Durvalumab Alone or in Combination With Novel Agents in Subjects With NSCLC

Study Overview
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Brief Summary
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The purpose of this study is to compare the clinical activity of durvalumab alone vs durvalumab in combination with novel agents. The overall study goal is early identification of novel durvalumab combinations that are more active than durvalumab alone in the treatment of patients with unresectable, Stage III NSCLC who have not progressed after cCRT.

Detailed Description
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Study D9108C00001 (COAST) is a Phase 2, open-label, multicenter, randomized multidrug platform study assessing the efficacy and safety of durvalumab alone vs durvalumab in combination with novel agents in subjects with locally advanced, unresectable, Stage III non-small cell lung cancer (NSCLC).

Official Title
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A Phase 2 Open-label, Multicenter, Randomized, Multidrug Platform Study of Durvalumab (MEDI4736) Alone or in Combination With Novel Agents in Subjects With Locally Advanced, Unresectable (Stage III) Non-small Cell Lung Cancer (COAST)

Conditions
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Stage III Non-small Cell Lung Cancer, Unresectable

Intervention / Treatment
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* Drug: Durvalumab + Oleclumab
* Drug: Durvalumab
* Drug: Durvalumab + Monalizumab


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Written informed consent and any locally required authorization obtained from the subject prior to performing any protocol-related procedures, including screening evaluation Age 18 years or older Body weight ≥ 35 kg Subjects must have histologically or cytologically documented NSCLC who present with locally advanced, unresectable, Stage III disease Subjects must have completed, without progressing, definitive cCRT within 42 days prior to being randomized into the study: Provision of tumor tissue sample, when available, from original diagnosis obtained before initiation of chemoradiotherapy Life expectancy ≥ 12 weeks Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Subjects must have at least one previously irradiated tumor lesion that can be measured by RECIST v1.1 Main Exclusion Criteria: Mixed small cell and non-small cell lung cancer histology Current or prior use of immunosuppressive medication within 14 days before the first dose of study drug. Prior exposure to any anti-PD1, anti-PD-L1, or anti-CTLA4 antibody for treatment of NSCLC Subjects with history of ≥ Grade 2 pneumonitis from prior chemoradiation therapy Subjects with a history of venous thrombosis within the past 3 months Subjects with history of myocardial infarction, transient ischemic attack, or stroke in the past 6 months Congestive heart failure Active or prior documented autoimmune or inflammatory disorders History of active primary immunodeficiency Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) History of allogenic organ transplantation QTcF interval ≥ 470 ms History of another primary malignancy Concurrent enrollment in another therapeutic clinical study or during the follow-up period of an interventional study. Enrollment in observational studies will be allowed Females who are pregnant, lactating, or intend to become pregnant during their participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Factorial Assignment
Interventional Model Description: At study onset subjects will be randomized equally to all study treatment arms open for enrollment and will remain on study treatment for up to 12 months. Study treatment will be discontinued upon disease progression, unacceptable toxicity, or other reason. The treatment arms are Control Arm, Arm A and Arm B.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Control Arm (Durvalumab monotherapy)<br>durvalumab IV | Drug: Durvalumab<br>* Durvalumab<br>* Other names: Durvalumab (MEDI-4736);|
| Experimental: Arm A (durvalumab + oleclumab):<br>durvalumab IV and oleclumab IV | Drug: Durvalumab + Oleclumab<br>* Durvalumab + Oleclumab<br>* Other names: Oleclumab (MEDI-9447);|
| Experimental: Arm B (durvalumab + monalizumab)<br>durvalumab IV and monalizumab IV | Drug: Durvalumab + Monalizumab<br>* Durvalumab + Monalizumab<br>* Other names: Monalizumab (IPH2201);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) rate as a measure of antitumor activity of durvalumab alone vs durvalumab in combination with novel agents | Best overall response of confirmed CR or confirmed PR according to RECIST v1.1 | ORR at 16weeks after randomization is the timing for radiologic assessment of the primary endpoint | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events as a measure of safety during the treatment period | The secondary endpoint of safety as assessed by the presence of adverse events and serious adverse events | From time of informed consent through treatment period (12 months) or up to 3 months post last dose of study treatment | 
| Duration of Response (DoR) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents | The duration from the first documentation of a subsequently confirmed OR to the first documentation of a disease progression according to RECIST v1.1 or death due to any cause, whichever occurs first. Only subjects who have achieved OR (confirmed CR or confirmed PR) will be evaluated for DoR | From time of first documented response until disease progression or up to a maximum of 5 years after randomization | 
| Disease Control (DC) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents | confirmed CR, confirmed PR, or SD based on RECIST v1.1 | From time of randomization until disease progression or up to a maximum of 5 years | 
| Progression-Free Survival (PFS) and Progression-Free Survival 12 month landmark rate (PFS-12) as a measure of efficacy of durvalumab alone vs durvalumab in combination with novel agents | From randomization until the first documentation of disease progression according to RECIST v1.1 or death due to any cause, whichever occurs first | From time of randomization until disease progression or up to a maximum of 5 years | 
| Serum durvalumab concentration levels | Pharmacokinetics of durvalumab | From randomization up to 15 months after first treatment | 
| Serum concentration levels of durvalumab or novel agents | Pharmacokinetics of durvalumab alone and/or in combination with novel agents | From randomization up to 15 months after first treatment | 
| Development of detectable anti-drug antibody (ADA) to durvalumab | Immunogenicity of durvalumab | From randomization up to 15 months after first treatment | 
| Development of detectable anti-drug antibody (ADA) to durvalumab or novel biologic agents | Immunogenicity of durvalumab alone and/or in combination with novel biologic agents | From randomization up to 15 months after first treatment | 
| Number of patients with clinically significant laboratory values as a measure of safety | Assess the presence of clinically significant laboratory values taken at times indicated in the assessment schedule from baseline in terms of number of patients with abnormal values | From screening until disease progression or death, up to a maximum of 5 years after randomization | 
| Incidence of clinically significant vital sign values as a measure of safety | Assess the presence of clinically significant vital sign values from baseline | From screening until disease progression or death, up to a maximum of 5 years after randomization | 

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