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.
Inclusion Criteria:
- Kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation in tumor
tissue or blood
- Histological documentation of disease: Part 1: Histologically or cytologically
confirmed solid tumor malignancy that is metastatic or unresectable, Part 2: (a)
unresectable, locally advanced (Stage IIIB) or metastatic (Stage IV) non-small cell
lung cancer (NSCLC), (b) Solid tumor malignancy other than NSCLC that is metastatic or
unresectable
- Received or was ineligible for standard treatment options. For NSCLC: previously
received a platinum-containing chemotherapy regimen and an anti- programmed
death-ligand 1 (PD1/PDL1) antibody, unless participant refused or was ineligible to
receive such therapy; and for colorectal cancer (CRC): previously received at least 2
prior lines of therapy, including a fluoropyrimidine, oxaliplatin, and irinotecan,
unless participant refused or was ineligible to receive such therapy. For Participants
in France only: NSCLC: Previously received a platinum-containing chemotherapy regimen
and an anti-PD1/PDL1 antibody or was ineligible to receive such therapy. CRC:
Previously received at least 2 prior lines of therapy, including a fluoropyrimidine,
oxaliplatin, and irinotecan or was ineligible to receive such therapy
- Measurable or evaluable disease: Part 1: either measurable or evaluable disease, Part
2: At least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1
- Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1
Exclusion Criteria:
- Symptomatic brain metastases or known leptomeningeal disease; asymptomatic brain
metastases are allowed if they have been treated, have been stable for greater than or
equal to (>=) 4 weeks as documented by radiographic imaging, and do not require
prolonged (greater than [>]14 days) systemic corticosteroid therapy. Participants who
have had complete surgical resection of or received stereotactic radiosurgery to less
than or equal to (<=) 3 metastatic lesions will be permitted to enroll in the study
within 14 days of such treatment if they have recovered from treatment, are clinically
stable, and do not require prolonged systemic corticosteroid therapy as noted above
- Prior treatment with an inhibitor specific to KRAS G12C
- Prior solid organ transplantation
- History of malignancy (other than the disease under study) within 2 years before the
first administration of study drug. Exceptions include squamous and basal cell
carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the
opinion of the investigator, with concurrence with the sponsor's medical monitor, is
considered cured with minimal risk of recurrence within 2 years
- Inability to take an orally administered drug, or medical disorder or prior surgical
resection that may affect the absorption of the study drug. Such conditions include,
but are not limited to, malabsorption syndrome, symptomatic inflammatory bowel
disease, partial or complete bowel obstruction, or resection of the stomach or small
bowel. If any of these conditions exist, the investigator should discuss with the
sponsor to determine participant eligibility
