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

32 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment Ipilimumab, Yervoy, Nivolumab, Opdivo, and Radiation Therapy for sarcoma?

Research shows that combining ipilimumab and nivolumab can lead to long-term remission in some patients with advanced soft tissue sarcoma, even when other treatments have failed. Additionally, aggressive preoperative radiation has been found to increase the chances of saving limbs in sarcoma patients. ^{1 2 3 4 5}

Is the combination of immunotherapy and radiation therapy generally safe for humans?

Research shows that combining immunotherapy drugs like nivolumab or ipilimumab with radiation therapy has been safely used in patients with conditions like melanoma and lung cancer, with limited severe side effects. This suggests that the treatment is generally safe for humans, although individual experiences may vary. ^{6 7 8 9 10}

How is the treatment of Ipilimumab and Nivolumab with radiation unique for sarcoma?

This treatment is unique because it combines immunotherapy drugs (Ipilimumab and Nivolumab) with radiation to potentially enhance the immune system's ability to fight sarcoma, especially in cases where tumors are resistant to standard immune checkpoint inhibitors. This approach leverages the synergistic effects of radiation and immunotherapy, which has shown promising results in other cancers like melanoma. ^{7 11 12 13 14}

What is the purpose of this trial?

This phase II trial studies how well nivolumab with and without ipilimumab and radiation therapy when given before surgery works in treating patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving nivolumab, ipilimumab, and radiation therapy may work better in treating patients with undifferentiated pleomorphic sarcoma.

Research Team

Christina L. Roland

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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]

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]

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]

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]

References

1. 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]

2. Germany pubmed.ncbi.nlm.nih.gov

Anti-PD-1 therapy in advanced sarcomas: is cutaneous primary site a stronger predictor of response than histologic subtype? [2023]

3. 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]

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

Disparity in limb-salvage surgery among sarcoma patients. [2022]

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

Landscape of Immune-Related Markers and Potential Therapeutic Targets in Soft Tissue Sarcoma. [2021]

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

Durability of response in metastatic melanoma patients after combined treatment with radiation therapy and ipilimumab. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Dramatic Response to Concurrent Anti-PD-1 Therapy and Radiation in Resistant Tumors with Sarcomatoid Differentiation. [2020]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of immune checkpoint inhibitors in combination with palliative radiotherapy in advanced melanoma: A systematic review. [2021]

9. Ireland pubmed.ncbi.nlm.nih.gov

Toxicity of definitive and post-operative radiation following ipilimumab in non-small cell lung cancer. [2022]

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

Safety and Efficacy of Radiation Therapy in Advanced Melanoma Patients Treated With Ipilimumab. [2022]

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

A Prospective, Phase 1 Trial of Nivolumab, Ipilimumab, and Radiotherapy in Patients with Advanced Melanoma. [2021]

12. England 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. [2018]

13. China pubmed.ncbi.nlm.nih.gov

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

14. China pubmed.ncbi.nlm.nih.gov

The optimism surrounding stereotactic body radiation therapy and immunomodulation. [2018]