Neoadjuvant Immunoradiation for Lung Cancer

No longer recruiting at 1 trial location

Overseen By Patrick Forde, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Immunosuppressants, PD-1 inhibitors

Disqualifiers: Prior chest radiation, Autoimmune disorders, Active infection, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: 2

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore a new treatment method called "immunoradiation" for patients with stage IIIA non-small cell lung cancer (NSCLC). The study tests two treatment combinations: durvalumab (an immunotherapy drug) with radiation, and the addition of tremelimumab (another immunotherapy drug). These treatments are administered before surgery to determine if they can shrink the cancer and enhance surgical effectiveness. Individuals with stage IIIA NSCLC who are eligible for lung surgery (a lobectomy) and have not received certain prior treatments may qualify for this trial. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant advancements in cancer treatment.

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 use immunosuppressive medications within 14 days before starting the trial drugs, except for certain types of steroids. It's best to discuss your specific medications with the study team.

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

Research has shown that combining durvalumab and tremelimumab with radiation is generally safe, though some side effects may occur. One study found that this combination causes more immune-related side effects than using durvalumab alone, but serious issues are rare, making the treatment manageable for most people.

When using durvalumab with radiation alone, studies have shown it is well-tolerated. Patients have found durvalumab to be safe, with side effects that are usually manageable. Notably, the FDA has already approved durvalumab for other uses, which adds confidence in its safety.

Overall, both treatment options in the study have undergone safety testing in humans before. While side effects can occur, they are usually not severe and can be managed effectively. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for lung cancer because they combine immunotherapy with radiation in a novel way. Unlike standard treatments that primarily focus on surgery and chemotherapy, these investigational treatments use drugs like Durvalumab and Tremelimumab to boost the immune system's ability to fight cancer. Durvalumab blocks PD-L1, a protein that helps cancer evade immune detection, while Tremelimumab targets CTLA-4, another immune checkpoint, enhancing the body's natural defenses. This approach aims to increase the effectiveness of radiation therapy, potentially leading to better outcomes for patients.

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

This trial will compare two treatment approaches for non-small-cell lung cancer (NSCLC). One arm will study the combination of durvalumab and tremelimumab with radiation. Research has shown that using durvalumab and tremelimumab together may help treat NSCLC, as studies have found that this combination can extend life and delay cancer progression. Another arm will study durvalumab with radiation. The PACIFIC trial found significant benefits for patients with stage III NSCLC that cannot be surgically removed, including longer life and delayed cancer progression. Both treatments boost the immune system to fight cancer more effectively, offering hope for better outcomes in lung cancer. ^{3 6 7 8 9}

Who Is on the Research Team?

Patrick Forde, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for adults over 18 with stage IIIA non-small cell lung cancer (NSCLC) that can be removed by surgery. Participants must weigh more than 30kg, have a life expectancy over 6 months, and be in good physical condition (ECOG Performance Status of 0-1). They should not have had certain prior treatments or conditions like chest radiation or active pneumonitis, and women must not be pregnant.

Inclusion Criteria

Ability to understand and willingness of sign consent form

My lung cancer can be removed with surgery according to my thoracic surgeon.

You are expected to live for more than 6 months.

Exclusion Criteria

I haven't taken any experimental drugs within the last 28 days or 5 half-lives.

I have not had major surgery within the last 28 days.

I have received an organ transplant from another person.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Neoadjuvant immunoradiation with durvalumab or durvalumab plus tremelimumab administered every 4 weeks for 2 doses, concurrently with standard thoracic radiation, followed by one dose of immunotherapy alone in the pre-surgical window

8 weeks

2 visits (in-person) for immunotherapy, daily visits for radiation

Surgery

Surgical resection (lobectomy) for patients with stage IIIA NSCLC

Adjuvant Chemotherapy

Standard of care adjuvant chemotherapy may be administered post-surgery as deemed appropriate by the treating investigator

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Lobectomy
• Standard of care adjuvant chemotherapy
• Thoracic Radiation
• Tremelimumab

Trial Overview The study tests 'immunoradiation' using durvalumab alone or combined with tremelimumab alongside standard thoracic radiation before surgical removal of the tumor. If safe, a second group will test both drugs with radiation pre-surgery. Post-surgery, standard chemotherapy may follow as decided by the doctor.

How Is the Trial Designed?

Group I: Durvalumab with Radiation Experimental Treatment 4 Interventions

Drug: Durvalumab Other Names: MEDI4736 MEDI4736 1500mg via IV infusion every 4 weeks for up to 3 doses/cycles Intervention: Radiation: Thoracic Radiation 5 days per week in once daily fractionation, 1.8-2.0 Gy per fraction Intervention: Procedure/Surgery: lobectomy patients may proceed to surgery post drug and radiation intervention for lung lobectomy Intervention: Drug: Standard of care adjuvant chemotherapy patients may or may not proceed to adjuvant chemotherapy post trial drug and radiation intervention and surgery

Group II: Durvalumab and Trememlimumab with Radiation Experimental Treatment 5 Interventions

Drugs: Durvalumab + Tremelimumab Other Names: MEDI4736 and CP-675 MEDI4736 1500mg via IV infusion every 4 weeks for up to 3 doses/cycles + CP-675 206 75mg via IV infusion every 4 weeks up 3 doses/cycles Intervention: Radiation: Thoracic Radiation 5 days per week in once daily fractionation, 1.8-2.0 Gy per fraction Intervention: Procedure/Surgery: lobectomy patients may proceed to surgery post drug and radiation intervention for lung lobectomy Intervention: Drug: Standard of care adjuvant chemotherapy patients may or may not proceed to adjuvant chemotherapy post trial drug and radiation intervention and surgery

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

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]

In a study of 96 lung cancer patients who received thoracic radiotherapy (TRT) after PD-(L)1 inhibitor treatment, nearly 49% developed symptomatic treatment-related pneumonitis, indicating a significant safety concern with this treatment sequence.

Independent risk factors for developing pneumonitis included pulmonary emphysema and lung V20 exposure, highlighting the need for careful patient selection and monitoring when using TRT after PD-(L)1 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of thoracic radiotherapy after PD-(L)1 inhibitor treatment in patients with lung cancer. Chen, Y., Liu, X., Huang, Z., et al.[2022]

The Checkmate-816 trial showed that combining neoadjuvant immunotherapy with platinum-based chemotherapy is effective for treating resectable non-small cell lung cancer, highlighting a promising approach in cancer therapy.

This trial reinforces the importance of personalized therapy and understanding the biology of lung cancer to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

When immunotherapy meets surgery in non-small cell lung cancer. Herbst, RS., Wang, M., Chen, L.[2022]

In a study of 802 patients with resectable non-small-cell lung cancer (NSCLC), the combination of durvalumab (an immunotherapy) with platinum-based chemotherapy significantly improved event-free survival compared to placebo, with a hazard ratio of 0.68, indicating a 32% reduction in the risk of disease progression, recurrence, or death.

Durvalumab also led to a higher rate of pathological complete response (17.2% vs. 4.3% for placebo), demonstrating its efficacy in enhancing treatment outcomes, while the safety profile was similar to that of the placebo group, with no significant increase in severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. Heymach, JV., Harpole, D., Mitsudomi, T., et al.[2023]

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 randomized phase II trial involving 60 patients with resectable non-small cell lung cancer, the addition of sub-ablative radiation to neoadjuvant durvalumab did not increase mortality or major complications compared to durvalumab alone, indicating a safe combination treatment approach.

Both treatment groups experienced similar rates of grade 3/4 adverse events (38% each), with anemia and hypotension being the most common, suggesting that the safety profile of durvalumab remains consistent regardless of the addition of radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgical resection after neoadjuvant durvalumab and radiation is feasible and safe in non-small cell lung cancer: Results from a randomized trial. Lee, B., Mynard, N., Nasar, A., et al.[2022]

Citations

1. imfinzihcp.com imfinzihcp.com/nsclc/stage-3/efficacy.html

IMFINZI® Efficacy for unresectable Stage III NSCLC Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. J Clin Oncol. 2022;40(12): ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37497677/

Durvalumab real-world treatment patterns and outcomes in ... Durvalumab real-world treatment patterns and outcomes in patients with stage III non-small-cell lung cancer treated in a US community setting.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.01308

Five-Year Survival Outcomes From the PACIFIC Trial These updated analyses demonstrate robust and sustained OS and durable PFS benefit with durvalumab after chemoradiotherapy.

4. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2819200

International Cost-Effectiveness Analysis of Durvalumab in ... This economic evaluation compares the cost-effectiveness of durvalumab for maintenance treatment of stage III non–small cell lung cancer ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1709937

Durvalumab after Chemoradiotherapy in Stage III Non– ... Among patients with locally advanced, unresectable NSCLC, progression-free survival was 11 months longer among patients who received durvalumab ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9015199/

Five-Year Survival Outcomes From the PACIFIC Trial An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39147210/

Concerning Safety and Efficacy of Concurrent and ... - PubMed The primary endpoint of progression-free survival at 12 months was 20% (50% for PDL1≥1% vs 0% for PDL1 unavailable or <1%). Median overall ...

8. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00494-7/fulltext

A phase II clinical trial evaluating the safety and efficacy of ... This study demonstrates that single agent durvalumab is safe and well tolerated in the 1st line treatment of patients with advanced NSCLC and ECOG PS of 2, with ...

9. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2024/imfinzi-approved-in-us-for-limited-stage-sclc.html

Imfinzi approved in the US as first and only immunotherapy ... Based on ADRIATIC Phase III trial results which showed a 27% reduction in the risk of death versus placebo. AstraZeneca's Imfinzi ...