a phase 1/2, open-label, multicenter, fih study to evaluate safety, tolerability, pk and anti-tumor activity of yh42946

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

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.

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

Keywords: yh42946-101