Clinical trial NCT06616766: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: NSCLC (Non-small Cell Lung Cancer)
Solid Tumor
Keywords: YH42946-101
Lead sponsor: Yuhan Corporation
Sponsor class: INDUSTRY
First posted: 2024-09-27
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

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

  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

Primary outcomes:
measure: Treatment Emergent Adverse Events(TEAE)s
timeFrame: Through study completion, during the first 21 days of DLT evaluation period.
measure: Objective Response Rate (ORR)
timeFrame: Through dose expansion part completion, approximately 12 months
Secondary outcomes:
measure: AUClast
timeFrame: Through study completion, approximately 12 months
measure: AUCinf
timeFrame: Through study completion, approximately 12 months
measure: Cmax
timeFrame: Through study completion, approximately 12 months
measure: Tmax
timeFrame: Through study completion, approximately 12 months
measure: Objective Response Rate (ORR)
timeFrame: Through study completion, approximately 12 months
Other outcomes:
measure: Overall survival(OS)
timeFrame: Through study completion, approximately 3.5 year
Locations:
city: Fairfax
country: United States
facility: Next Oncology Virginia
state: Virginia
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheongbuk-do
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Suwon-si
country: Korea, Republic of
facility: The Catholic Univ. of Korea St. Vincent's Hospital
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center, University of Ulsan
Study officials:
affiliation: Yuhan Corporation
name: Jeongmin Kim
role: STUDY_DIRECTOR
References: