Clinical Trials /

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

NCT04006301

Description:

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).

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: CR108652
  • SECONDARY ID: 2019-000565-21
  • SECONDARY ID: 74699157STM1001
  • NCT ID: NCT04006301

Conditions

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

Interventions

DrugSynonymsArms
JNJ-74699157ARS-3248Part 1: Dose Escalation

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1: Dose EscalationExperimentalParticipants 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.
  • JNJ-74699157
Part 2: Dose ExpansionExperimentalTwo 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.
  • JNJ-74699157

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Number of Participants with Dose-Limiting Toxicity (DLT)
Time Frame:Up to 2 years
Safety Issue:
Description:DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.

Secondary Outcome Measures

Measure:Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-74699157
Time Frame:Up to 4 years
Safety Issue:
Description:Cmax is the maximum observed plasma concentration.
Measure:Part 1 and Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-74699157
Time Frame:Up to 4 years
Safety Issue:
Description:Tmax is defined as actual sampling time to reach maximum observed plasma concentration.
Measure: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
Safety Issue:
Description:AUC (0-last) is the area under the plasma concentration-time curve from time zero to last observed quantifiable concentration.
Measure: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
Safety Issue:
Description: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.
Measure:Part 1: Overall Response Rate
Time Frame:Up to 4 years
Safety Issue:
Description: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.
Measure:Part 1 and Part 2: Duration of Response (DOR)
Time Frame:Up to 4 years
Safety Issue:
Description: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).
Measure:Change From Baseline in QTc Interval Based on the Fridericia Correction (QTcF) Method
Time Frame:Baseline up to 4 years
Safety Issue:
Description:Change from baseline in QTcF intervals will be assessed.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Janssen Research & Development, LLC

Trial Keywords

  • KRAS G12C

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