to be generally well-tolerated in patients with advanced soft tissue sarcoma, with common side effects including fatigue and cough. Some patients experienced more severe side effects like high blood sugar and heart inflammation, but these were less common. Another study found that sintilimab plus doxorubicin was also safe, with manageable side effects such as low white blood cell count and anemia. ^{1 3 4 6 7}

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

The combination of Ipilimumab and Nivolumab is unique for treating soft tissue sarcoma because it uses immunotherapy (a treatment that helps your immune system fight cancer) to target the cancer cells, which is different from traditional chemotherapy. This combination has shown promise in patients who have not responded to other treatments, offering a new option for those with advanced stages of the disease. ^{1 2 3 4 5}

Research Team

A P Chen

Principal Investigator

National Cancer Institute LAO

Eligibility Criteria

Adults (18+) with advanced soft tissue sarcoma, including specific types like undifferentiated pleomorphic sarcoma and liposarcoma. Participants must have measurable disease, acceptable organ function, controlled blood pressure without multiple medications, and no prior treatment with certain inhibitors or the study drugs. They should not be pregnant or breastfeeding and must agree to use effective contraception.

Inclusion Criteria

Platelets >= 75,000/mcL

Serum albumin >= 2.8g/dL

I am 18 years old or older.

Exclusion Criteria

I cannot swallow pills.

My heart's electrical cycle is longer than normal.

Patients who are receiving any other investigational agents

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab and ipilimumab intravenously in Arm A or cabozantinib, nivolumab, and ipilimumab in Arm B. Treatment cycles repeat every 21 days for 4 cycles, followed by nivolumab every 28 days.

12 weeks for initial cycles, then ongoing every 28 days

4 visits (in-person) for initial cycles, then monthly visits

Crossover Treatment

Participants in Arm A may crossover to Arm B upon disease progression to receive cabozantinib and nivolumab.

Varies based on progression

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Cabozantinib (Tyrosine Kinase Inhibitor)
• Ipilimumab, Nivolumab (Checkpoint Inhibitor)

Trial Overview The trial is testing if adding Cabozantinib to immunotherapy drugs Ipilimumab and Nivolumab improves outcomes in patients with advanced soft tissue sarcomas. It's a phase II trial where some participants will receive all three drugs while others will only get the immunotherapies.

Participant Groups

Group I: Arm B (cabozantinib, nivolumab, ipilimumab) Experimental Treatment 7 Interventions

Patients receive cabozantinib PO QD or QOD, nivolumab IV over 30-60 minutes on day 1, and ipilimumab IV over 60-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity for 4 cycles. Patients then receive nivolumab IV over 30 minutes on day 1 and cabozantinib PO QD or QOD of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients crossing over after ≥ 4 ipilimumab + nivolumab (Arm A) cycles will receive cabozantinib and nivolumab only on Arm B; patients that cross over after \< 4 ipilimumab + nivolumab (Arm A) cycles will receive the remaining cycles of ipilimumab (totaling 4 doses) plus nivolumab in combination with cabozantinib. Patients who crossover start with the every 3 weeks cycle 1 treatment even if they will not be receiving ipilimumab. Patients also undergo CT or MRI scans, tumor biopsies, and collection of blood and urine samples throughout.

Group II: Arm A (nivolumab, ipilimumab) Active Control 6 Interventions

Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 60-90 minutes on day 1 of each cycle. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity for 4 cycles. Patients then receive nivolumab IV over 30 minutes on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans, tumor biopsies, and collection of blood and urine samples throughout the trial. Patients can crossover from Arm A to Arm B at the time of disease progression.

Ipilimumab, Nivolumab is already approved in Canada, Canada, Japan, Japan for the following indications:

Approved in Canada as Yervoy for:

• Melanoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma

Approved in Japan as Yervoy for:

• Melanoma

Approved in Japan as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma

Who Is Running the Clinical Trial?

National Cancer Institute LAO

Lead Sponsor

Trials

2

Recruited

5,100+

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

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 88 metastatic soft tissue sarcoma (STS) patients treated with checkpoint inhibitors, the therapy demonstrated notable efficacy, with 20 patients achieving a partial response and one patient achieving a complete response, particularly in undifferentiated pleomorphic sarcoma and leiomyosarcoma subtypes.

The median progression-free survival was 4.1 months and overall survival was 19.1 months, indicating that checkpoint inhibitors can be a viable treatment option for metastatic STS, although 72.2% of patients discontinued treatment due to disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas. Monga, V., Skubitz, KM., Maliske, S., et al.[2020]

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 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]

Olaratumab, an anti-PDGFRα monoclonal antibody, has been conditionally approved for use with doxorubicin in treating advanced soft tissue sarcoma, showing improvements in progression-free and overall survival.

The combination therapy has a tolerable safety profile similar to doxorubicin alone, with the main exception being infusion-related reactions, and ongoing research aims to further define its role and identify predictive biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaratumab in the management of advanced soft tissue sarcoma. Zobniw, CM., Trinh, VA., Posey, K., et al.[2019]

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]

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. Switzerland pubmed.ncbi.nlm.nih.gov

A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas. [2020]

3. 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]

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

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

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

The Role of Immunotherapy in the Management of Soft Tissue Sarcomas: Current Landscape and Future Outlook. [2023]

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

Olaratumab in the management of advanced soft tissue sarcoma. [2019]

7. 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]