A Study of Durvalumab as Consolidation Therapy in Non-Small Cell Lung Cancer Patients

Study Overview
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Brief Summary
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This is a Phase III, randomised, double-blind, placebo-controlled, multicentre study assessing the efficacy and safety of durvalumab compared with placebo, as consolidation therapy in patients with locally advanced, unresectable, non-small cell lung cancer (Stage III), who have not progressed following definitive, platinum-based, chemoradiation therapy.

Detailed Description
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Approximately 400 patients will be randomized in a 2:1 to receive treatment with durvalumab or placebo therapy. The primary objective of this study is to assess the efficacy of durvalumab treatment compared with placebo in terms of PFS.

Official Title
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A Phase III, Randomised,Double-Blind,Placebo-Controlled,Study of Durvalumab as Consolidation Therapy in Patients With Locally Advanced,Unresectable NSCLC, Who Have Not Progressed Following Definitive, Platinum-Based Chemoradiation Therapy

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Durvalumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age≥18 years Documented NSCLC and present with locally advanced, unresectable (Stage III) disease; Receipt of concurrent or sequential chemoradiation therapy, No progression following definitive, platinum-based, concurrent or sequential chemoradiation therapy World Health Organization (WHO) PS of 0 or 1; No prior exposure to any anti CTLA-4, anti-PD-1, anti-PD-L1, or anti PD L2 antibodies, excluding therapeutic anticancer vaccines Adequate organ and marrow function required Life expectancy of at least 12 weeks Tumor PD-L1 status, with the Ventana SP263 PD-L1 IHC assay determined by a reference laboratory, must be known prior to randomization. Tumour sample requirements are as follows: Provision of a tumour tissue sample (newly acquired sample <=3 months old is preferred, but an archived sample <=6 months old is acceptable) in a quantity sufficient to allow for analysis. Exclusion Criteria: History of allogeneic organ transplantation, or another primary malignancy, or active primary immunodeficiency. Active or prior documented autoimmune or inflammatory disorders Uncontrolled intercurrent illness that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent Active infection including tuberculosis hepatitis B hepatitis C (HCV), or human immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2 antibodies). Mixed small cell and NSCLC histology, sarcomatoid variant Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 from the prior chemoradiation therapy. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab Therapy<br>Durvalumab (PD-L1 monoclonal antibody)1500 mg every 4 weeks [q4w] intravenously [iv] until clinical progression/deterioration or confirmed radiological progression) | Drug: Durvalumab<br>* Durvalumab 1500 mg every 4 weeks [q4w] intravenously [iv] until clinical progression/ deterioration or confirmed radiological progression.<br>* Other names: MEDI4736;|
| Placebo Comparator: Placebo Therapy<br>Placebo (matching placebo for infusion every 4 weeks iv until clinical progression/deterioration or confirmed radiological progression) | Other: Placebo<br>* Matching placebo for infusion every 4 weeks iv until clinical progression/deterioration or confirmed radiological progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) according to RECIST 1.1. | To assess the efficacy of durvalumab treatment compared with placebo in terms of PFS. | from date of randomisation until disease progression, assessed up to 29 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The efficacy of durvalumab treatment compared to placebo in terms of Overall Survival (OS). | To further assess the efficacy of durvalumab compared with placebo in terms of OS. | from date of randomisation until the date of death, assessed up to 65 months. | 
| The efficacy of durvalumab treatment compared to placebo in terms of proportion of patients alive at 24 months (OS24) from randomisation. | To further assess the efficacy of durvalumab compared with placebo in terms of OS24. | at 24 months from participants' randomisation. | 
| Objective Response Rate (ORR) assessed by BICR according to RECIST 1.1. | To further assess the efficacy of durvalumab compared with placebo in terms of ORR. | from date of randomisation until progression, or the last evaluable assessment in the absence of progression, assessed up to 29 months. | 
| Duration of Response (DoR) assessed by BICR according to RECIST 1.1. | To further assess the efficacy of durvalumab compared with placebo in terms of DOR. | from date of randomisation until progression, or the last evaluable assessment in the absence of progression, assessed up to 29 months. | 
| Proportion of patients alive and progression free from randomisation to second progression (PFS2) as defined by local standard clinical practice. | The date of PFS2 assessment and Investigator opinion of progression status (progressed or non-progressed) at each assessment will be recorded in the PFS2 eCRF. | from randomisation to second progression. assessed up to 65 months. | 
| Proportion of patients alive and progression free at 12 months from randomisation (PFS12) assessed by BICR according to RECIST 1.1. | To further assess the efficacy of durvalumab compared with placebo in terms of PFS12. | at 12 months from participants' randomisation. | 
| Proportion of patients alive and progression free at 18 months from randomisation (PFS18) assessed by BICR according to RECIST 1.1. | To further assess the efficacy of durvalumab compared with placebo in terms of PFS18. | at 18 months from participants' randomisation. | 
| Proportion of patients at time to death or distant metastasis (TTDM) assessed by BICR according to RECIST 1.1. | To further assess the efficacy of durvalumab compared with placebo in terms of TTDM. | date of randomisation until the first date of distant metastasis or death in the absence of distant metastasis, assessed up to 65 months. | 
| Concentration of durvalumab in blood and non-compartmental PK parameters (such as peak concentration and trough, as data allow) (sparse sampling) | To assess the PK of durvalumab | at scheduled visits from randomisation to 3months after treatment discontinuation. | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | All AE data will be listed and the treatment-emergence status will be flagged in the listing. | from randomisation until 3 months after treatment discontinuation. | 
| Detection of ADA neutralising antibodies titres for all randomised patients | To investigate the immunogenicity of durvalumab | at scheduled visits from randomisation to 6months after treatment discontinuation. | 
| IHC analysis of tumoural PD-L1 expression and spatial distribution within the tumour microenvironment relative to efficacy outcome OS. | To investigate the relationship between a patient's baseline tumour PD-L1 expression and OS with durvalumab compared with placebo. | from date of randomisation until the date of death from any cause, whichever came first, assessed up to 65 months. | 
| IHC analysis of tumoural PD-L1 expression and spatial distribution within the tumour microenvironment relative to efficacy outcome PFS. | To investigate the relationship between a patient's baseline tumour PD-L1 expression and PFS with durvalumab compared with placebo. | from date of randomisation until disease progression, assessed up to 29 months. | 
| IHC analysis of tumoural PD-L1 expression and spatial distribution within the tumour microenvironment relative to efficacy outcome ORR. | To investigate the relationship between a patient's baseline tumour PD-L1 expression and ORR with durvalumab compared with placebo. | from date of randomisation until progression, or the last evaluable assessment in the absence of progression, assessed up to 29 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Double-Blind, PD-L1, MEDI4736, Durvalumab, PFS, OS