A Global Study to Assess the Effects of Durvalumab + Domvanalimab Following Concurrent Chemoradiation in Participants With Stage III Unresectable NSCLC

Study Overview
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Brief Summary
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This is a Phase III, randomised, double-blind, placebo-controlled, multicentre, international study assessing the efficacy and safety of durvalumab (MEDI4736) and domvanalimab (AB154) compared with durvalumab plus placebo in adults with locally advanced (Stage III), unresectable NSCLC whose disease has not progressed following definitive platinum-based cCRT.

Official Title
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A Phase III, Randomised, Double-blind, Placebo-controlled, Multicentre, International Study of Durvalumab Plus Domvanalimab(AB154) in Participants With Locally Advanced (Stage III), Unresectable Non-small Cell Lung Cancer Whose Disease Has Not Progressed Following Definitive Platinum-based Concurrent Chemoradiation Therapy

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Domvanalimab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Participant must be ≥ 18 years at the time of screening. Histologically- or cytologically-documented NSCLC and have been treated with concurrent CRT for locally advanced, unresectable (Stage III) disease Provision of a tumour tissue sample obtained prior to CRT Documented tumour PD-L1 status ≥ 1% by central lab Documented EGFR and ALK wild-type status (local or central). Patients must not have progressed following definitive, platinum-based, concurrent chemoradiotherapy Participants must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy Participants must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 66 Gy) as part of the chemoradiation therapy, to be randomised. Radiation therapy should be administered by intensity modulated RT (preferred) or 3D-conforming technique. WHO performance status of 0 or 1 at randomization Adequate organ and marrow function EXCLUSION CRITERIA: History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease, or adequately treated carcinoma in situ or Ta tumours treated with curative intent and without evidence of disease. Mixed small cell and non-small cell lung cancer histology. Participants who receive sequential (not inclusive of induction) chemoradiation therapy for locally advanced (Stage III) unresectable NSCLC. Participants with locally advanced (Stage III) unresectable NSCLC who have progressed during platinum-based cCRT. Any unresolved toxicity CTCAE >Grade 2 from the prior chemoradiation therapy (excluding alopecia). Participants with ≥ grade 2 pneumonitis from prior chemoradiation therapy. History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, or idiopathic pneumonitis - regardless of time of onset prior to randomisation. Evidence of active non-CRT induced pneumonitis (≥ Grade 2), active pneumonia, active ILD, active or recently treated pleural effusion, or current pulmonary fibrosis Active or prior documented autoimmune or inflammatory disorders (with exceptions) Active EBV infection, or known or suspected chronic active EBV infection at screening Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.

Ages Eligible for Study
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Minimum Age: 18 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: Arm A: Durvalumab + Domvanalimab<br>Durvalumab and domvanalimab as an IV infusion q4w, starting on Day 1 for up to a maximum of 12 months | Drug: Durvalumab<br>* Durvalumab IV (Intravenous infusion)<br>Drug: Domvanalimab<br>* Domvanalimab IV (Intravenous infusion)<br>|
| Active Comparator: Arm B: Durvalumab + Placebo<br>Durvalumab + placebo as an IV infusion q4w starting on Day 1 for up to a maximum of 12 months | Drug: Durvalumab<br>* Durvalumab IV (Intravenous infusion)<br>Other: Placebo<br>* Placebo IV (Intravenous infusion)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Defined as time from randomisation until progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR), or death due to any cause in participants with PD-L1 TC ≥ 50%. | Up to 8 years after first patient randomised | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Defined as time from randomisation until progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR), or death due to any cause in participants with PD-L1 TC ≥ 1% | Up to 8 years after first patient randomised | 
| Overall Survival (OS) | Overall Survival (OS) | Approximately 8 years after first patient randomized | 
| Objective Response Rate (ORR) | Objective Response Rate (ORR) per RECIST 1.1 as assessed by BICR | Approximately 8 years after first patient randomized | 
| Duration of Response (DoR) | Duration of Response (DoR) using BICR assessment according to RECIST 1.1 | Approximately 8 years after first patient randomized | 
| Time from randomization to second progression (PFS2) | Time from randomization to second progression (PFS2) | Approximately 8 years after first patient randomized | 
| Time from randomization to first date of distant metastasis or death (TTDM) | Time from randomization until the first date of distant metastasis or death in the absence of distant metastasis (TTDM). | Approximately 8 years after first patient randomized | 
| Time to first subsequent therapy (TFST) | Time to first subsequent therapy (TFST) | Approximately 8 years after first patient randomized | 
| Concentration of Durvalumab and Domvanalimab | The pharmacokinetics (PK) of Durvalumab and Domvanalimab as determined by concentration | Approximately 12 weeks after last IP dose | 
| PFS6, PFS12, PFS18, PFS24 | PFS at 6, 12, 18 and 24 months (proportion per Kaplan-Meier) | Approximately 6, 12, 18 and 24 months after last patient randomized | 
| Anti-Drug Antibodies (ADAs) | The immunogenicity of Durvalumab and domvanalimab as assessed by presence of Anti-Drug Antibodies (ADAs) | Approximately 12 weeks after last IP dose. | 
| Time to deterioration in pulmonary symptoms (TTFCD) | Time to deterioration in pulmonary symptoms (TTFCD) | Approximately 8 years after first patient randomized | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, non-small cell lung cancer, locally advanced