The purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of JNJ-74699157 in participants with advanced solid tumors harboring a kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation (Part 1: Dose escalation) and to determine the safety and preliminary antitumor activity of JNJ-74699157 at the RP2D regimen in participants with advanced solid tumors harboring a KRAS G12C mutation (Part 2: Dose expansion).
KRAS is one of the most frequently mutated genes in human cancer. KRAS mutations lead to activation of cellular signaling that promotes tumor growth, and KRAS may therefore be a candidate target for anticancer therapy. This study will evaluate JNJ-74699157, a potent and specific, orally bioavailable inhibitor of the glycine-to-cysteine (G12C) mutant KRAS protein, which is found in non-small cell lung cancers and other solid tumor types. This study will enroll participants with advanced solid tumors harboring the KRAS G12C mutation and will be conducted in 2 parts. Part 1 (Dose Escalation) will be carried out in sequential cohorts of single or multiple participants at doses assigned by the study evaluation team to determine the MTD and RP2D of JNJ-74699157. Participants in Part 2 (Dose Expansion) will receive JNJ-74699157 at the RP2D determined in Part 1 to determine the safety and preliminary antitumor activity of the RP2D. Key efficacy assessments include radiographic imaging evaluations, physical examination, and tumor markers. Safety evaluations will include monitoring of adverse events, vital signs, laboratory evaluations, cardiac monitoring and physical examination findings. The study consists of a screening phase, treatment phase, and a post-treatment follow-up phase. An end-of-treatment visit will occur within 30 days of the last dose of study drug or prior to the start of a subsequent anticancer therapy, whichever comes first. The study duration will be up to 4 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
10
Participants will receive JNJ-74699157 orally.
Florida Cancer Specialists
Sarasota, Florida, United States
H. Lee Moffitt Cancer & Research Institute
Tampa, Florida, United States
Sarah Cannon Research Institute
Nashville, Tennessee, United States
NEXT Oncology
San Antonio, Texas, United States
Centre Leon Bérard
Lyon, France
Hopital de la Timone
Marseille, France
Institut Gustave Roussy
Villejuif, France
Part 1: Number of Participants with Dose-Limiting Toxicity (DLT)
DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.
Time frame: Up to 2 years
Part 1 and Part 2: Number of Participants with Adverse Events (AEs)
An AE is any untoward medical occurrence in a participant who received study drug without regard to causal relationship.
Time frame: Up to 4 years
Part 1 and Part 2: Number of Participants with AE's by Severity
Severity of AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life threatening consequences; Grade 5: Death.
Time frame: Up to 4 years
Part 2: Overall Response Rate (ORR)
ORR is defined as the percentage of participants who have a partial response (PR) or better response as per RECIST v.1.1. PR criteria in solid tumors (RECIST) is greater than or equal to (\>=) 30 percent (%) decrease in the sum of the diameters of all index lesions compared with baseline in 2 observations at least 4 weeks apart, in absence of new lesions or unequivocal progression of non-index lesions.
Time frame: Up to 4 years
Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-74699157
Cmax is the maximum observed plasma concentration.
Time frame: Up to 4 years
Part 1 and Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-74699157
Tmax is defined as actual sampling time to reach maximum observed plasma concentration.
Time frame: Up to 4 years
Part 1 and 2: Area Under Plasma-concentration Time Curve from Time 0 to Time of Last Quantifiable Concentration (AUC [0-last])
AUC (0-last) is the area under the plasma concentration-time curve from time zero to last observed quantifiable concentration.
Time frame: Up to 4 years
Part 1 and 2: Percentage of KRAS G12C Protein in Tumor Tissue Covalently Bound with JNJ-74699157 or its Metabolites
Percentage of kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) protein in tumor tissue covalently bound with JNJ-74699157 or its metabolites will be evaluated using mass spectroscopy.
Time frame: Up to 4 Years
Part 1: Overall Response Rate
ORR is defined as the percentage of participants who have a PR or better response as per RECIST v.1.1. PR criteria in solid tumors (RECIST) is \>=30 percent % decrease in the sum of the diameters of all index lesions compared with baseline in 2 observations at least 4 weeks apart, in absence of new lesions or unequivocal progression of non-index lesions.
Time frame: Up to 4 years
Part 1 and Part 2: Duration of Response (DOR)
DOR is defined as the duration from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease (PD), as defined in the RECIST v1.1, or death due to any cause, whichever occurs first. PD is assessed if the sum of the diameters has increased by \>=20% and \>=5 millimeter (mm) from nadir (including baseline if it is the smallest sum).
Time frame: Up to 4 years
Change From Baseline in QTc Interval Based on the Fridericia Correction (QTcF) Method
Change from baseline in QTcF intervals will be assessed.
Time frame: Baseline up to 4 years
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