A Phase III Double-Blind, Placebo-Controlled Study of Adjuvant Durvalumab in Resected Stage IB-IIIA Non-Small Cell Lung Cancer with PD-L1 Expression ≥25%

Trial ID: 2024-517856-36-00
Protocol: BR31
Sponsor: NVALT-studies Stichting

Trial statistics

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100

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Diseases & Conditions

Non-small cell lung cancer

Objectives

The primary objective of this study is to assess the impact of adjuvant therapy with **DURVALUMAB** (MEDI4736) compared to placebo on the **disease-free survival** of patients with completely resected non-small cell lung cancer (NSCLC) at stages IB (≥ 4cm), II, or IIIA, with PD-L1 expression TC ≥ 25% and EGFR-/ALK- status. This is clinically relevant as it aims to determine the efficacy of DURVALUMAB in prolonging the period without disease recurrence, which is crucial for improving long-term outcomes in NSCLC patients.

Secondary objectives include:

Comparing disease-free survival in the MEDI4736 arm to the placebo arm across various patient sub-populations defined by PD-L1 expression levels and EGFR/ALK status.
Comparing overall survival and lung cancer-specific survival between the MEDI4736 and placebo arms in these sub-populations.
Evaluating the nature, severity, and frequency of toxicities between treatment arms.
Assessing quality of life differences between the two arms in the defined sub-populations.
Determining the survival benefits deemed necessary by participants to justify adjuvant immunotherapy and the factors influencing their preferences.
Evaluating the incremental cost-effectiveness and cost-utility ratios for MEDI4736.
Assessing the prognostic and predictive significance of PD-L1 expression.
Evaluating changes in plasma/serum cytokines and other biomarkers post-treatment and at the first disease event.
Exploring polymorphisms that may be associated with outcomes.

Participants

The clinical trial involves a total of **760 participants** diagnosed with completely resected primary stage IB (≥ 4cm), II, and IIIA **non-small cell lung cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, including a histologically confirmed diagnosis of primary non-small cell carcinoma of the lung, classified post-operatively as Stage IB (≥ 4cm in the longest diameter), II, or IIIA. The trial does not include vulnerable populations. Participants' general health status is characterized by the complete surgical resection of the primary non-small cell lung cancer, with all gross disease removed and surgical margins negative for the tumor. The selection process ensures that participants have undergone standard pre-surgical imaging and complete surgical resection, adhering to established guidelines for lymph node mapping and resection techniques. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.

Plans and Procedures

The clinical trial is a **Phase III**, **double-blind**, **placebo-controlled**, and **randomized** study designed to evaluate the efficacy of adjuvant therapy with **DURVALUMAB** in patients with completely resected non-small cell lung cancer (NSCLC). The primary objective is to assess the impact of DURVALUMAB, administered via **intravenous infusion** for one year, on disease-free survival (DFS) in patients with NSCLC characterized by PD-L1 expression TC ≥ 25% and EGFR-/ALK- status. The trial is expected to conclude by March 28, 2025, with recruitment having commenced on February 24, 2015.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on histological diagnosis and post-operative staging criteria. The trial includes follow-up visits at regular intervals to monitor the patient's health status, treatment adherence, and any adverse effects. The end-of-study visit will evaluate the primary and secondary endpoints, including overall survival, lung cancer-specific survival, and quality of life. The expected duration of participant involvement is up to 48 weeks, corresponding to the maximum treatment period with DURVALUMAB.

Participants may be withdrawn from the study early if they experience unacceptable adverse effects, disease progression, or if they withdraw consent. The trial's design ensures rigorous monitoring and data collection to evaluate the safety and efficacy of the investigational product, with secondary endpoints exploring various sub-populations and biomarkers. The study's methodology adheres to international guidelines, ensuring the reliability and validity of the findings.

Treatment

The clinical trial involves the administration of **DURVALUMAB**, an experimental medication, which is a **solution for infusion**. The active substance in DURVALUMAB is a protein classified under "Protein - Other." DURVALUMAB is administered via the **intravenous** route. The dosing regimen for DURVALUMAB is specified as a maximum daily dose of 20 mg/kg/h, with a total maximum dose of 260 mg/kg/h over the treatment period. The maximum treatment period is 48 weeks. DURVALUMAB is not formulated for pediatric use in this study.

The study also includes the use of a **placebo**, referred to as MEDI4736 Placebo. The placebo is used as a comparator treatment in this double-blind, randomized study. The placebo is administered in a manner consistent with the experimental treatment to maintain the study's blinding. The pharmaceutical form, dosage, and route of administration for the placebo are designed to match those of DURVALUMAB, ensuring that participants and investigators remain unaware of the treatment allocation. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the measurement of **Disease Free Survival (DFS)** in patients with non-small cell lung cancer (NSCLC) that exhibit PD-L1 expression TC ≥ 25% and are EGFR-/ALK-. This primary endpoint will provide a direct comparison between the adjuvant therapy with MEDI4736 and placebo. Secondary endpoints include DFS in five additional patient sub-populations defined by varying PD-L1 expression levels and EGFR/ALK status, overall survival (OS), lung cancer-specific survival, and the adverse effects and tolerability of MEDI4736. Quality of life assessments, survival benefits as judged by participants, and economic evaluations such as cost-effectiveness and cost-utility will also be considered. Additionally, the trial will evaluate the predictive and prognostic significance of PD-L1 expression, changes in plasma/serum cytokines, and other blood and tissue-based biomarkers post-treatment with MEDI4736, as well as exploratory pharmacogenomic assays conducted at baseline.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, with the treatment period extending up to 48 weeks. The trial is designed as a Phase III prospective, double-blind, placebo-controlled, randomized study, ensuring rigorous assessment of the therapeutic impact of MEDI4736. The study will utilize validated scales and laboratory tests to ensure the accuracy and reliability of the data collected. The trial's main objective is to determine the impact of MEDI4736 on disease-free survival, providing critical insights into its potential as an adjuvant therapy for patients with completely resected NSCLC.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically confirmed diagnosis of primary non-small cell carcinoma of the lung according to WHO Classification of Tumours (WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. WHO/IARC Classification of Tumours, 4th Edition, Volume 7). Patients with large-cell neuroendocrine carcinomas are not eligible.
Patients must be classified post-operatively as Stage IB (≥ 4cm in the longest diameter), II or IIIA on the basis of pathologic criteria.
Surgery: -A pre-surgical PET scan of the thorax and a MRI or CT scan of the brain is considered standard of care and thus must be done prior to surgery. Patients in whom this was not done prior to surgery may still be enrolled providing that appropriate imaging is performed prior to randomization. -Complete surgical resection of the primary NSCLC is also mandatory. All gross disease must have been removed at the end of surgery. All surgical margins of resection must be negative for tumour. Resection may be accomplished by open or VATS techniques. -Lymph node mapping is defined by The International Association for the Study of Lung Cancer (IASLC) lymph node map. The nodal tissue should be labelled according to the recommendations of the American Thoracic Society. Surgeons are strongly encouraged to dissect or sample all accessible nodal levels in accordance with the European Society of Thoracic Surgeons guidelines. Accordingly, it is recommended that a minimum of 3 (three) lobe specific mediastinal nodal stations (N2), one of which should include station 7, and at least one N1 station - inclusive of the ones removed with the pulmonary specimen have been sampled at the end of the procedure. -If preoperative CT and/or PET are suspicious for mediastinal nodal involvement, it is recommended that invasive mediastinal staging with mediastinoscopy or EBUS-TBNA be performed. Station 5 or 6 lymph nodes may be accessed by anterior mediastinotomy or VATS. This may also occur at the time of the surgical resection. If invasive staging shows disease in regional lymph nodes, they must be surgically removed. It is recommended that complete mediastinal lymph node dissection be undertaken for stage IIIA tumours. -Surgery may consist of lobectomy, sleeve resection, bilobectomy or pneumonectomy as determined by the attending surgeon based on the intraoperative findings. Patients who have had only segmentectomies or wedge resections are not eligible for this study. Note: Where a resection has been extended by means of a wedge resection of an adjacent lobe in order to ensure complete resection of a tumour at or crossing a fissure between lobes, as long as the margins are clear this is acceptable. Where the resection of a second tumour nodule, even where not considered to be a co-primary, is undertaken by means of a wedge resection of a separate lobe then the patient is not eligible.

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Exclusion Criteria

A combination of small cell and non-small cell lung cancer, pulmonary carcinoid tumour or large-cell neuroendocrine carcinoma (LCNEC).
Patients with a history of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer, or other malignancies curatively treated with no evidence of disease for ≥ 5 years following the end of treatment and which, in the opinion of the treating physician, do not have a substantial risk of recurrence of the prior malignancy.
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. NOTE: patients with Grave’s disease and/or psoriasis not requiring systemic therapy within the last two years from randomization and patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement are not excluded.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	24 Feb 2015	5
France	Not Recruiting	24 Feb 2015	358
Hungary	Not Recruiting	24 Feb 2015	1
Italy	Not Recruiting	24 Feb 2015	116
The Netherlands	Not Recruiting	24 Feb 2015	—
Poland	Not Recruiting	24 Feb 2015	8
Romania	Not Recruiting	24 Feb 2015	9
Spain	Not Recruiting	24 Feb 2015	119
Netherlands	—	—	39