The purpose of study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of Amivantamab as a monotherapy and in combination with lazertinib, and to determine the recommended Phase 2 dose (RP2D) (monotherapy), recommended Phase 2 combination dose (RP2CD) (combination therapy), and to determine recommended Phase 2 Dose (RP2q3W) with combination chemotherapy (Amivantamab in combination with standard of care carboplatin and pemetrexed) in 21 day treatment cycle for participants with advanced non-small cell lung cancer (NSCLC).
This open label (all participants know the identity of the study drug), multicenter (more than one study site), first-in-human study consists of 2 parts. Part 1 is a Amivantamab Monotherapy and Combination Dose Escalations and Part 2 Amivantamab Monotherapy and Combination Dose Expansions. In Part 1, participants with evaluable NSCLC will be enrolled into cohorts at increasing dose levels of Amivantamab monotherapy, the RP2CD of the Amivantamab and lazertinib combination which will be administered in 28 day treatment cycles, and RP2q3W of Amivantamab in combination with standard of care carboplatin and pemetrexed (chemotherapy combination) which will be administered in 21 day treatment cycles. The dose will be escalated until the maximum tolerated dose (MTD, or maximum administered dose \[MAD\], if no MTD is found) is reached. Part 1 will follow a traditional 3+3 design. At each dose level, 3 participants will complete Cycle 1. If no dose limiting toxicity (DLT) occurs in these 3 participants, then escalation will continue in a new cohort of 3 participants. Data from Part 1 will be used to determine one or more RP2D regimen(s). In Part 2, participants with documented epidermal growth factor receptor (EGFR) mutations and measurable disease, whose disease has progressed after previous treatment will be enrolled and receive Amivantamab at the RP2D determined in Part 1 as a monotherapy at the RP2D regimen(s), or in combination with lazertinib at the RP2CD regimen. For both parts, the study consists of following periods: an optional pre-Screening period; a Screening period (up to 28 days prior to the first dose of study drug); a Treatment period (first dose of study drug until 30(+7) days after the last dose of study drug or prior to starting any subsequent anti-cancer treatment, whichever comes first); and a Follow Up period (approximately 6 months). All participants will be followed for survival in the post-treatment follow-up period until the end of study and safety will be monitored throughout the study.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
751
The first cohort of participants will receive IV infusions of Amivantamab 140 mg as monotherapy. Each subsequent cohort will receive IV infusions of Amivantamab at increased dose level until maximum tolerated dose is reached or all planned doses are administered. Participants will receive lazertinib and Amivantamab at predefined dose levels, based upon observed safety and protocol defined criteria. The duration of each treatment cycle is 28 days. In Chemotherapy Combination Cohort, participants will receive Amivantamab, administered on a 21-day cycle, in combination with the administration of standard of care carboplatin and pemetrexed.
Participants will receive IV infusion of Amivantamab as monotherapy at RP2D regimen or in combination lazertinib at RP2CD regimen as determined in Part 1.
Lazertinib will be administered in combination with Amivantamab at predefined dose levels, based upon observed safety and protocol defined criteria. Lazertinib will be administered daily on the 28-day Amivantamab treatment cycle.
Participants will receive carboplatin in combination with pemetrexed and Amivantamab as an IV infusion on 21-day treatment cycle in Part 1 Chemotherapy Combination Cohort only.
Participants will receive pemetrexed in combination with carboplatin and Amivantamab as an IV infusion on 21-day treatment cycle in Part 1 Chemotherapy Combination Cohort only.
Unnamed facility
Duarte, California, United States
Unnamed facility
La Jolla, California, United States
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Orange, California, United States
Unnamed facility
Santa Monica, California, United States
Unnamed facility
West Hollywood, California, United States
Unnamed facility
Part 1: Number of Participants With Dose Limiting Toxicity (DLT)
The Dose Limiting Toxicity (DLT) is based on drug related adverse events and includes unacceptable hematologic toxicity, non-hematologic toxicity of Grade 3 or higher, or elevations in hepatic enzymes suggestive of drug-induced liver injury.
Time frame: Up to Day 28
Part 2: Number of Participants With Adverse Events (AEs) and Serious AEs
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Screening up to follow-up (30 [+7] days after the last dose)
Part 2: Overall Response Rate (ORR)
Overall response rate (ORR) is defined as the percentage of participants who achieve either a CR or PR as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1). CR: disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (\< 10 mm short axis) and normalisation of tumour marker levels; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.
Time frame: Up to End of Treatment Follow (EOT) Up Period (30 [+7] days after the last dose)
Part 2: Duration of Response (DOR)
DOR will be calculated as time from initial response of CR (disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (\[\<\] 10 \[mm\] short axis) and normalisation of tumour marker levels) or PR (at least a 30 \[%\] decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits or durable stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits) to progressive disease (PD) or death due to underlying disease, whichever comes first, only for participants who achieve CR or PR.
Time frame: Up to EOT Follow Up Period (30 [+7] days after the last dose)
Part 2: Percentage of Participants With Clinical Benefit
Clinical benefit rate is defined as the percentage of participants achieving complete response (CR): disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (less than \[\<\] 10 millimeter \[mm\] short axis) and normalisation of tumour marker levels or partial response (PR): at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits or durable stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.
Time frame: Up to EOT Follow Up Period (30 [+7] days after the last dose)
Trough Serum Concentration (Ctrough) of Amivantamab
Ctrough is the observed serum concentration immediately prior to the next administration.
Time frame: Up to EOT (30 days after last dose)
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Amivantamab
The AUCtau is the area under the serum concentration-time curve during a dose interval time period (tau)
Time frame: Up to EOT (30 days after last dose)
Maximum Serum Concentration (Cmax) of Amivantamab
The Cmax is the maximum observed serum concentration of Amivantamab.
Time frame: Cycle 1 Day 1: predose through end of infusion (EOT) or Follow Up (approximately 16 months) (each cycle is of 28 days)
Time to Reach Maximum Observed Serum Concentration (Tmax) of Amivantamab
The Tmax is defined as time to reach maximum observed serum concentration of Amivantamab.
Time frame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
Area Under the Serum Concentration-Time Curve From t1 to t2 Time (AUC[t1-t2]) of Amivantamab
The AUC(t1-t2) is the area under the serum Amivantamab concentration-time curve from time t1 to t2.
Time frame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Amivantamab
The AUCtau is the area under the serum concentration-time curve during a dose interval time period (tau)
Time frame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
Trough Serum Concentration (Ctrough) of Amivantamab
The Ctrough is the observed serum concentration immediately prior to the next administration.
Time frame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
Maximum Serum Concentration (Cmax) of Lazertinib
Cmax is the maximum observed serum concentration of lazertinib.
Time frame: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)
Time to Reach Maximum Observed Serum Concentration (Tmax) of Lazertinib
Tmax is defined as time to reach maximum observed serum concentration of lazertinib.
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Tampa, Florida, United States
Unnamed facility
Chicago, Illinois, United States
Unnamed facility
Bethesda, Maryland, United States
Unnamed facility
Boston, Massachusetts, United States
Unnamed facility
Detroit, Michigan, United States
...and 59 more locations
Time frame: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)
Trough Serum Concentration (Ctrough) of Lazertinib
Ctrough is the observed serum concentration immediately prior to the next administration.
Time frame: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)
Accumulation ratio (R) of Amivantamab
The R is the accumulation ratio calculated as Cmax or AUC after multiple doses divided by Cmax or AUC after the first dose, respectively.
Time frame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
Number of Participants With Anti-Drug Antibodies (ADA)
Serum levels of antibodies to Amivantamab for evaluation of potential immunogenicity.
Time frame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
Progression-Free Survival (PFS)
PFS is defined as the time from first infusion of study drug to PD or death due to any cause.
Time frame: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)
Time to Treatment Failure (TTF)
TTF is defined as the time from the first infusion of the study drug 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 RECIST v1.1 defined disease progression.
Time frame: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)
Overall Survival (OS)
OS is defined as the time from first infusion of study drug to death due to any cause.
Time frame: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)