A Study of JNJ-86974680 in Participants With Advanced Non-small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine a safe and tolerable dose(s) of JNJ-86974680 for further research in combination with cetrelimab and radiation therapy.

Official Title
-----------------
A Phase 1 Study of JNJ-86974680, an A2a Receptor Antagonist, Administered as Monotherapy and in Combination With Cetrelimab and Radiotherapy for Advanced Non-small Cell Lung Cancer

Conditions
-----------------
Carcinoma, Non-small-Cell Lung

Intervention / Treatment
-----------------
* Drug: JNJ-86974680
* Drug: Cetrelimab
* Radiation: Radiation Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Individuals with histologically or cytologically confirmed stage IIIB-IV non-small cell lung cancer (NSCLC) Must have been treated with (a) anti-programmed death protein 1 (anti-PD-1) or programmed cell death ligand 1 (PD-L1) therapy and (b) platinum-based chemotherapy and have progressed. Individuals who cannot tolerate or have previously refused platinum-based chemotherapy are eligible to enroll based on progression after anti-PD-1/PD-L1 therapy alone Can have a prior or concurrent second malignancy (other than the disease under study), which due to natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s) Have an eastern cooperative oncology group (ECOG) performance status of 0 or 1 Adequate liver function: Participants with no underlying hepatic metastases are eligible if they have: i) aspartate aminotransferase (AST) less than (<)3 x upper limit of normal (ULN), ii) alanine aminotransferase (ALT) <3 x ULN, and iii) Total bilirubin <1.5 x ULN Participants with known hepatic metastases are eligible if they have: i) AST <5 x ULN, ii) ALT <5 x ULN, and iii) Total bilirubin <3 x ULN Part 1: NSCLC with a known actionable genetic mutation (for example, epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 [ROS1], v-raf murine sarcoma viral oncogene homolog B1 [BRAF]) must have received all approved targeted therapies and have progressed. Participants with unknown mutation status due to a failed testing status or lack of access to testing are allowed in the study Part 2: Participants must have at least 3 lesions on baseline scan, one of which is evaluable as a target lesion for response assessment per RECIST Version 1.1 Part 2: Agree to submit tumor samples prior to study treatment which can be an archival tumor tissue sample obtained within 3 months prior to start of treatment and without any therapy for NSCLC being administered within these 3 months, or newly obtained core or incisional biopsy of a tumor lesion during screening Exclusion Criteria: Active disease involvement of the central nervous system with the exception of definitively locally treated brain metastases that are clinically stable Active autoimmune disease that requires systemic immunosuppressive medications (for example, chronic corticosteroid, methotrexate, or tacrolimus) within the 12 months prior to signing consent Active infection or condition that requires treatment with systemic anti-infective agents (for example, antibiotics, antifungal or antivirals) within 7 days prior to the first dose of study treatment or chronic use of anti-infective agents History of solid organ or hematologic stem cell transplantation Part 2: NSCLC with an actionable genetic mutation for which an approved therapy is available: EGFR, ALK, ROS1, or BRAF. Confirmation of the absence of actionable mutations is required

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: JNJ-86974680+Cetrelimab<br>Participants will receive JNJ-86974680 alone (dose 1, dose 2, dose 3, and dose 4) daily in 4 cohorts and then along with a set dose of cetrelimab. | Drug: JNJ-86974680<br>* JNJ-86974680 will be administered.<br>Drug: Cetrelimab<br>* Cetrelimab will be administered.<br>|
| Experimental: Part 2: JNJ-86974680+Cetrelimab+Radiation Therapy (RT)<br>Participants will receive treatment with the identified safe dose of JNJ-86974680 in combination with cetrelimab from part 1, in conjunction with radiation. | Drug: JNJ-86974680<br>* JNJ-86974680 will be administered.<br>Drug: Cetrelimab<br>* Cetrelimab will be administered.<br>Radiation: Radiation Therapy<br>* Radiation therapy will be administered.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) by Severity | An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event. | Up to 2 years 5 months | 
| Number of Participants with Dose Limiting Toxicities (DLTs) | The DLTs are specific adverse events and are defined as any of the following: non-hematologic toxicity and hematological toxicity. | Up to 2 years 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of JNJ-86974680 | Cmax is defined as maximum observed plasma concentration of JNJ-86974680. | Up to 2 years 5 months | 
| Minimum Concentration (Cmin) of JNJ-86974680 | Cmin is defined as the minimum observed plasma concentration of JNJ-86974680. | Up to 2 years 5 months | 
| Time to Reach the Maximum Observed Plasma Concentration (Tmax) of JNJ-86974680 | Tmax is defined the time to reach the maximum observed plasma concentration of JNJ-86974680. | Up to 2 years 5 months | 
| Terminal Elimination Half-life (t1/2) of JNJ-86974680 | T1/2 is defined as terminal elimination half-life of JNJ-86974680. | Up to 2 years 5 months | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC0-t) of JNJ-86974680 | (AUC0-t) is defined as area under the plasma concentration of JNJ-86974680 versus time curve from the time of dose administration to time of last quantifiable concentration (0-t). | Up to 2 years 5 months | 
| Area Under the Plasma Concentration-time Curve of JNJ-8697468 over the Dosing Interval (tau) | AUCtau is defined as the area under the plasma concentration-time curve of JNJ-8697468 over the dosing interval (tau). | Up to 2 years 5 months | 
| Apparent Clearance (CL/F) of JNJ-86974680 | Apparent clearance of JNJ-86974680 was defined as a measure of the rate at which a drug got metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. | Up to 2 years 5 months | 
| Apparent Volume of Distribution (V/F) of JNJ-86974680 | V/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of JNJ-86974680. | Up to 2 years 5 months | 
| Part 2: Overall Response Rate (ORR) | ORR is defined as the percentage of participants who have a best response of complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors (RECIST) version (v)1.1, maintained for at least 4 weeks. | Up to 2 years 5 months | 
| Part 2: Complete Response Rate (CRR) | CRR is defined as the proportion of participants with a best response of CR. | Up to 2 years 5 months | 
| Part 2: Duration of Response (DOR) | DoR is defined as the time from the date of first initial documentation of a response to the date of first documented evidence of progression of disease according to immunotherapy response evaluation criteria in solid tumors (iRECIST) or death due to any cause, whichever occurs first. | Up to 2 years 5 months | 
| Part 2: Disease Control Rate (DCR) | DCR is defined as the percentage of participants who achieve a best of response of PR, CR, or stable disease using RECIST v1.1. | Up to 2 years 5 months |