Immunotherapy + Radiation for Advanced Lung Cancer

(COSINR Trial)

Overseen By Cancer Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must not be taking: Systemic steroids

Disqualifiers: Prior chemotherapy, Active TB, Autoimmune disease, 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: Up to 100 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to treat advanced lung cancer by combining immunotherapy with radiation. Researchers are testing two approaches: one where radiation occurs first and another where both treatments are administered simultaneously. The main goal is to determine the safety of these combined treatments. Individuals with stage IV non-small cell lung cancer and at least two spots targetable by radiation may qualify for this study. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I need to stop my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on systemic steroid therapy at a dose greater than 10 mg of prednisone daily or equivalent, you may not be eligible to participate.

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

Research shows that combining nivolumab and ipilimumab with stereotactic body radiotherapy (SBRT) has generally been safe for patients with non-small cell lung cancer. Previous studies found that this combination is well-tolerated, even with radiation targeting the brain, suggesting broad safety.

However, safety data specific to this trial is still being collected. This phase focuses on understanding the treatment's safety. Researchers aim to find the best way to use the treatment without causing significant side effects.

In other studies, some patients experienced side effects, but these were usually manageable. The trial is designed to carefully monitor patients and adjust doses if needed, ensuring that patient safety remains a top priority. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ipilimumab and nivolumab with radiation for advanced lung cancer because it offers a novel approach to treatment. Unlike the standard chemotherapy and radiation treatments, this combination uses immunotherapy drugs that work by stimulating the body's immune system to better recognize and attack cancer cells. Ipilimumab and nivolumab are immune checkpoint inhibitors that target specific pathways to enhance the immune response against tumors. Additionally, the trial explores two different timing strategies—sequential and concurrent administration with radiation—which could offer insights into optimizing treatment effectiveness and minimizing side effects. This approach has the potential to improve outcomes for patients with advanced lung cancer by harnessing the body's natural defenses in a more targeted way.

What evidence suggests that this trial's treatments could be effective for advanced lung cancer?

Research has shown that combining the drugs nivolumab and ipilimumab with stereotactic body radiotherapy (SBRT) may offer promise for patients with advanced non-small cell lung cancer. In this trial, participants will be randomized into two treatment arms: the Sequential Arm and the Concurrent Arm. In the Sequential Arm, patients will complete SBRT to 2-4 sites before beginning treatment with nivolumab/ipilimumab shortly after. In the Concurrent Arm, patients will start treatment with nivolumab/ipilimumab first and complete planned SBRT within 2 weeks. Some studies have found that this combination can help treat stage IV non-small cell lung cancer, potentially improving cancer control. Patients who received these treatments experienced good short-term benefits with manageable side effects. Additionally, using SBRT to boost the immune system along with these drugs has been explored as a new way to combat cancer spread. Overall, these early findings suggest that this treatment approach could benefit patients with advanced lung cancer. ^{1 4 5 6 7}

Who Is on the Research Team?

Steven Chmura, MD, PhD

Principal Investigator

University of Chicago

Are You a Good Fit for This Trial?

This trial is for adults over 18 with stage IV non-small cell lung cancer (NSCLC) who have good organ function and performance status. They must not be pregnant, agree to use birth control, and can't have had certain prior treatments like chemotherapy or immunotherapy for NSCLC. Patients with specific genetic mutations in their tumors must have tried targeted therapies first.

Inclusion Criteria

Be willing and able to provide written informed consent/assent for the trial.

Have an investigator determined life expectancy of at least 6 months.

My cancer has spread, and I have at least two tumors that can be measured and treated with targeted radiation.

Exclusion Criteria

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

You are allergic to nivolumab or ipilimumab.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Stereotactic body radiotherapy (SBRT) delivered in 3-5 fractions over 1-1.5 weeks

1-1.5 weeks

Treatment

Patients receive nivolumab/ipilimumab either sequentially or concurrently with SBRT

Up to 100 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Stereotactic Body Radiation Therapy

Trial Overview The study tests the safety of combining nivolumab/ipilimumab immunotherapy with stereotactic body radiotherapy (SBRT), either sequentially or at the same time. It aims to find a safe radiation dose and assess how these treatments affect the immune system within tumors across different locations in the body.

How Is the Trial Designed?

Group I: Sequential Arm Experimental Treatment 3 Interventions

Patients will be randomized to either the Sequential Arm or the Concurrent Arm. Patients in the Sequential Arm will complete SBRT to 2-4 sites and then begin treatment with nivolumab/ipilimumab between 1-7 days after completion of SBRT.

Group II: Concurrent Arm Experimental Treatment 3 Interventions

Patients will be randomized to either the Sequential Arm or the Concurrent Arm. Patients in the Concurrent Arm will begin treatment with nivolumab/ipilimumab first and must complete planned SBRT to 2-4 sites within 2 weeks (prior to second dose of nivolumab).

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 Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

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]

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]

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]

Recent advancements in immunotherapy for non-small cell lung cancer (NSCLC), including drugs like nivolumab and pembrolizumab, have shown significant efficacy in treating metastatic cases and unresectable stage III NSCLC.

Combining radiation therapy (RT) with immunotherapy has demonstrated potential to enhance tumor immunity, leading to ongoing trials that aim to optimize treatment strategies for NSCLC, emphasizing the importance of careful patient selection for better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy and Immunotherapy Combinations for Lung Cancer. Agrawal, V., Benjamin, KT., Ko, EC.[2021]

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]

In a study of 60 patients receiving combined immunotherapy and thoracic radiation therapy (iRT), no patients experienced severe grade ≥4 toxicities, indicating a favorable safety profile for this treatment approach.

While some patients did experience grade 3 toxicities, particularly pulmonary and hematologic issues, the overall short-term safety of iRT suggests it can be administered without significant risk of severe adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. Verma, V., Cushman, TR., Selek, U., et al.[2022]

Concurrent immunoradiotherapy, combining immune checkpoint inhibitors with radiotherapy, showed a 30% overall response rate in 16 patients with metastatic melanoma who had progressed on nivolumab, with a notable 68.8% response rate in lesions within the radiation fields.

Nivolumab combined with radiotherapy demonstrated a 100% response rate inside the radiation fields, suggesting it may be more effective than ipilimumab in this setting, although some patients experienced grade 3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. Nomura, M., Otsuka, A., Yoshimura, M., et al.[2019]

The combination of PD-1/PD-L1 blockade with thoracic radiotherapy is now the standard treatment for locally advanced non-small-cell lung cancer, but safety data is primarily from retrospective studies and small clinical trials.

There is a need for longer and more rigorous follow-up studies to better understand the pulmonary safety and potential toxicity of this combined therapy in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rethinking pulmonary toxicity in advanced non-small cell lung cancer in the era of combining anti-PD-1/PD-L1 therapy with thoracic radiotherapy. Li, M., Gan, L., Song, A., et al.[2019]

In a study of 133 patients with metastatic cancers receiving immune checkpoint inhibitors and radiation, 34.6% experienced immune-related adverse events (ir-AEs), with higher rates observed in those receiving both CTLA-4 and PD-1 inhibitors (71% vs 29%).

The combination of palliative radiation and immune checkpoint inhibitors was generally well tolerated, with most ir-AEs being mild, suggesting that this treatment approach can be safely integrated in clinical practice for patients needing both therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy. Bang, A., Wilhite, TJ., Pike, LRG., et al.[2022]

Combining anti-PD-L1 immunotherapy with radiation therapy has shown promising results in increasing progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma and metastatic non-small cell lung cancer (NSCLC), based on several preclinical studies and two early clinical trials.

Low doses of radiation enhance T-cell activity, which is further boosted by anti-PD-L1 therapy, suggesting that this combination can effectively overcome the immune suppression caused by PD-L1, leading to better tumor control and regression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation Therapy Plus Anti-Programmed Death Ligand 1 Immunotherapy: A Review on Overall Survival. Krcik, EM.[2019]

In a study of 85 patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab, those who received radiotherapy (RT) prior to or during treatment had a significantly longer progression-free survival (PFS) of 2.8 months compared to 1.3 months for those who did not receive RT.

The combination of RT and nivolumab did not increase toxicity, suggesting that RT may enhance the effectiveness of anti-PD-1 therapy without adding adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prior or concurrent radiotherapy and nivolumab immunotherapy in non-small cell lung cancer. Ratnayake, G., Shanker, M., Roberts, K., et al.[2020]

Citations

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