Radiation Therapy + Durvalumab for Lung Cancer

Overseen By Erin E Rogers

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Nebraska

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Autoimmune disorders, Uncontrolled illness, 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)

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for non-small cell lung cancer (NSCLC) by combining a special type of radiation therapy with Durvalumab (also known as Imfinzi, an immunotherapy drug). The goal is to determine if this combination can better control the cancer both at its origin and elsewhere in the body. People with stage III NSCLC who have already received certain types of chemotherapy and radiation may be suitable candidates for this study. Participants will receive the treatment and be monitored for improvements or side effects. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative therapy.

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 take any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment while participating in this study.

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

Research has shown that durvalumab is generally safe for individuals with various solid cancers. Studies have found it to have a manageable safety profile, even when combined with tremelimumab. Specifically, for lung cancer patients, durvalumab has been used safely without causing new or unexpected side effects.

Regarding consolidative hypofractionated radiation therapy (hfRT), research indicates it effectively controls tumors locally with minimal side effects. The main serious side effects reported involve the lungs and heart, such as lung inflammation from radiation (radiation pneumonitis) and heart damage from treatment (cardiotoxicity). However, these severe issues are rare.

Overall, both durvalumab and hfRT have demonstrated promising safety results in past research, suggesting they could be well-tolerated options for lung cancer treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining hypofractionated radiation therapy (hfRT) with Durvalumab for lung cancer because it offers a novel approach to treatment. Unlike traditional radiation therapy, which often involves multiple sessions over several weeks, hfRT delivers a higher dose of radiation in just two sessions, potentially reducing treatment time and improving patient convenience. Additionally, Durvalumab is an anti-PD-L1 therapy that enhances the immune system's ability to fight cancer, offering a promising new mechanism of action compared to conventional chemotherapy. This combination aims to boost the effectiveness of radiation while harnessing the power of immunotherapy, potentially leading to better outcomes for patients.

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

Research has shown that hypofractionated radiation therapy (hfRT) can be very effective for lung cancer. One study found that patients lived without their cancer worsening for an average of 14.3 months and lived overall for an average of 43.3 months, outperforming traditional radiation therapy. Additionally, 83% of patients were alive one year after treatment, and 77% were alive after two years with hfRT.

In this trial, participants will receive both hfRT and Durvalumab. Durvalumab is an immune therapy that helps the body's natural defenses fight cancer cells. Research found that patients who received Durvalumab had a 55.9% chance of their cancer not worsening after 12 months, compared to 35.3% for those who did not receive it. Combining these treatments in this trial may help control lung cancer more effectively. ^{6 7 8 9 10}

Who Is on the Research Team?

Chi Zhang, MD, PhD

Principal Investigator

University of Nebraska

Are You a Good Fit for This Trial?

Adults over 19 with stage III non-small cell lung cancer (NSCLC) who've had or are candidates for chemoradiation therapy. They must have good organ function, an ECOG performance status of 0-1, and a life expectancy over 12 weeks. Women must not be pregnant and participants should agree to birth control measures.

Inclusion Criteria

I am 20 years old or older.

Adequate normal organ and marrow function as defined below: Hemoglobin ≥9.0 g/dL (5.59 mmol/L) (patients can be transfused to meet this criterion), Absolute neutrophil count (ANC) > 1500 per mm3, Platelet count ≥100 x 109/L (>100,000 per mm3), Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN), AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal, Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula, Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause, Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I do not have any serious ongoing illnesses that could affect my participation in the study.

I have previously received treatments targeting my immune system.

I have a history or current infection of TB, hepatitis B, hepatitis C, or HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Definitive Chemoradiation Therapy (dCRT)

Participants undergo definitive chemoradiation therapy for stage III NSCLC

6-8 weeks

Consolidative Hypofractionated Radiation Therapy (hfRT) with Durvalumab

Participants receive consolidative hypofractionated radiation therapy and adjuvant anti-PD-L1 therapy with durvalumab

12 months

Bi-weekly visits for durvalumab infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months during durvalumab therapy, then every 4-6 months

What Are the Treatments Tested in This Trial?

Interventions

• Consolidative Hypofractionated Radiation Therapy (hfRT)
• Durvalumab

Trial Overview The trial tests if combining hypofractionated radiation therapy (hfRT) to target remaining lung cancer with Durvalumab, an anti-PD-L1 drug, is safe and improves tumor control better than either treatment alone.

How Is the Trial Designed?

Group I: Hypofractionated radiation therapy (hfRT) with Durvalumab Experimental Treatment 2 Interventions

Combining consolidative radiation therapy (RT) using a hypofractionated regimen (hfRT) of 10Gy x 2 fractions for boosting the residual primary lung cancer with adjuvant anti-PD-L1 therapy (durvalumab), dose of 10 mg/kg infusion every two weeks concurrently for up to 12 months or disease progression.

Consolidative Hypofractionated Radiation Therapy (hfRT) is already approved in European Union, United States for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)
• Extensive-stage small cell lung cancer (ES-SCLC)
• Biliary tract cancer (BTC)
• Hepatocellular carcinoma (HCC)
• Endometrial cancer

Approved in United States as Imfinzi for:

• Unresectable Stage III non-small cell lung cancer (NSCLC)
• Extensive-stage small cell lung cancer (ES-SCLC)
• Locally advanced or metastatic biliary tract cancer (BTC)
• Unresectable hepatocellular carcinoma (uHCC)
• Primary advanced or recurrent endometrial cancer

Who Is Running the Clinical Trial?

University of Nebraska

Lead Sponsor

Trials

563

Recruited

1,147,000+

Chi Zhang

Lead Sponsor

Trials

1

Recruited

40+

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

The DEDALUS phase 2 trial is investigating a new treatment approach for 45 patients with unresectable stage III non-small cell lung cancer (NSCLC), combining induction chemo-immunotherapy with de-intensified radiotherapy and the immunotherapy drug durvalumab.

The primary focus of the study is to assess safety by monitoring severe adverse events within 6 months, while secondary goals include evaluating progression-free survival (PFS) and overall survival (OS), indicating a comprehensive approach to understanding both the safety and effectiveness of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of a Single-Arm, Phase 2, Multi-Center Study of Chemo-Immunotherapy Followed by Hypo-Fractionated RT and Maintenance Immunotherapy in Patients With Unresectable Stage III NSCLC: The DEDALUS Trial. Filippi, AR., Agustoni, F., Arcangeli, S., et al.[2023]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

The DUART trial is a Phase II study investigating the safety and tolerability of durvalumab in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) who cannot undergo chemotherapy due to poor performance status or other health issues.

This study aims to evaluate whether durvalumab can improve survival outcomes for these patients compared to the current standard of care, which is radiotherapy alone, based on promising results from the PACIFIC trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. Filippi, AR., Dziadziuszko, R., García Campelo, MR., et al.[2022]

In a study of 68 patients with locally advanced non-small cell lung cancer treated with intensity-modulated radiotherapy (IMRT), the administration of durvalumab significantly improved distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS), with hazard ratios of 0.31, 0.33, and 0.32 respectively.

The study also found that while grade 2 or higher radiation pneumonitis (RP) was associated with worse DMFS, reducing the incidence of RP could enhance patient outcomes, highlighting the importance of managing treatment-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after chemoradiotherapy for locally advanced non-small cell lung cancer prolonged distant metastasis-free survival, progression-free survival and overall survival in clinical practice. Yamamoto, T., Tsukita, Y., Katagiri, Y., et al.[2022]

In a study of 56 patients with non-small cell lung cancer (NSCLC), those treated with intensity-modulated radiation therapy (IMRT) had a significantly lower incidence of grade 2 or higher radiation pneumonitis (RP) compared to those treated with three-dimensional conformal radiotherapy (3D-CRT), with rates of 27.0% versus 64.0%.

The study identified that the radiation technique (IMRT vs. 3D-CRT) and the volume of lung receiving radiation (V20) were significant risk factors for developing RP, suggesting that IMRT may be a safer option for reducing RP in NSCLC patients undergoing concurrent chemoradiotherapy followed by durvalumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the incidence of ≥ grade 2 radiation pneumonitis between intensity-modulated radiotherapy and three-dimensional conformal radiotherapy in patients with unresectable non-small cell lung cancer treated with durvalumab after concurrent chemoradiotherapy. Masuo, M., Shinohara, E., Kitano, M., et al.[2023]

In a study of 107 patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) and intensity-modulated radiotherapy (IMRT), the median progression-free survival (PFS) was 20.7 months, indicating effective treatment outcomes.

Factors associated with longer PFS included a favorable response to CCRT, a radiation dose of 62 Gy or more, and having stage IIIA NSCLC, while shorter durations of durvalumab treatment and lower radiation doses were linked to increased mortality risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. Takeda, Y., Kusaba, Y., Tsukita, Y., et al.[2022]

In a study involving 576 patients with unresectable stage III non-small cell lung cancer (NSCLC), the PD-L1 inhibitor durvalumab showed a favorable safety profile, with only 22.7% of patients experiencing adverse events, primarily mild esophagitis.

Durvalumab treatment after concurrent chemoradiotherapy (cCRT) resulted in consistent outcomes across both PD-L1 positive and negative patients, indicating its potential as a standard care option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nationwide Real-Life Safety and Treatment Exposure Data on Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III, Locally Advanced, Non-small Cell Lung Cancer: Analysis of Patients Enrolled in the French Early Access Program. Avrillon, V., Daniel, C., Boisselier, P., et al.[2022]

Citations

1. esmoopen.com esmoopen.com/article/S2059-7029(24)00556-8/fulltext

215TiP A phase II study of durvalumab (MEDI 4736) ... DURVALUNG study aims to evaluate the efficacy of durvalumab maintenance specifically in frail LD-SCLC pts who have not progressed following concomitant or ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6038862/

Safety and efficacy of durvalumab (MEDI4736) in various ... Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.8536

A phase II study of durvalumab (MEDI4736) immediately ... Progression-free survival (PFS) and overall survival (OS) were better in the subgroup of patients administered durvalumab within 14 days after ...

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

Durvalumab after Chemoradiotherapy in Stage III Non– ... The 12-month progression-free survival rate was 55.9% (95% CI, 51.0 to 60.4) with durvalumab and 35.3% (95% CI, 29.0 to 41.7) with placebo, and ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02352948

NCT02352948 | A Global Study to Assess the Effects ... This study is a Phase III, randomised, open label, multi-centre study assessing the efficacy and safety of MEDI4736 (durvalumab) versus Standard of Care in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10894375/

Phase I/II study to evaluate consolidative hypofractionated ... The goal of this study is to evaluate the safety and efficacy of combining consolidative hypofractionated radiation therapy (hfRT) using stereotactic body ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04748419?term=NCT04748419&rank=1

Study Details | NCT04748419 | Safety & Efficacy of ... Primary endpoints include the safety of boost hfRT and concurrent anti-PD-L1 therapy adjuvantly following dCRT, and the 12-month progression-free survival to ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1525730425001482

Factors Associated with Local Control and Toxicity of ... Hypofractionated radiation therapy offers excellent local control and low toxicity. Severe toxicities include radiation pneumonitis, cardiotoxicity, and ...

9. mdpi.com mdpi.com/2072-6694/16/19/3384

A Systematic Review of Phase II/III Trials ... There was no evidence that hypofractionation improves survival as compared to conventionally fractionated radiation therapy.

10. redjournal.org redjournal.org/article/S0360-3016(20)32681-X/fulltext

Safety and Efficacy of Hypofractionated Radiotherapy ... Radiation toxicity was minimal. The median and 3-year OS, PFS were 27.3 months, 41.8.1%; 17.6months, 42.7%, respectively. The 1- and 3 ...