A Safety Study of Oral Venetoclax in Combination With Intravenous Pembrolizumab in Adult Participants With Previously Untreated Non-Small Cell Lung Cancer (NSCLC) With High Programmed Cell Death Ligand-1 (PD-L1) Expression

Study Overview
=================
Brief Summary
-----------------
Non-Small Cell Lung Cancer (NSCLC) is a solid tumor, a disease in which cancer cells form in the tissues of the lung. It is the most common form of lung cancer, accounting for around 85% of lung cancers. The purpose of this study is to evaluate the safety and efficacy (how well the study drug works against the disease) of venetoclax in combination with pembrolizumab in participants with NSCLC. Venetoclax is a drug that kills cancer cells by blocking a protein (part of a cell) that allows cancer cells to stay alive. Pembrolizumab is approved drug for the treatment of NSCLC. It works with your immune system to help fight certain cancers. The study is split into two portions - dose escalation and randomization. Participants are assigned one of the three treatment groups to receive pembrolizumab alone or in combination with venetoclax. Each group receives a different treatment. Participants who are at least 18 years of age with a diagnosis of NSCLC will be enrolled. Around 100 participants will be enrolled in the study in approximately 44 sites across United States. Participants will receive intravenous (IV) infusion of pembrolizumab alone or in combination with oral venetoclax tablets. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Official Title
-----------------
A Phase 1b Study of Venetoclax in Combination With Pembrolizumab in Subjects With Previously Untreated NSCLC Whose Tumors Have High PD-L1 Expression

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

Intervention / Treatment
-----------------
* Drug: Venetoclax
* Drug: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically documented advanced or metastatic NSCLC with no known epidermal growth factor receptor (EGFR) sensitizing (activating) mutation or anaplastic lymphoma kinase (ALK) translocation. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. High PD-L1 tumor expression (tumor proportion score >= 50%) as determined by a Food and Drug Administration (FDA)-approved test. Willing to provide tissue biopsy sample prior to start of study. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Exclusion Criteria: Received prior systemic treatment for their advanced or metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the diagnosis of metastatic disease. History of or ongoing interstitial lung disease or pneumonitis that required oral or intravenous (IV) steroids. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a participant has signs/symptoms suggestive of SARS-CoV-2 infection, they should undergo molecular (e.g., polymerase chain reaction [PCR]) testing to rule out SARS-CoV-2 infection.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Phase: Venetoclax + Pembrolizumab<br>Participants will receive escalating doses of venetoclax in combination with pembrolizumab Dose A. | Drug: Venetoclax<br>* Tablet: Oral<br>* Other names: ABT-199;Drug: Pembrolizumab<br>* Intravenous (IV) Infusion<br>* Other names: Keytruda;|
| Experimental: Randomization Phase: Venetoclax + Pembrolizumab<br>Participants will receive venetoclax at dose levels determined in the dose escalation phase in combination with pembrolizumab Dose A. | Drug: Venetoclax<br>* Tablet: Oral<br>* Other names: ABT-199;Drug: Pembrolizumab<br>* Intravenous (IV) Infusion<br>* Other names: Keytruda;|
| Active Comparator: Randomization Phase: Pembrolizumab Monotherapy<br>Participants will receive pembrolizumab Dose A | Drug: Pembrolizumab<br>* Intravenous (IV) Infusion<br>* Other names: Keytruda;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose-Limiting Toxicities (DLTs) | DLTs are adverse events that are considered to have a reasonable possibility of relationship to the administration of venetoclax and pembrolizumab and cannot be attributed by the investigator to a clearly identifiable cause such as disease progression, concurrent illness or concomitant medication. | Up to 28 Days | 
| Change in the Sum of the Longest Diameter (SLD) | Change in the SLD is assessed by exposure-response modeling | Up to 35 Cycles (Each Cycle is 21 Days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Venetoclax | Maximum plasma concentration (Cmax) of venetoclax | Up to Cycle 1 (Each Cycle is 21 Days) | 
| Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | Time to maximum observed plasma concentration (Tmax) of venetoclax | Up to Cycle 1 (Each Cycle is 21 Days) | 
| Area Under the Plasma Concentration-Time Curve Over Time from 0 to 24 (AUC0-24) of Venetoclax in Plasma | Area Under the Plasma Concentration-time Curve (AUC) from 0-24 (AUC0-24) | Up to Cycle 1 (Each Cycle is 21 Days) | 
| Objective Response Rate (ORR) | ORR will be defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR). | Up to 35 Cycles (Each Cycle is 21 Days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non Small Cell Lung Cancer (NSCLC), Cancer, Venetoclax, Pembrolizumab, PD-L1 Expression, ABT-199