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

Primary Purpose

Neoplasms, Advanced Solid Tumors, Non-small Cell Lung Cancer

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

JNJ-74699157

About this trial

This is an interventional treatment trial for Neoplasms focused on measuring KRAS G12C

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Florida Cancer Specialists
H. Lee Moffitt Cancer & Research Institute
Sarah Cannon Research Institute
NEXT Oncology
Centre Leon Bérard
Hopital de la Timone
Institut Gustave Roussy

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Part 1: Dose Escalation

Part 2: Dose Expansion

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

Secondary Outcome Measures

Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-74699157

Cmax is the maximum observed plasma concentration.

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.

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.

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.

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.

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).

Change From Baseline in QTc Interval Based on the Fridericia Correction (QTcF) Method

Change from baseline in QTcF intervals will be assessed.

Full Information

NCT ID

NCT04006301

First Posted

July 2, 2019

Last Updated

November 5, 2020

Sponsor

Janssen Research & Development, LLC

1. Study Identification

Unique Protocol Identification Number

NCT04006301

Brief Title

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

2. Study Status

Record Verification Date

November 2020

Overall Recruitment Status

Completed

Study Start Date

July 26, 2019 (Actual)

Primary Completion Date

July 13, 2020 (Actual)

Study Completion Date

July 13, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Janssen Research & Development, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neoplasms, Advanced Solid Tumors, Non-small Cell Lung Cancer, Colorectal Cancer

Keywords

KRAS G12C

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: Dose Escalation

Arm Type

Experimental

Arm Description

Arm Title

Part 2: Dose Expansion

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

JNJ-74699157

Other Intervention Name(s)

ARS-3248

Intervention Description

Participants will receive JNJ-74699157 orally.

Primary Outcome Measure Information:

Title

Part 1: Number of Participants with Dose-Limiting Toxicity (DLT)

Description

DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.

Time Frame

Up to 2 years

Title

Part 1 and Part 2: Number of Participants with Adverse Events (AEs)

Description

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

Title

Part 1 and Part 2: Number of Participants with AE's by Severity

Description

Time Frame

Up to 4 years

Title

Part 2: Overall Response Rate (ORR)

Description

Time Frame

Up to 4 years

Secondary Outcome Measure Information:

Title

Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-74699157

Description

Cmax is the maximum observed plasma concentration.

Time Frame

Up to 4 years

Title

Part 1 and Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-74699157

Description

Tmax is defined as actual sampling time to reach maximum observed plasma concentration.

Time Frame

Up to 4 years

Title

Part 1 and 2: Area Under Plasma-concentration Time Curve from Time 0 to Time of Last Quantifiable Concentration (AUC [0-last])

Description

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

Title

Part 1 and 2: Percentage of KRAS G12C Protein in Tumor Tissue Covalently Bound with JNJ-74699157 or its Metabolites

Description

Time Frame

Up to 4 Years

Title

Part 1: Overall Response Rate

Description

Time Frame

Up to 4 years

Title

Part 1 and Part 2: Duration of Response (DOR)

Description

Time Frame

Up to 4 years

Title

Change From Baseline in QTc Interval Based on the Fridericia Correction (QTcF) Method

Description

Change from baseline in QTcF intervals will be assessed.

Time Frame

Baseline up to 4 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Janssen Research & Development, LLC Clinical Trial

Organizational Affiliation

Janssen Research & Development, LLC

Official's Role

Study Director

Facility Information:

Facility Name

Florida Cancer Specialists

City

Sarasota

State/Province

Florida

ZIP/Postal Code

34232

Country

United States

Facility Name

H. Lee Moffitt Cancer & Research Institute

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

Facility Name

Sarah Cannon Research Institute

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37203

Country

United States

Facility Name

NEXT Oncology

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78229

Country

United States

Facility Name

Centre Leon Bérard

City

Lyon Cedex 8

ZIP/Postal Code

69373

Country

France

Facility Name

Hopital de la Timone

City

Marseille

ZIP/Postal Code

13885

Country

France

Facility Name

Institut Gustave Roussy

City

Villejuif

ZIP/Postal Code

94800

Country

France

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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

IPD Sharing URL

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

Citations:

PubMed Identifier

35325211

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.

Results Reference

derived

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

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