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

Yuhan

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Solid Tumor; NSCLC (Non-small Cell Lung Cancer)

Treatments: Drug: YH42946

Study type: Interventional

Funder types: Industry

Identifiers

NCT06616766

YH42946-101

Details and patient eligibility

About

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.

Full 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.

Enrollment: 161 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Sequential Assignment

Masking: None (Open label)

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161 participants in 1 patient group

Part 1 and Part 2

Experimental group

Description:

Part 1: Dose escalation arm to determine the MTD Part 2: Dose expansion part to select RD. Several independent cohorts are planned.

Treatment:

Drug: YH42946