A Phase 1/2, Open-label, Multicenter, FIH Study to Evaluate Safety, Tolerability, PK and Anti-tumor Activity of YH42946

A Phase 1/2, Open-label, Multicenter, FIH Study to Evaluate the Safety, Tolerability, PK and Anti-tumor Activity of YH42946 in Patients With Locally Advanced or Metastatic Solid Tumors With HER2 Aberration and EGFR Exon 20 Insertion

The goal of this YH42946-101 is to evaluate the safety, Tolerability, Pharmacokinetics and anti-tumor activity of YH42946 in patients with locally advanced of metastatic solid tumors with HER2 aberration and EGFR exon 20 insertions.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor; NSCLC (Non-small Cell Lung Cancer)
• Intervention / Treatment: Drug: YH42946

Detailed Description

YH42946 is a novel, orally available tyrosine kinase inhibitor targeting HER2. YH42946 showed potency for diverse HER2 aberrations including HER2 overexpression, amplification, or mutation, as well as EGFR Ex20ins.

This is a Phase 1/2, open-label, multicenter, first-in-human study of YH42946. The study has 2 parts. The first part is dose escalation part to identify the maximum tolerated dose. The second part is dose expansion part to select 2 doses for RD selection at the first cohort, after then RD will be determined to ensure its efficacy. Several independent cohorts are planned.

• Study Type: Interventional
• Enrollment (Estimated): 161
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Yuhan Corporation Clinical Operation Team 1; Phone Number: 8228280576; Email: clinicaltrials@yuhan.co.kr

Study Locations

• South Korea
  • Seoul, South Korea, 03080
    • Recruiting
    • Seoul National University Hospital
    • Contact: Do-Youn Oh
  • Seoul, South Korea, 06351
    • Recruiting
    • Samsung Medical Center
    • Contact: Sehoon Lee
  • Seoul, South Korea, 03722
    • Recruiting
    • Severance Hospital, Yonsei University
    • Contact: Byoung Chul Cho
  • Seoul, South Korea
    • Recruiting
    • Asan Medical Center, University of Ulsan
    • Principal Investigator: Sang-We Kim
    • Contact: Sang-We Kim
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Recruiting
      • Seoul National University Bundang Hospital
      • Contact: Keun-Wook Lee
    • Suwon, Gyeonggi-do, South Korea, 16247
      • Recruiting
      • The Catholic Univ. of Korea St. Vincent's Hospital
      • Contact: Byoung Yong Shim
  • North Chungcheong
    • Cheongju-si, North Chungcheong, South Korea, 28644
      • Recruiting
      • Chungbuk National University Hospital
      • Principal Investigator: Ki-Hyeong Lee
      • Contact: Ki-Hyeong Lee
• United States
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • NEXT Oncology Virginia
      • Contact: Alexander I. Spira

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ECOG performance status 0 or 1
• Estimated life expectancy of at least 3 months
• Patients who have progressed on or after all available standard therapies or for whom standard treatment is inappropriate
• Mandatory provision of archived or fresh tumor tissue in quantity sufficient to allow for retrospective confirmation of HER2 or EGFR mutation
• A patient with a history of brain metastases must have had all lesions treated

• Adequate organ function defined as all of the following:

  • Adequate bone marrow function (within 1 week prior to first administration): Neutrophils≥1.5 x10*9 cells/L (Criteria must be met without the use of Granulocyte-Colony Stimulating Factor (G-CSF) within last week prior to testing.); platelet count≥75 x10*9 cells/L; Hb ≥9g/dL (Criteria must be met without packed red blood cell (pRBC) transfusion within last week prior to testing.)
  • Adequate hepatic function: Serum bilirubin≤1.5 x upper limit of normal (ULN), and serum transaminase (either aspartate transaminase (AST) or alanine transaminase (ALT)) ≤ 3 x ULN if no demonstrable liver metastases, or otherwise ≤ 5 x ULN if transaminase elevation is attributable to liver metastases (within 1 week prior to first administration)
  • Adequate renal function: Serum creatinine ≤ 1.5 x ULN or Estimated glomerular filtration rate (eGFR) > 60 mL/min per 1.73 m*2 according to the site's calculation method.

[Dose Escalation part only]

• Histologically or cytologically confirmed diagnosis of advanced, and/or metastatic non-hematologic malignancy
• Documented HER2 or EGFR mutation (HER2 mutation or EGFR exon 20 insertion, HER2 amplification or overexpression)

[Dose Expansion part only]

• Patients with histologically or cytologically confirmed locally advanced or metastatic NSCLC HER2 exon 20 insertion (Cohort 1)

Exclusion Criteria:

• Patient with symptomatic or progressive brain metastases
• Known or suspected leptomeningeal disease (LMD)
• Uncontrolled spinal cord compression
• History of acute coronary syndromes, including myocardial infarction, coronary artery bypass graft, unstable angina, coronary angioplasty or stenting within past 24 weeks
• History of or current Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
• Medical, psychiatric, cognitive or other conditions that compromise the patients ability to understand the patient information, to give informed consent, to comply with the study protocol or to complete the study
• Any severe concurrent disease or condition (includes active infections, cardiac arrhythmia) that in the judgment of the Investigator would make study participation inappropriate for the patient
• History of (non-infectious) interstitial lung disease (ILD) or pneumonitis that required steroids, or any evidence of current ILD or pneumonitis

• History of a second primary cancer with the exception of

  1. curatively treated non-melanomatous skin cancer,
  2. curatively treated cervical or breast carcinoma in situ, or
  3. other malignancy with no known active disease present and no treatment administered during the last 2 years
• Infection with human immunodeficiency virus (HIV) or prior hepatitis B or active chronic hepatitis B or active hepatitis C
• Major surgery within 4 weeks prior to the first dose of study treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 and Part 2; Part 1: Dose escalation arm to determine the MTD Part 2: Dose expansion part to select RD. Several independent cohorts are planned.	Drug: YH42946; YH42946

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Emergent Adverse Events(TEAE)s	To assess the safety and tolerability of YH42946	Through study completion, during the first 21 days of DLT evaluation period.
Objective Response Rate (ORR)	Anti-tumor activity according to RECIST v1.1	Through dose expansion part completion, approximately 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUClast	To characterize the pharmacokinetics (PK) of YH42946	Through study completion, approximately 12 months
AUCinf	To characterize the pharmacokinetics (PK) of YH42946	Through study completion, approximately 12 months
Cmax	To characterize the pharmacokinetics (PK) of YH42946	Through study completion, approximately 12 months
Tmax	To characterize the pharmacokinetics (PK) of YH42946	Through study completion, approximately 12 months
Objective Response Rate (ORR)	To assess the anti-tumor activity according to RECIST v1.1	Through study completion, approximately 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival(OS)	To assess the overall survival of YH42946	Through study completion, approximately 3.5 year

Collaborators and Investigators

• Sponsor: Yuhan Corporation
• Investigators: Study Director: Judith Ertle, MD, Yuhan Corporation

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2024
• Primary Completion (Estimated): March 15, 2028
• Study Completion (Estimated): July 29, 2028

Study Registration Dates

• First Submitted: September 23, 2024
• First Submitted That Met QC Criteria: September 26, 2024
• First Posted (Actual): September 27, 2024

Study Record Updates

• Last Update Posted (Estimated): November 4, 2025
• Last Update Submitted That Met QC Criteria: November 2, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: YH42946-101
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: YH42946-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified individual participant data (including data dictionaries) that underline the results reported in study-related publications will be made available during the period beginning 1 year and ending 5 years after all trial primary and secondary endpoints were assessed. Only requests from researchers who provide a methodologically sound proposal will be reviewed and approved by the sponsor. The analysis type should be in accordance with aims in the proposal approved by the sponsor. Proposals should be directed to clinicaltrials@yuhan.co.kr

A summary of the study results will be posted in the publicly accessible database (i.e. clinicaltrials.gov) no later than 1 year after the study's primary completion date.

• IPD Sharing Time Frame: Beginning 1 year and ending 5 years after all trial endpoints were assessed
• IPD Sharing Access Criteria: Only requests from researchers who provide a methodologically sound proposal will be reviewed and approved by the sponsor. The analysis type should be in accordance with aims in the proposal approved by the sponsor. Proposals should be directed to clinicaltrials@yuhan.co.kr
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No