A Global Study to Assess the Effects of Durvalumab With Oleclumab or Durvalumab With Monalizumab Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a Phase III, randomised, double-blind, multicentre, international study assessing the efficacy and safety of durvalumab (MEDI4736) in combination with oleclumab (MEDI9447) or durvalumab (MEDI4736) with monalizumab (IPH2201) in adults with locally advanced (Stage III), unresectable NSCLC, who have not progressed following platinum-based cCRT.

Official Title
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A Phase III, Double-blind, Placebo-controlled, Randomised, Multicentre, International Study of Durvalumab Plus Oleclumab and Durvalumab Plus Monalizumab in Patients With Locally Advanced (Stage III), Unresectable Non-small Cell Lung Cancer (NSCLC) Who Have 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: Oleclumab
* Drug: Monalizumab
* 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 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, adequately resected non-melanoma skin cancer and curatively treated in situ disease, or adequately treated carcinoma in situ or Ta tumours 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 - diagnosed in the past 6 months prior to randomization. Active or prior documented autoimmune or inflammatory disorders (with exceptions) 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 and Oleclumab<br>Durvalumab on Day 1 of each 28-day cycle + Oleclumab on Days 1 and 15 of cycles 1 and 2, then on Day 1 of each subsequent 28-day cycle for up to 12 months | Drug: Durvalumab<br>* Durvalumab IV (intravenous infusion)<br>Drug: Oleclumab<br>* Oleclumab IV (intravenous infusion)<br>|
| Experimental: Arm B: Durvalumab and Monalizumab<br>Durvalumab + Monalizumab on Day 1 of each 28-day cycle for up to 12 months. Placebo infusion will be administered on Day 15 of cycles 1 and 2 only | Drug: Durvalumab<br>* Durvalumab IV (intravenous infusion)<br>Drug: Monalizumab<br>* Monalizumab IV (intravenous infusion)<br>Other: Placebo<br>* Placebo IV (intravenous infusion)<br>|
| Active Comparator: Arm C: Durvalumab and Placebo<br>Durvalumab on Day 1 of each 28-day cycle + Placebo on Days 1 and 15 of cycles 1 and 2, then on Day 1 of each subsequent 28-day cycle for up to 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 Surival (PFS) | Progression Free Survival (PFS) as assessed by BICR, per RECIST 1.1. | Up to 5 years after first patient randomized. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) | Up to 9 years after first patient randomized | 
| Objective response rate (ORR) | Objective response rate (ORR) per RECIST 1.1 as assessed by BICR | Up to 5 years after first patient randomized | 
| Overall survival (OS) at 24 months | Overall survival (OS) at 24 months | Up to 9 years after first patient randomized | 
| Duration of response (DoR) | Duration of response (DoR) per RECIST 1.1 as assessed by BICR | Up to 5 years after first patient randomized | 
| Progression free survival (PFS) at 6, 12, 18, and 24 months | Progression free survival (PFS) at 6, 12, 18, and 24 months respectively, per RECIST 1.1 as assessed by BICR | From date of randomization until 24 months | 
| Time from randomization to second progression (PFS2) | Time from randomization to second progression (PFS2) | Up to 5 years after first patient randomized | 
| Time from randomization to first date of distant metastasis or death (TTDM) | Time from randomization to first date of distant metastasis or death (TTDM) | Up to 5 years after first patient randomized | 
| Time from randomization to start date of first subsequent therapy (TFST) | Time from randomization to start date of first subsequent therapy (TFST) | Up to 9 years after first patient randomized | 
| Progression free survival (PFS) as assessed by Investigator | Progression free survival (PFS) as assessed by Investigator | Up to 5 years after first patient randomized | 
| IHC analysis of PD-L1 TC expression | IHC analysis of PD-L1 TC expression relative to efficacy outcomes | Up to 5 years after first patient randomized | 
| Concentration of Durvalumab | To assess the Pharmacokinetics of Durvalumab when in combination with Monalizumab or Oleclumab - serum peak and trough concentrations | From date of randomization until 3 months after date of last IP dose | 
| Anti-drug antibodies (ADAs) | The immunogenicity of durvalumab, oleclumab, and monalizumab as assessed by presence of anti-drug antibodies (ADAs) | From date of randomization until 3 months after date of last IP dose | 
| Time to deterioration in pulmonary symptoms (TTFCD) | Time to deterioration in pulmonary symptoms (TTFCD) | Up to 5 years after last patient randomized | 
| Concentration of Oleclumab | To assess the Pharmacokinetics of Oleclumab when in combination with Durvulumab - serum peak and trough concentrations | From date of randomization until 3 months after last dose of IP | 
| Concentration of Monalizumab | To assess the Pharmacokinetics of Monalizumab when in combination with Durvalumab - serum peak and trough concentrations | From date of randomization until 3 months after last dose of IP | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Small Cell Lung Cancer, Locally Advanced NSCLC