Immunotherapy + Chemotherapy for Soft Tissue Sarcoma

Not currently recruiting at 31 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute LAO

Must not be taking: CYP3A4 inducers

Disqualifiers: Pregnancy, Uncontrolled illness, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 12 weeks for initial cycles, then ongoing every 28 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of immunotherapy drugs ipilimumab and nivolumab alone versus their combination with cabozantinib in treating advanced soft tissue sarcoma, a cancer that has spread. Immunotherapy helps the immune system target cancer cells, while cabozantinib blocks certain proteins and blood vessels to stop cancer cell growth. The trial aims to determine if the combination of all three drugs is more effective than the two immunotherapy drugs alone. Suitable participants have a confirmed diagnosis of advanced soft tissue sarcoma that cannot be surgically removed. As a Phase 2 trial, this research focuses on measuring 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 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.

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

Research shows that combining nivolumab and ipilimumab results in a safety profile that most patients can handle, with serious side effects being rare. Common side effects include fatigue and skin reactions, which are usually mild.

When cabozantinib is added to nivolumab and ipilimumab, studies suggest this combination is generally well-tolerated. It has been researched for its ability to control the disease, and while it can cause side effects, they are often manageable. Common issues might include fatigue or changes in blood pressure, but these are usually not severe.

Overall, both treatment options are manageable for patients, with side effects that are mostly mild to moderate. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for soft tissue sarcoma, like traditional chemotherapy, aim to kill cancer cells directly. But this investigational treatment is unique because it combines immunotherapy with chemotherapy. Nivolumab and ipilimumab are immunotherapy drugs that harness the body's immune system to target cancer cells more precisely. Additionally, cabozantinib, used in one of the treatment arms, is a tyrosine kinase inhibitor that disrupts cancer cell growth and blood supply. Researchers are excited because this combination has the potential to enhance treatment effectiveness and offer new hope where standard options may fall short.

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

In this trial, participants in Arm A will receive a combination of ipilimumab and nivolumab. Studies have shown that this combination can yield promising results for some types of soft tissue sarcoma, with manageable side effects. It has improved survival rates compared to some standard treatments. Participants in Arm B will receive an additional drug, cabozantinib, alongside ipilimumab and nivolumab. Research suggests that adding cabozantinib might enhance treatment effectiveness, helping to control the disease and slow cancer growth. These findings indicate that the three-drug combination in Arm B might be more effective than the two-drug combination in Arm A. Overall, these treatments show potential in managing advanced soft tissue sarcoma. ^{1 3 5 6 7}

Who Is on the Research Team?

A P Chen

Principal Investigator

National Cancer Institute LAO

Are You a Good Fit for This Trial?

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 can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

I cannot swallow pills.

My heart's electrical cycle is longer than normal.

Patients who are receiving any other investigational agents

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Ipilimumab, Nivolumab

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Yervoy for:

• Melanoma
• Colorectal cancer
• Renal cell carcinoma
• Hepatocellular carcinoma
• Non-small cell lung cancer

Approved in United States 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
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in European Union as Yervoy for:

• Melanoma

Approved in European Union 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
• Esophageal squamous cell carcinoma

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+

Published Research Related to This Trial

Recent clinical trials have shown that immune checkpoint inhibitors can be effective in treating soft tissue sarcomas (STS), with varying efficacy depending on the specific histologic subtype of the tumor.

Combination therapies that include immune checkpoint inhibition alongside local or systemic treatments have demonstrated increased effectiveness, and targeted immunotherapies using engineered T cells are showing promise, particularly for patients with tumors expressing specific antigens like NY-ESO-1 and MAGE-A4.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Immunotherapy in the Management of Soft Tissue Sarcomas: Current Landscape and Future Outlook. Banks, LB., D'Angelo, SP.[2023]

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]

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 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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.17_suppl.LBA11504

Randomized phase II trial of cabozantinib combined with ... The combination of nivolumab (N) and ipilimumab (I) previously was evaluated in soft tissue sarcoma (STS) and demonstrated activity as well as ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04551430

Cabozantinib Combined With PD-1 and CTLA-4 Inhibition ... The hypothesis of this study is that the response rate of soft tissue sarcoma will be improved with the addition of PD-1 and CTLA-4 inhibition to ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10408188/

New immunotherapy strategies for patients with sarcomas In addition to chemotherapy combinations, studies have reported safety and efficacy data for combining ICIs with tyrosine kinase inhibitors.

4. targetedonc.com targetedonc.com/view/cabozantinib-triplet-shown-to-be-efficacious-metastatic-soft-tissue-sarcoma

Cabozantinib Triplet Shown to be Efficacious Metastatic ... Cabozantinib (Cabometyx) with nivolumab (Opdivo) plus ipilimumab (Yervoy) led to improvement in disease-control rate (DCR) and progression-free survival (PFS)

5. ecancer.org ecancer.org/en/video/11303-cabozantinib-with-nivolumab-ipilimumab-shows-superior-efficacy-compared-to-cabozantinib-alone-in-soft-tissue-sarcoma

Cabozantinib with nivolumab/ipilimumab shows superior ... Dr Van Tine says that the study found that combining cabozantinib with ipilimumab/nivolumab gave a superior disease control rate and progression ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05836571

Study Details | NCT05836571 | Testing Ipilimumab and ... 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 ...

7. onclive.com onclive.com/view/cabozantinib-plus-nivolumab-ipilimumab-generates-pfs-and-dcr-in-metastatic-soft-tissue-sarcoma

Cabozantinib Plus Nivolumab/Ipilimumab Improves PFS ... The addition of nivolumab and ipilimumab to cabozantinib led to an improvement in disease control rate and progression-free survival vs cabozantinib alone.