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

Official title

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

Overview

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.

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.

Interventions

• Drug YH42946
  YH42946

Primary outcome measures

• Treatment Emergent Adverse Events(TEAE)s [Time frame: Through study completion, during the first 21 days of DLT evaluation period.]
• Objective Response Rate (ORR) [Time frame: Through dose expansion part completion, approximately 12 months]

Secondary outcome measures (5)

• AUClast [Time frame: Through study completion, approximately 12 months]
• AUCinf [Time frame: Through study completion, approximately 12 months]
• Cmax [Time frame: Through study completion, approximately 12 months]
• Tmax [Time frame: Through study completion, approximately 12 months]
• Objective Response Rate (ORR) [Time frame: Through study completion, approximately 12 months]

Eligibility criteria

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

• curatively treated non-melanomatous skin cancer,
• curatively treated cervical or breast carcinoma in situ, or
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

South Korea · 7 centers

• Seoul National University Bundang Hospital — Seongnam-si
• The Catholic Univ. of Korea St. Vincent's Hospital — Suwon
• Chungbuk National University Hospital — Cheongju-si
• Seoul National University Hospital — Seoul
• Severance Hospital, Yonsei University — Seoul
• Samsung Medical Center — Seoul
• Asan Medical Center, University of Ulsan — Seoul

United States · 1 center

• Next Oncology Virginia — Fairfax

Identifiers

NCT: NCT06616766 · YH42946-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗