Clinical trial NCT04006301: First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation
Official title: A First-in-Human Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of JNJ-74699157 in Participants With Advanced Solid Tumors Harboring the KRAS G12C Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Advanced Solid Tumors
Non-small Cell Lung Cancer
Colorectal Cancer
Keywords: KRAS G12C
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2019-07-05
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Part 1: Number of Participants with Dose-Limiting Toxicity (DLT)
timeFrame: Up to 2 years
measure: Part 1 and Part 2: Number of Participants with Adverse Events (AEs)
timeFrame: Up to 4 years
measure: Part 1 and Part 2: Number of Participants with AE's by Severity
timeFrame: Up to 4 years
measure: Part 2: Overall Response Rate (ORR)
timeFrame: Up to 4 years
Secondary outcomes:
measure: Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-74699157
timeFrame: Up to 4 years
measure: Part 1 and Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-74699157
timeFrame: Up to 4 years
measure: Part 1 and 2: Area Under Plasma-concentration Time Curve from Time 0 to Time of Last Quantifiable Concentration (AUC [0-last])
timeFrame: Up to 4 years
measure: Part 1 and 2: Percentage of KRAS G12C Protein in Tumor Tissue Covalently Bound with JNJ-74699157 or its Metabolites
timeFrame: Up to 4 Years
measure: Part 1: Overall Response Rate
timeFrame: Up to 4 years
measure: Part 1 and Part 2: Duration of Response (DOR)
timeFrame: Up to 4 years
measure: Change From Baseline in QTc Interval Based on the Fridericia Correction (QTcF) Method
timeFrame: Baseline up to 4 years
Other outcomes:
Locations:
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer & Research Institute
state: Florida
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: San Antonio
country: United States
facility: NEXT Oncology
state: Texas
city: Lyon Cedex 8
country: France
facility: Centre Leon Bérard
city: Marseille
country: France
facility: Hopital de la Timone
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Wang J, Martin-Romano P, Cassier P, Johnson M, Haura E, Lenox L, Guo Y, Bandyopadhyay N, Russell M, Shearin E, Lauring J, Dahan L. Phase I Study of JNJ-74699157 in Patients with Advanced Solid Tumors Harboring the KRAS G12C Mutation. Oncologist. 2022 Jul 5;27(7):536-e553. doi: 10.1093/oncolo/oyab080.