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

78 Participants Needed

Trial Summary

What is the purpose of this trial?

Trial Design * Patients with stage IV non-small cell lung cancer are randomized to nivolumab/ipilimumab plus either sequential or concurrent stereotactic body radiotherapy (SBRT). * The primary endpoint is the phase I safety endpoint of SBRT dose for each body site. * The same starting SBRT dose levels are used in each arm. If two or more patients experience a dose-limiting toxicity (DLT) at the starting dose level, then the reduced dose level will be used (Section 7.1-Page 72). * DLT is defined as any grade ≥3 toxicity possibly, likely, or definitely related to SBRT plus nivolumab/ipilimumab (the combination and not the individual components). * Irradiated metastases will be grouped into one of five locations, which have different SBRT doses, and the DLTs will be attributed to the relevant organ system. * The starting and decreased SBRT dose levels are found in Table 2 (Page 20). * SBRT will be delivered in 3-5 fractions over the course of 1-1.5 weeks. * Patients in the sequential arm will begin immunotherapy between 1-7 days after completion of SBRT * Given the accrual data for IRB15-1130, the investigators anticipate that approximately 1/3 of patients will contribute metastasis to 2 locations. Since there are 2 arms, and 5 metastasis locations with 6 patients per location for the starting dose level, this translates to 40 patients for the starting dose level, and another 40 patients should each of the 5 locations require de-escalation to the lower dose level. * Secondary endpoints include comparisons of efficacy and toxicity between the arms, as well as interrogation of changes in the immune microenvironment induced by the two approaches.

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.

What data supports the effectiveness of combining immunotherapy drugs like Ipilimumab and Nivolumab with radiation treatments like SABR for advanced lung cancer?

Research suggests that combining immunotherapy with radiation treatments like SABR can enhance the immune system's ability to fight cancer, potentially improving survival rates in patients with advanced lung cancer. Studies have shown that this combination can lead to better treatment responses and longer survival in similar conditions, such as advanced melanoma and non-small cell lung cancer. ^{1 2 3 4 5}

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

Research shows that combining immunotherapy (like Ipilimumab and Nivolumab) with radiation therapy has been studied for safety in conditions like metastatic melanoma and lung cancer. While some studies report manageable side effects, there are concerns about lung-related side effects, especially in lung cancer, suggesting that careful monitoring is needed. ^{6 7 8 9 10}

How is the treatment of Ipilimumab and Nivolumab with radiation unique for advanced lung cancer?

This treatment is unique because it combines immunotherapy drugs, Ipilimumab and Nivolumab, with radiation therapy to potentially enhance the immune system's ability to fight cancer, offering a synergistic effect that may improve survival in patients with advanced lung cancer. ^{1 11 12 13 14}

Research Team

Steven Chmura, MD, PhD

Principal Investigator

University of Chicago

Eligibility Criteria

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

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

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

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.

I have not been in a clinical trial for a new treatment or device in the last 4 weeks.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

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

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

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

Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. [2022]

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

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

5. Australia pubmed.ncbi.nlm.nih.gov

Prior or concurrent radiotherapy and nivolumab immunotherapy in non-small cell lung cancer. [2020]

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

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

7. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. [2019]

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

Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. [2022]

9. Netherlands 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. [2019]

10. United States 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. [2022]

11. China pubmed.ncbi.nlm.nih.gov

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

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

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

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

Radiotherapy and Immunotherapy Combinations for Lung Cancer. [2021]

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

Combining Immunotherapy with Radiation Therapy in Non-Small Cell Lung Cancer. [2020]