Study to Evaluate Monotherapy and Combination Immunotherapies in Participants With PD-L1 Positive Non-small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
This randomized phase 2 open-label study will evaluate the safety and efficacy of zimberelimab (AB122) monotherapy, domvanalimab (AB154) in combination with zimberelimab, and domvanalimab in combination with zimberelimab and etrumadenant (AB928) in front-line, PD-L1 positive, metastatic non-small cell lung cancer.

Detailed Description
-----------------
This is an open-label phase 2 study in participants with non-small cell lung cancer which will assess the safety, efficacy and tolerability of zimberelimab as monotherapy and in combination with other immunotherapeutics across multiple treatment arms. Approximately 150 participants will be randomized to 1 of 3 treatment arms: 1) zimberelimab, 2) zimberelimab + domvanalimab (anti-TIGIT antibody), 3) zimberelimab + domvanalimab + etrumadenant (dual adenosine receptor antagonist). Participants that progress on the zimberelimab monotherapy arm may cross-over to receive the third arm combination of zimberelimab + domvanalimab + etrumadenant. The primary objective of this clinical study is to evaluate the efficacy of each combination therapy by assessing: 1) objective response rate (ORR) of participants with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and 2) progression free survival (PFS).

Official Title
-----------------
A Phase 2 Study to Evaluate the Safety and Efficacy of AB122 Monotherapy, AB154 in Combination With AB122, and AB154 in Combination With AB122 and AB928 in Front-Line, Non-Small Cell Lung Cancer

Conditions
-----------------
Lung Cancer, Non Small Cell Lung Cancer, Nonsquamous Non Small Cell Lung Cancer, Squamous Non Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Domvanalimab
* Drug: Etrumadenant
* Drug: Zimberelimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female participants; age ≥ 18 years Histologically confirmed, treatment naïve, metastatic squamous or non-squamous NSCLC with documented high PD-L1 expression, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 Must have at least 1 measurable lesion per RECIST v1.1 Adequate organ and marrow function Exclusion Criteria: Use of any live vaccines against infectious diseases within 28 days of first dose of investigational medicinal products (IMPs) Any gastrointestinal condition that would preclude the use of oral medications (eg, difficulty swallowing, nausea, vomiting, or malabsorption) History of trauma or major surgery within 28 days prior to the first dose of IMP Concurrent medical condition requiring the use of supra-physiologic doses of corticosteroids (> 10 mg/day of oral prednisone or equivalent) or immunosuppressive medications Positive test results for Hepatitis B surface antigen, Hepatitis C virus antibody with presence of Hepatitis C qualitative RNA or human immunodeficiency virus (HIV-1 and/or HIV-2) antibody at screening Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy. Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (zimberelimab monotherapy)<br>Participants will receive zimberelimab as an intravenous (IV) infusion. | Drug: Zimberelimab<br>* Zimberelimab is a fully human anti-PD-1 monoclonal antibody<br>* Other names: AB122;|
| Experimental: Arm 2 (domvanalimab and zimberelimab combination therapy)<br>Participants will receive domvanalimab IV in combination with zimberelimab IV infusion. | Drug: Domvanalimab<br>* Domvanalimab is a humanized monoclonal antibody targeting human TIGIT<br>* Other names: AB154;Drug: Zimberelimab<br>* Zimberelimab is a fully human anti-PD-1 monoclonal antibody<br>* Other names: AB122;|
| Experimental: Arm 3 (domvanalimab, etrumadenant, and zimberelimab combination therapy)<br>Participants will receive oral etrumadenant in combination with domvanalimab IV and zimberelimab IV infusion | Drug: Domvanalimab<br>* Domvanalimab is a humanized monoclonal antibody targeting human TIGIT<br>* Other names: AB154;Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is a fully human anti-PD-1 monoclonal antibody<br>* Other names: AB122;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR as assessed by RECIST v1.1 | From randomization until death from any cause (up to approximately 3-5 years) | 
| Progression-free survival (PFS) | PFS as assessed by RECIST v1.1 | From randomization until death from any cause (up to approximately 3-5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DoR) | DoR as assessed by RECIST v1.1 | From the date of first occurrence of a documented objective response to first documentation of disease progression or death from any cause, whichever occurs first (up to approximately 3-5 years) | 
| Disease control rate (DCR) | DCR as assessed by RECIST v1.1 | From the date of first occurrence of a documented objective response to first documentation of disease progression on death from any cause, whichever occurs first (up to approximately 3-5 years) | 
| Overall Survival (OS) | OS as assessed at the time of PFS | From randomization to death from any cause (up to approximately 5 years) | 
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) | The number and percentage of participants that experience TEAE | From Screening until up to 30 days after the last dose (approximately 5 years) | 
| Pharmacokinetics of zimberelimab | Serum concentration of zimberelimab as determined by validated assays | Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, 60 and 100 days post last dose (in total, an average of 2 years) | 
| Pharmacokinetics of domvanalimab | Serum concentration of domvanalimab as determined by validated assays | Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, 60 and 100 days post last dose (in total, an average of 2 years) | 
| Pharmacokinetics of etrumadenant | Serum concentration of etrumadenant as determined by validated assays | Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, 60 and 100 days post last dose (in total, an average of 2 years) | 
| Immunogenicity of zimberelimab | Percentage of participants who develop treatment-emergent anti-drug antibodies to zimberelimab | Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, and 100 days post last dose (in total, an average of 2 years). | 
| Immunogenicity of domvanalimab | Percentage of participants who develop treatment-emergent anti-drug antibodies to domvanalimab | Collected during all treatment cycles (each cycle is 21 or 28 days), up to 14 days post last dose, 30, and 100 days post last dose (in total, an average of 2 years). | 

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