Immunotherapy + Radiation for Sarcoma Before Surgery

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anticoagulants, Immunotherapy

Disqualifiers: Unresectable disease, Active malignancy, Autoimmune, 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: 7

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of combining immunotherapy drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), with radiation therapy in patients with certain types of sarcoma, a cancer that forms in connective tissues. The researchers aim to determine if these treatments can shrink tumors and make them easier to remove surgically. Participants may receive nivolumab alone, with radiation, with ipilimumab, or all three together before surgery. The trial seeks patients with untreated, surgically removable sarcomas who have not previously received immunotherapy. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant advancements in sarcoma treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are using anticoagulants (blood thinners) at therapeutic levels or if you require systemic treatment with corticosteroids or other immunosuppressive medications within 14 days of starting the study drugs.

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

A previous study found that nivolumab, a type of immunotherapy, was well-tolerated by patients with various cancers, including sarcoma. Reports show that serious side effects occurred in about 10% to 18% of patients when combined with radiation therapy, indicating that most did not experience major problems.

When nivolumab is used with another drug, ipilimumab, safety remains acceptable. Some patients experienced immune-related side effects, such as kidney issues, but these were uncommon.

The combination of nivolumab, ipilimumab, and radiation therapy has been studied for safety, with the main goal of identifying any major side effects. Overall, the treatments were generally safe, with manageable side effects.

In summary, while some patients might experience side effects, most reported side effects can be managed. Current research considers these treatments generally safe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for sarcoma because they combine immunotherapy with radiation in innovative ways. Unlike traditional treatments that might focus solely on surgery or chemotherapy, this approach uses drugs like nivolumab and ipilimumab to boost the immune system's ability to fight cancer cells. Nivolumab and ipilimumab are checkpoint inhibitors that target specific proteins on immune cells, enhancing their ability to detect and destroy cancer cells. Additionally, the integration of radiation therapy (RT) with these drugs is designed to weaken cancer cells and make them more vulnerable to immune attack. This combination could potentially offer more effective and less invasive treatment options for sarcoma patients, sparking hope for improved outcomes.

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

Research has shown that nivolumab may effectively treat certain types of sarcoma. In this trial, participants in Arm A will receive nivolumab alone, which, in studies, stopped cancer growth or caused shrinkage in about 82.5% of patients. Participants in Arm B will receive a combination of nivolumab and ipilimumab, with studies indicating that about 25% of patients with sarcomas like angiosarcoma experienced a positive response. Arm C will test nivolumab combined with radiation therapy, which can enhance the treatment's effectiveness against tumors. Arm D will evaluate the combination of nivolumab, ipilimumab, and radiation therapy; one study showed that 79% of patients experienced a partial response, meaning their tumors became smaller. These treatments help the immune system fight cancer cells and prevent their spread. ^{1 2 3 6 7}

Who Is on the Research Team?

Christina L. Roland

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with specific sarcomas (undifferentiated pleomorphic or dedifferentiated liposarcoma) that can be surgically removed. Participants must be fit for surgery, not have had prior treatments like chemotherapy or immunotherapy for their sarcoma, and agree to provide tumor samples. Women of childbearing age must use effective contraception, and men too if their partners are of childbearing potential.

Inclusion Criteria

Patients must be willing to provide tumor samples at the time points

You are expected to live for at least 6 more months.

I will be checked by the anesthesia team before my surgery.

Exclusion Criteria

Prisoners or subjects who are involuntarily incarcerated

My condition cannot be treated with surgery due to its complexity or risk.

I've had chemotherapy or targeted therapy for my current sarcoma but have recovered from any side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Neoadjuvant Treatment

Participants receive nivolumab with or without ipilimumab and radiation therapy before surgery

6-10 weeks

Multiple visits for IV administration and radiation therapy

Surgery

Participants undergo standard of care surgery to remove the tumor

Within 2 weeks after treatment completion

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Follow-up visits at 6 and 18 weeks, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Radiation Therapy

Trial Overview The study tests the effectiveness of nivolumab alone or combined with ipilimumab plus radiation therapy before surgery in treating certain sarcomas. Nivolumab and ipilimumab are antibodies that may help the immune system fight cancer; radiation uses high-energy x-rays to kill tumor cells.

How Is the Trial Designed?

Group I: Arm D (nivolumab, ipilimumab, RT) Experimental Treatment 3 Interventions

Patients receive nivolumab as in Arm C, ipilimumab as in Arm B, and RT as in Arm C in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 71.

Group II: Arm C (nivolumab, RT) Experimental Treatment 2 Interventions

Patients receive nivolumab IV over 1 hour on days 1, 15, 29, and 43. Patients also undergo RT QD for 5 days during days 15-47 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 71.

Group III: Arm B (nivolumab, ipilimumab) Experimental Treatment 2 Interventions

Patients receive nivolumab as in Arm A. Patients also receive ipilimumab IV over 90 minutes on day 1 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 43.

Group IV: Arm A (nivolumab) Experimental Treatment 1 Intervention

Patients receive nivolumab IV over 1 hour on days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery within 2 weeks after day 43.

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Combining anti-PD-1 therapy (nivolumab) with radiation has been shown to be safe and effective in treating patients with relapsed sarcomatoid renal carcinoma and heavily pretreated pleomorphic sarcoma, leading to dramatic and durable responses in both cases.

This approach may help overcome resistance to immune checkpoint inhibitors, particularly in tumor types that are typically less responsive to such treatments, suggesting a potential new strategy for enhancing cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dramatic Response to Concurrent Anti-PD-1 Therapy and Radiation in Resistant Tumors with Sarcomatoid Differentiation. Tolay, S., Nair, R., McIntosh, AF., et al.[2020]

In a phase 1 study involving 20 patients with stage IV melanoma, combining radiotherapy with nivolumab and ipilimumab was found to be safe, with treatment-related severe adverse events occurring in 40% of patients in one cohort and 30% in another, but no severe events linked to radiotherapy itself.

Patients showed positive responses to treatment outside the irradiated areas, indicating potential systemic immunologic effects, as evidenced by increased T-cell receptor diversity in some responders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective, Phase 1 Trial of Nivolumab, Ipilimumab, and Radiotherapy in Patients with Advanced Melanoma. Postow, MA., Knox, SJ., Goldman, DA., et al.[2021]

Radiation therapy (RT) is crucial for controlling non-small cell lung cancer (NSCLC), but it often fails to prevent distant metastases, leading to poor patient outcomes.

Recent advancements in combining RT with immune checkpoint blockade immunotherapy show promise in enhancing systemic anti-tumor responses in NSCLC, similar to successful strategies seen in melanoma, with ongoing clinical trials exploring this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experiences of combining immunotherapy and radiation therapy in non-small cell lung cancer: lessons from melanoma. Kalbasi, A., Rengan, R.[2020]

Two cases of patients with multiple in-transit metastatic melanomas were successfully treated using intensity-modulated radiotherapy (IMRT) combined with immune checkpoint inhibitors ipilimumab or nivolumab.

The combination of IMRT and immune checkpoint inhibitors suggests a potential enhancement of antitumor effects, indicating a promising approach for improving treatment outcomes in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two cases. Fujimura, T., Kambayashi, Y., Furudate, S., et al.[2018]

Stereotactic ablative body radiotherapy (SABR) not only delivers high doses of radiation to tumors but also has significant immunomodulatory effects that can enhance the body's anti-tumor immune response.

Combining SABR with immune checkpoint inhibitors can improve treatment outcomes by overcoming tumor-induced immunosuppression and preparing tumors for a stronger adaptive immune response, as shown in early phase clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The optimism surrounding stereotactic body radiation therapy and immunomodulation. Tharmalingam, H., Hoskin, PJ.[2018]

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]

Combining palliative radiotherapy (pRT) with immune checkpoint inhibitors (ICI) in melanoma treatment significantly improved objective response rates, complete response rates, and one-year local control, indicating enhanced efficacy of the treatment.

The combination treatment did not lead to a significant increase in adverse events or immune-related adverse events compared to ICI alone, suggesting that it is a safe option for patients with advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of immune checkpoint inhibitors in combination with palliative radiotherapy in advanced melanoma: A systematic review. Ben Shimol, J., Guzman-Prado, Y., Karlinskaya, M., et al.[2021]

In a study of 84 patients with advanced sarcomas treated with off-label anti-PD1 immunotherapy, those with cutaneous primary tumors showed a significantly higher clinical benefit rate of 58%, compared to 11% for non-cutaneous tumors, indicating that tumor location is a key factor in treatment efficacy.

Patients with cutaneous sarcomas also experienced longer progression-free survival (8.6 months vs. 2.5 months) and overall survival (19.0 months vs. 9.2 months), suggesting that cutaneous primary site is a stronger predictor of response to immunotherapy than histological subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 therapy in advanced sarcomas: is cutaneous primary site a stronger predictor of response than histologic subtype? Miao, R., Swank, J., Melzer, D., et al.[2023]

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]

In a long-term follow-up of patients with metastatic melanoma treated with ipilimumab and radiation therapy, two out of three patients who achieved a complete response (CR) remain alive and free of melanoma, although they developed chronic treatment-induced hypophysitis.

The durability of the complete responses appears to be linked to the occurrence of grade 2-3 hypophysitis, suggesting that this side effect may be a marker of effective treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durability of response in metastatic melanoma patients after combined treatment with radiation therapy and ipilimumab. Sodji, QH., Gutkin, PM., Swetter, SM., et al.[2022]

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. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1605958/full

The real-world safety of Nivolumab: a pharmacovigilance ... Furthermore, this trial demonstrated superior 5-year overall survival rates for combination therapy (52%) and nivolumab monotherapy (44%) versus ...

7. opdivo.com opdivo.com/clinical-trial-results

Clinical Trial Results It is not known if OPDIVO is safe and effective in children younger than 12 years of age with melanoma or MSI-H or dMMR metastatic colorectal cancer. It is not ...