First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation

• ClinicalTrials.gov Identifier: NCT04006301
• Recruitment Status: Completed
• First Posted: July 5, 2019
• Last Update Posted: November 6, 2020
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Neoplasms; Advanced Solid Tumors; Non-small Cell Lung Cancer; Colorectal Cancer	Drug: JNJ-74699157	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: July 26, 2019
• Actual Primary Completion Date: July 13, 2020
• Actual Study Completion Date: July 13, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: Dose Escalation; Participants with advanced solid tumors harboring the kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation will receive oral administration of JNJ-74699157. The dose levels will be escalated sequentially based on the decisions of the Study Evaluation Team (SET) until the recommended Phase 2 Dose (RP2D) has been identified.	Drug: JNJ-74699157; Participants will receive JNJ-74699157 orally.; Other Name: ARS-3248
Experimental: Part 2: Dose Expansion; Two groups of participants with either non-small cell lung cancer or other solid tumors harboring KRAS G12C mutation will receive JNJ-74699157 at RP2D determined in Part 1.	Drug: JNJ-74699157; Participants will receive JNJ-74699157 orally.; Other Name: ARS-3248

Outcome Measures

Primary Outcome Measures :

1. Part 1: Number of Participants with Dose-Limiting Toxicity (DLT) [ Time Frame: Up to 2 years ]
   DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.
2. Part 1 and Part 2: Number of Participants with Adverse Events (AEs) [ Time Frame: Up to 4 years ]
   An AE is any untoward medical occurrence in a participant who received study drug without regard to causal relationship.
3. Part 1 and Part 2: Number of Participants with AE's by Severity [ Time Frame: Up to 4 years ]
   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.
4. Part 2: Overall Response Rate (ORR) [ Time Frame: Up to 4 years ]
   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.

Secondary Outcome Measures :

1. Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-74699157 [ Time Frame: Up to 4 years ]
   Cmax is the maximum observed plasma concentration.
2. Part 1 and Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-74699157 [ Time Frame: Up to 4 years ]
   Tmax is defined as actual sampling time to reach maximum observed plasma concentration.
3. Part 1 and 2: Area Under Plasma-concentration Time Curve from Time 0 to Time of Last Quantifiable Concentration (AUC [0-last]) [ Time Frame: Up to 4 years ]
   AUC (0-last) is the area under the plasma concentration-time curve from time zero to last observed quantifiable concentration.
4. Part 1 and 2: Percentage of KRAS G12C Protein in Tumor Tissue Covalently Bound with JNJ-74699157 or its Metabolites [ Time Frame: Up to 4 Years ]
   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.
5. Part 1: Overall Response Rate [ Time Frame: Up to 4 years ]
   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.
6. Part 1 and Part 2: Duration of Response (DOR) [ Time Frame: Up to 4 years ]
   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).
7. Change From Baseline in QTc Interval Based on the Fridericia Correction (QTcF) Method [ Time Frame: Baseline up to 4 years ]
   Change from baseline in QTcF intervals will be assessed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Florida

Florida Cancer Specialists

Sarasota, Florida, United States, 34232

H. Lee Moffitt Cancer & Research Institute

Tampa, Florida, United States, 33612

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

United States, Texas

NEXT Oncology

San Antonio, Texas, United States, 78229

France

Centre Leon Bérard

Lyon Cedex 8, France, 69373

Hopital de la Timone

Marseille, France, 13885

Institut Gustave Roussy

Villejuif, France, 94800

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

More Information

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT04006301
• Other Study ID Numbers: CR108652; 2019-000565-21 ( EudraCT Number ); 74699157STM1001 ( Other Identifier: Janssen Research & Development, LLC )
• First Posted: July 5, 2019
• Last Update Posted: November 6, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency.

As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

• URL: https://www.janssen.com/clinical-trials/transparency

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Janssen Research & Development, LLC:

KRAS G12C

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases