Immunotherapy + Radiation for Advanced Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: GnRH analogues

Must not be taking: Corticosteroids, IL-2

Disqualifiers: Autoimmune disorders, HIV, Hepatitis B, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

13 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects of anti-CTLA4-NF monoclonal antibody (mAb) (BMS986218), nivolumab, and stereotactic body radiation therapy in treating patients with solid malignancies that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as anti-CTLA4-NF mAb (BMS-986218) 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. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving -CTLA4-NF mAb (BMS986218), nivolumab, and stereotactic body radiation therapy may kill more tumor cells.

Will I have to stop taking my current medications?

The trial requires that patients stop taking prior systemic anti-cancer therapies for a period of 5 drug half-lives or 4 weeks, whichever is shorter, before enrolling. However, patients with metastatic castration-resistant prostate cancer can continue their maintenance therapy with certain medications. The protocol does not specify about other medications, so it's best to discuss with the trial team.

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

Research shows that combining immunotherapy drugs like ipilimumab with stereotactic ablative radiotherapy (SABR) can improve survival rates in patients with metastatic cancers. Additionally, studies suggest that SABR can enhance the immune system's response to cancer, especially when used with immune checkpoint inhibitors, potentially leading to better outcomes in non-small cell lung cancer. ^{1 2 3 4 5}

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

The combination of immunotherapy drugs like ipilimumab and nivolumab with radiation therapy has shown low toxicities in some studies, but it can cause immune-related side effects affecting the skin, gut, liver, and hormone systems. These side effects can often be managed with medications that suppress the immune system. ^{1 6 7 8 9}

What makes the treatment of Anti-CTLA4 Monoclonal Antibody BMS-986218, Nivolumab, and Stereotactic Body Radiation Therapy unique for advanced cancer?

This treatment is unique because it combines high-precision radiation therapy (SABR) with immunotherapy drugs (Anti-CTLA4 and Nivolumab) to enhance the body's immune response against cancer. The radiation helps to prime the immune system, while the drugs work to overcome the cancer's defenses, potentially leading to a more effective and prolonged anti-tumor response. ^{2 4 10 11 12}

Research Team

James Welsh

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with metastatic solid cancers, not breastfeeding or donating sperm, and willing to use contraception. They must have normal organ/marrow function, no severe allergies to immunotherapy drugs, and can't be on certain medications. Eligible even if they've had prior cancer treatments (except anti-CTLA4-NF drugs) or controlled autoimmune disorders.

Inclusion Criteria

I agree to follow the study's contraception rules or abstain from sex as required.

I have brain metastases but no symptoms, and I haven't taken steroids for 2 weeks.

I have had cancer treatment with immunotherapy and my cancer got worse, but it's not required.

Exclusion Criteria

I am not on treatments like IL-2, interferon, chemotherapy, or high-dose steroids while receiving BMS-986218.

I have hypothyroidism from an autoimmune condition and take hormone replacement.

I do not have any health or mental conditions that could make this study unsafe for me.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive anti-CTLA4 monoclonal antibody BMS-986218 and undergo SBRT. In Arm II, patients also receive nivolumab starting in cycle 2. Treatment cycles repeat every 28 days.

Up to 2 years

Radiation

Patients undergo stereotactic body radiation therapy (SBRT) on days 36-39 (days 8-11 of cycle 2).

4 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion at 30 and 60 days, and 6 and 12 months after the last cycle.

12 months

Treatment Details

Interventions

• Anti-CTLA4 Monoclonal Antibody BMS-986218
• Nivolumab
• Stereotactic Body Radiation Therapy

Trial Overview The trial is testing a combination of an experimental drug BMS986218 with Nivolumab and precise radiation therapy on patients with metastatic cancers. The goal is to see how well this trio works together in stopping cancer growth by enhancing the body's immune response.

Participant Groups

Group I: Arm II (BMS-986218, SBRT, nivolumab) Experimental Treatment 3 Interventions

Patients receive anti-CTLA4 monoclonal antibody BMS-986218 and SBRT as in Arm 1. Beginning cycle 2, patients also receive nivolumab IV over 30 minutes starting on day 1. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (BMS-986218, SBRT) Experimental Treatment 2 Interventions

Patients receive anti-CTLA4 monoclonal antibody BMS-986218 IV over 30 minutes on day 1. Treatment repeats every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo SBRT on days 36-39 (days 8-11 of cycle 2).

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

In a phase II trial involving 106 patients with metastatic cancers, the combination of ipilimumab and stereotactic ablative radiotherapy (SABR) showed promising long-term survival rates, with 5-year overall survival rates of 15%.

Patients receiving SABR targeting lung metastases had significantly better overall survival (18.67 months) and progression-free survival (6.87 months) compared to those with liver metastases, highlighting the importance of tumor location in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year overall survival with ipilimumab and stereotactic ablative radiotherapy for metastatic disease. He, K., Hong, DS., Tang, C., et al.[2023]

Stereotactic ablative radiotherapy (SABR) may enhance the immune response in patients with non-small cell lung cancer (NSCLC) when combined with immune checkpoint inhibitors, potentially improving treatment outcomes.

Recent studies, including prospective trials, suggest that this combination therapy could lead to better survival rates compared to traditional palliative radiotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation and immunotherapy combinations in non-small cell lung cancer. Azghadi, S., Daly, ME.[2021]

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]

In a phase 1 trial involving 37 treatment-naive patients with stage IV NSCLC, combining concurrent stereotactic body radiotherapy (SBRT) with nivolumab and ipilimumab showed no dose-limiting toxicities, indicating a favorable safety profile for this multimodal treatment approach.

The study reported a median progression-free survival of 5.8 months and demonstrated that concurrent therapy was well tolerated, suggesting that this combination could effectively control metastasis in widely metastatic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV NSCLC Study. Bestvina, CM., Pointer, KB., Karrison, T., et al.[2022]

In a phase II study involving 18 patients with metastatic colorectal cancer, both low-dose fractionated radiation (LDFRT) and hypofractionated radiation (HFRT) were found to be feasible and safe when combined with PD-L1/CTLA-4 blockade, although 84% of patients experienced treatment-related toxicity.

The best treatment response was stable disease in one patient, and the study did not show significant efficacy in terms of tumor shrinkage outside the radiation field, suggesting that while the combination impacts the immune microenvironment, it may not be effective for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer. Monjazeb, AM., Giobbie-Hurder, A., Lako, A., et al.[2022]

In a phase 2 study involving 130 patients with extensive-disease small-cell lung cancer, the phased administration of ipilimumab combined with paclitaxel and carboplatin improved immune-related progression-free survival (irPFS) compared to the control group, indicating a potential benefit of this treatment strategy.

While phased ipilimumab showed better irPFS, there was no significant improvement in overall survival (OS) or progression-free survival (PFS) compared to the control, and the rates of severe immune-related adverse events (irAEs) were relatively low, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Reck, M., Bondarenko, I., Luft, A., et al.[2022]

Ipilimumab, an anti-CTLA-4 antibody, and nivolumab/pembrolizumab, anti-PD-1 antibodies, are FDA-approved treatments that enhance the immune system's ability to fight various cancers, particularly melanoma.

While these immune checkpoint inhibitors are effective, they can cause immune-related adverse events (irAEs) affecting multiple organ systems, which can be managed with temporary immunosuppression using corticosteroids and other agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing immune checkpoint-blocking antibody side effects. Postow, MA.[2022]

Pembrolizumab, an immunotherapy targeting PD-1, showed limited effectiveness in a patient with metastatic renal cell carcinoma, highlighting that only 20-40% of patients benefit from such treatments due to individual tumor biology and immune checkpoint diversity.

The patient's rapid disease progression during treatment may be linked to a lack of tumor-infiltrating lymphocytes (TILs) and the specific radiation dose and schedule used, which could affect the tumor microenvironment and the potential synergy with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. Alexander, GS., Palmer, JD., Tuluc, M., et al.[2022]

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]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Five-year overall survival with ipilimumab and stereotactic ablative radiotherapy for metastatic disease. [2023]

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

Radiation and immunotherapy combinations in non-small cell lung cancer. [2021]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer. [2020]

4. China pubmed.ncbi.nlm.nih.gov

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

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

A Phase 1 Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV NSCLC Study. [2022]

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

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer. [2022]

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

Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. [2022]

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

Managing immune checkpoint-blocking antibody side effects. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic 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]