Immunotherapy + Radiation for Sarcoma

Overseen By Adrienne Victor, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Rochester

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Metastatic disease, Autoimmune disease, Hepatitis B/C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

14 Participants Needed

Trial Summary

What is the purpose of this trial?

Immunotherapy + Radiation in Resectable Soft Tissue Sarcoma

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on systemic corticosteroids or other immunosuppressive medications within 14 days of registration.

What data supports the effectiveness of the treatment combining immunotherapy and radiation for sarcoma?

Research shows that combining radiation with immunotherapy can enhance the body's immune response to tumors, leading to significant tumor shrinkage in some cases, such as in patients with resistant tumors and melanoma brain metastases. This combination has shown promise in improving outcomes by making tumor cells more vulnerable to immune attacks. ^{1 2 3 4 5}

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

Research shows that combining immunotherapy drugs like ipilimumab or nivolumab with radiation therapy has been generally safe in humans, with some patients experiencing immune-related side effects. These side effects were not significantly different from those seen with immunotherapy alone, and radiation-related side effects were more common at higher doses. ^{4 6 7 8 9}

How is the immunotherapy and radiation treatment for sarcoma different from other treatments?

This treatment combines immunotherapy drugs, ipilimumab and nivolumab, which help the immune system attack cancer cells, with radiation therapy to target sarcoma tumors. Unlike traditional chemotherapy, this approach uses the body's own defenses and has shown promise in cases where other treatments have failed, offering a novel option for patients with limited choices. ^{10 11 12 13 14}

Eligibility Criteria

Adults diagnosed with resectable soft tissue sarcoma, not pregnant or nursing, and able to consent. They must have a performance status allowing daily activity (ECOG 0-2), no HIV complications, agree to use effective contraception methods post-treatment, and be willing to undergo radiation therapy and surgery. Excluded are those with prior radiation in the area, certain autoimmune conditions or active hepatitis B/C, low blood counts or liver enzymes above normal limits.

Inclusion Criteria

I am willing to undergo blood tests for my study.

My sarcoma is aggressive and larger than 5 cm.

I am willing to undergo radiation therapy before surgery.

Exclusion Criteria

I have active inflammation of my colon due to an autoimmune condition.

I have an autoimmune condition affecting my adrenal glands.

I have active hepatitis B or C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants in Cohort A receive ipilimumab and nivolumab concurrently with standard of care radiation. Ipilimumab is given every 6 weeks (total two doses) and nivolumab every 2 weeks (total four doses).

6 weeks

Multiple visits for drug administration and monitoring

Surgical Resection

Standard surgical resection is performed 2 to 4 weeks after completion of radiotherapy.

2-4 weeks post-radiotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up data collected for up to 3 years post-treatment.

3 years

Regular follow-up visits

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Radiation Therapy

Trial Overview The trial is testing the combination of two immunotherapy drugs—ipilimumab and nivolumab—with neoadjuvant radiation therapy in patients who can surgically remove their soft tissue sarcoma. The goal is to see how well this combo works before surgery.

Participant Groups

Group I: Immunotherapy arm Experimental Treatment 2 Interventions

Cohort A will comprise adult soft tissue sarcoma patents who consent to and receive ipilimumab + nivolumab concurrently with standard of care radiation. Ipilimumab will be given at a dose of 1 mg/kg every 6 weeks (total two doses) and nivolumab given as a flat dose of 240 mg every 2 weeks (total four doses). Standard surgical resection will be done 2 to 4 weeks after completion of radiotherapy. Accrual is expected to occur over 2 years. Follow up data will be collected for up to 3 years post-treatment.

Group II: no immunotherapy arm Active Control 1 Intervention

Cohort B will comprise patients eligible for the trial who do not wish to receive immunotherapy but consent to the same blood draws, surveys, and specimen analysis as Cohort A. Cohort B will serve as a non-randomized but pragmatic and clinically relevant control group. Standard surgical resection will be done 2 to 4 weeks after completion of radiotherapy. Accrual is expected to occur over 2 years. Follow up data will be collected for up to 3 years post-treatment.

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?

University of Rochester

Lead Sponsor

Trials

883

Recruited

555,000+

Findings from Research

Combining radiation therapy with immunotherapy shows great potential for enhancing cancer treatment, as preclinical studies suggest that radiation can make tumor cells more vulnerable to immune attacks.

Clinical trials have begun to support the idea that this combination can effectively boost antitumor immune responses, with ongoing studies exploring various therapeutic vaccines alongside radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining radiation and immunotherapy for synergistic antitumor therapy. Ferrara, TA., Hodge, JW., Gulley, JL.[2021]

In a phase II trial involving 65 patients with metastatic microsatellite stable colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), combining radiation with immune checkpoint inhibitors ipilimumab and nivolumab achieved a disease control rate of 25% for CRC and 20% for PDAC, indicating some effectiveness in these challenging cancers.

The study found that patients who experienced disease control had higher levels of natural killer (NK) cells and expression of HERVK repeat RNA, suggesting that these immune factors may play a role in the response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial. Parikh, AR., Szabolcs, A., Allen, JN., et al.[2023]

In a study of 70 melanoma patients with brain metastases, those treated with ipilimumab had a significantly longer median survival of 18.3 months compared to 5.3 months for those who did not receive the treatment, indicating ipilimumab enhances overall survival.

Patients who received ipilimumab before radiotherapy showed a higher partial response rate (40%) to treatment compared to those who did not receive ipilimumab (9.1%), suggesting that the sequence of treatments may influence disease control in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and radiation therapy for melanoma brain metastases. Silk, AW., Bassetti, MF., West, BT., 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]

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]

In a phase 1 trial with 13 patients suffering from metastatic melanoma, the combination of ipilimumab and high-dose radiation therapy was found to be feasible and safe, with 25% of patients experiencing grade 3 or 4 adverse events.

Local control of the treated lesions was achieved in 11 out of 12 patients, and while only 3 patients showed clinical benefit in non-irradiated lesions, the results suggest that early radiation therapy may enhance the effectiveness of ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Dose Escalation Trial of Ipilimumab and Stereotactic Body Radiation Therapy in Metastatic Melanoma. Sundahl, N., De Wolf, K., Kruse, V., et al.[2019]

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]

Intensity modulated radiation therapy (IMRT) significantly improved tumor coverage for retroperitoneal sarcomas, increasing the percentage of the tumor receiving the prescribed dose from 95.3% with 3D-conformal treatment to 98.6% with IMRT.

IMRT also reduced the mean dose to surrounding organs at risk, such as the small bowel, from 36 Gy to 27 Gy, while maintaining effective treatment, suggesting it is a safer and more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity modulated radiation therapy for retroperitoneal sarcoma: a case for dose escalation and organ at risk toxicity reduction. Koshy, M., Landry, JC., Lawson, JD., et al.[2021]

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 phase 2 study involving 98 patients with rare and ultra-rare sarcomas, pembrolizumab showed an objective response rate of 6.2% at week 12, indicating some activity in these difficult-to-treat cancers.

The treatment was associated with manageable toxicity, with the most common severe adverse events being anemia and liver enzyme increases, and no deaths were linked to the drug itself, suggesting it may be a safe option for selected sarcoma histotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. Blay, JY., Chevret, S., Le Cesne, A., 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]

References

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

Combining radiation and immunotherapy for synergistic antitumor therapy. [2021]

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

Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial. [2023]

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

Ipilimumab and radiation therapy for melanoma brain metastases. [2022]

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

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

5. England pubmed.ncbi.nlm.nih.gov

Radiation therapy and immunotherapy: what is the optimal timing or sequencing? [2019]

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

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

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

Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. [2022]

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

Phase 1 Dose Escalation Trial of Ipilimumab and Stereotactic Body Radiation Therapy in Metastatic Melanoma. [2019]

9. 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]

10. Egypt pubmed.ncbi.nlm.nih.gov

Intensity modulated radiation therapy for retroperitoneal sarcoma: a case for dose escalation and organ at risk toxicity reduction. [2021]

11. 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]

12. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. [2023]

13. 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]

14. England pubmed.ncbi.nlm.nih.gov

Is immunotherapy in the future of therapeutic management of sarcomas? [2021]