The purpose of this study is to confirm the tolerability of recommended Phase 2 dose (RP2D) of Lazertinib (Phase 1), to determine the tolerability and identify the recommended Phase 2 combination dose of Lazertinib when combined with Amivantamab (JNJ-61186372) (Phase 1b), to characterize the safety and tolerability of Lazertinib and Amivantamab combinations at the RP2CD in participants with advanced non-small cell lung cancer (NSCLC) with documented advanced or metastatic epidermal growth factor receptor (EGFR) mutation (Phase 1b expansion cohorts A, B, C, D and E), to estimate the antitumor activity of Lazertinib and Amivantamab combinations at the RP2CD in participants with advanced NSCLC with documented advanced or metastatic EGFR mutation (Phase 1b expansion cohorts A, B, C, and D), to validate the biomarker identified in Phase 1b expansion Cohort D as a predictor of antitumor activity of Lazertinib and Amivantamab combination (Cohort E) or Amivantamab monotherapy (Cohort F) in participants with osimertinib-relapsed, chemotherapy-naïve, EGFR Exon19del or L858R mutated NSCLC, to identify the recommended Phase 2 dose (RP2ChD) of Lazertinib when combined with Amivantamab and standard of care chemotherapy and to determine the tolerability of the Lazertinib, Amivantamab, and platinum-doublet chemotherapy (LACP) combination (Phase 1b LACP combination cohort) and to characterize the safety and tolerability of Lazertinib at the RP2ChD and Amivantamab and standard of care chemotherapy in participants with advanced or metastatic EGFR-mutated NSCLC (Phase 1b LACP combination cohort), to assess 2 potential biomarker strategies to identify participants at increased, or decreased, probability of tumor response with JNJ-61186372 and lazertinib combination in participants with EGFR Exon19del or L858R mutated NSCLC progressed on or after osimertinib (Phase 1b expansion Cohort D).
Lung cancer is one of the most common types of cancer and is also the most common cause of death from cancer. NSCLC accounts for 85 percent (%) to 90% of lung cancers. Lazertinib is an oral, highly potent, mutant-selective, and irreversible EGFR-tyrosine kinase inhibitor (TKI) targeting both, the T790M mutation and activating EGFR mutations while sparing wild type EGFR. JNJ-61186372 (also referred to as amivantamab), is a low fucose, fully human immunoglobulin G1(IgG1)-based bispecific antibody. As a third generation EGFR-TKI targeting activating EGFR mutations, lazertinib has a distinct mechanism of action from JNJ-61186372, which targets the extracellular domains of both the EGFR and cMet proteins. The distinct mechanisms of action of lazertinib and JNJ-61186372 suggests potential to improve clinical outcomes through the combination of these two molecules. Phase 1 and 1b lazertinib + amivantamab, and Phase 1b LACP combination cohort are divided into 2 periods: screening and treatment period whereas Phase 1b expansion cohorts are divided into 3 periods: screening, treatment, and post-treatment follow up period. Safety assessment will include adverse events (AEs), serious adverse events (SAEs), physical examinations, Eastern Cooperative Oncology Group (ECOG) criteria for performance status, laboratory tests, vital signs, electrocardiograms, chest x-ray, baseline ophthalmologic examination (Phase 1b Expansion Cohorts), echocardiography or multigated acquisition, and concomitant medication usage. The overall duration of the study will be up to 5 years and 2 months.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
701
Lazertinib will be administered orally.
Amivantamab will be administered as an intravenous (IV) infusion.
Carboplatin will be administered as IV infusion.
Pemetrexed will be administered as IV infusion.
USC Norris Comprehensive Cancer Center
Los Angeles, California, United States
University of California Irvine
Orange, California, United States
UCSF Helen Diller Comprehensive
San Francisco, California, United States
Stanford University Medical Center
Stanford, California, United States
Cedars Sinai Medical Center
West Hollywood, California, United States
Percentage of Participants with Dose-Limiting Toxicity (DLT) (Phase 1)
DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.
Time frame: Until the end of first cycle (21 days for Phase 1)
Percentage of Participants with Dose-Limiting Toxicity (DLT) (Phase 1b)
DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.
Time frame: Until the end of first cycle (28 days for Phase 1b)
Overall Response Rate (ORR) (Phase 1b Expansion Cohorts A-D)
ORR is defined as the percentage of participants who achieve either a complete (CR) or partial response (PR) as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability (Phase 1b Expansion Cohorts A-E)
Adverse events (AEs) defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Criteria Version 5.0 in participants treated at the RP2CD regimen of Lazertinib and Amivantamab combination therapy. An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Time frame: Up to 2.5 years
Percentage of Participants with DLT (Phase 1b combination Lazertinib, Amivantamab, Platinum-doublet chemotherapy [LACP])
DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.
Time frame: Until the end of first cycle (21 days for Phase 1b combination LACP)
Number of Participants with AEs as a Measure of Safety and Tolerability (Phase 1b combination LACP)
AEs defined by the NCI-CTCAE criteria version 5.0 in participants treated with LACP combination regimen. An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Time frame: Up to 2.5 years
Overall Response Rate (ORR) per RECIST version 1.1 (v1.1) with NGS Analysis of Circulating Tumor ctDNA, IHC Analysis of EGFR and MET Expression (Phase 1b Expansion Cohort D)
ORR is defined as the percentage of participants who achieve either a complete (CR) or partial response (PR) as determined by the investigator using RECIST 1.1 criteria with Next Generation Sequencing (NGS) Analysis of Circulating Tumor Deoxyribonucleic Acid (ctDNA), Immunohistochemical (IHC) Analysis of Tumor Epidermal Growth Factor Receptor (EGFR) and MET Expression (Phase 1b Expansion Cohort D).
Time frame: Up to 2.5 years
ORR Among Participants with MET3+ Staining on Greater Than or Equal to (>=)25 Percent (%) of Tumor Cells (Phase 1b Expansion Cohorts E and F)
ORR among participants with MET3+ staining on \>=25 % of tumor cells will be reported. ORR is defined as the percentage of participants who achieve either a CR or PR as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
Duration of Response (DOR) Among Participants with MET3+ Staining on >=25% of Tumor Cells (Phase 1b Expansion Cohorts E and F)
DOR among participants with MET3+ staining on \>=25 % of tumor cells will be reported. DOR will be calculated as time from initial response of CR or PR to progressive disease (PD) or death due to any cause, whichever comes first, only for participants who achieve CR or PR as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
Clinical Benefit Rate (CBR) Among Participants with MET3+ Staining on >=25% of Tumor Cells (Phase 1b Expansion Cohorts E and F)
CBR among participants with MET3+ staining on \>=25% of tumor cells will be reported. CBR is defined as the percentage of participants achieving complete or partial response, or durable stable disease (duration of at least 11 weeks) as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability (Phase 1 and Phase 1b)
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
Time frame: Up to 2.5 years
Plasma Concentration of Lazertinib (Phase 1 and Phase 1b)
Plasma samples will be analyzed to determine concentrations of Lazertinib.
Time frame: Up to End of Treatment [EOT]) (30 days after last dose) (up to 2.5 years)
Serum Concentration of Amivantamab (Phase 1b)
Serum samples will be analyzed to determine concentrations of Amivantamab.
Time frame: Up to EOT (30 days after last dose) (up to 2.5 years)
Number of Participants with Anti-drug Antibodies Against Amivantamab (Phase 1b)
Number of participants with anti-drug antibodies against Amivantamab will be reported.
Time frame: Up to EOT (30 days after last dose) (up to 2.5 years)
Progression free survival (PFS) (Phase 1b Expansion)
PFS is defined as the time from first infusion of study intervention to PD or death due to any cause.
Time frame: Up to 2.5 years
Time to Treatment Failure (TTF) (Phase 1b Expansion)
TTF is defined as the time from the first administration of the study intervention to discontinuation of treatment for any reason, including disease progression, treatment toxicity, death, and will be utilized to capture clinical benefit for patients continuing treatment beyond as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
Overall Survival (OS) (Phase 1b Expansion)
OS is defined as the time from first infusion of study intervention to death due to any cause as determined by the investigator using RECIST 1.1 criteria.
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H. Lee Moffitt Cancer & Research Institute
Tampa, Florida, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Boston University Medical Center
Boston, Massachusetts, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States
...and 68 more locations
Time frame: Up to 2.5 years
Duration of Response (DOR) (Phase 1b expansion)
DOR will be calculated as time from initial response of CR or PR to progressive disease (PD) or death due to any cause, whichever comes first, only for participants who achieve CR or PR as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
Clinical Benefit Rate (CBR) (Phase 1b expansion)
CBR is defined as the percentage of participants achieving complete or partial response, or durable stable disease (duration of at least 11 weeks) as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
Number of Participants with Venous Thromboembolic (VTE) Events by Severity
Number of participants with VTE events including pulmonary embolism and deep vein thrombosis by severity defined by the NCI-CTCAE Criteria Version 5.0 will be reported.
Time frame: Up to 2.5 years
Number of Participants with Adverse Events (AEs) (Phase 1b Expansion Cohort F)
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
Time frame: Up to 2.5 years
ORR (Phase 1b expansion Cohorts E and F)
ORR is defined as the percentage of participants who achieve either a CR or PR as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
DOR (Phase 1b Expansion Cohorts E and F)
DOR will be calculated as time from initial response of CR or PR to PD or death due to any cause, whichever comes first, only for participants who achieve CR or PR as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
CBR (Phase 1b expansion Cohorts E and F)
CBR is defined as the percentage of participants achieving complete or partial response, or durable stable disease (duration of at least 11 weeks) as determined by the investigator using RECIST 1.1 criteria.
Time frame: Up to 2.5 years
Intracranial Progression free survival (PFS) (Phase 1b Expansion E and F)
Intracranial PFS is defined as the time from first infusion of study intervention until the date of objective intracranial disease progression or death, whichever comes first, based on Investigator assessment using RECIST v1.1.
Time frame: Up to 2.5 years