Clinical Trial of YH25448 in Patients with EGFR Mutation Positive Advanced NSCLC

YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. YH25448 is expected to beneficial for the NSCLC patients with brain metastasis due to good blood brain barrier (BBB) penetration property as well as for the treatment of primary lung lesion and extracranial lesions. This study will be conducted to evaluate the safety, tolerability and efficacy of YH25448 in locally advanced or metastatic NSCLC patients with EGFR mutations.

This is a first time in patient study primarily designed to evaluate the safety, tolerability, and efficacy of YH25448 in in patients with EGFR mutation positive (EGFRm+) advanced NSCLC with or without asymptomatic brain metastasis who progressed following prior therapy with an EGFR TKIs agent. This study is composed of 3 parts; part A is a dose escalation phase, part B is a dose expansion phase and part C is a dose extension phase.

In dose escalation phase, YH25448 will be escalated to reach either a maximum tolerated or absorbable dose in patients as defined by dose-limiting toxicity in NSCLC patients who progressed following prior EGFR TKIs treatment to evaluate the safety and tolerability. In dose expansion phase, further safety, tolerability, pharmacokinetic(PK) and efficacy will be evaluated at each dose level(s) of dose escalation phase in NSCLC patients who progressed following prior EGFR TKIs treatment and harbouring confirmed T790M mutation. In dose extension phase, additional 2 cohorts (2nd line therapy cohort, 1st line therapy cohort) will be enrolled to further assess the efficacy, safety, tolerability, and PK of YH25448 at the maximum tolerated dose (MTD) or recommended dose (RD) defined through dose escalation phase and dose expansion phase. Results of these studies will serve as the evidence for further clinical development.

This study will also characterize the metabolite(s) profile of YH25448 and determine PK of its metabolite(s) in biological samples if necessary. Also, exploratory correlation between biomarker profiles and pharmacokinetics/pharmacodynamics will be analyzed.

Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 3 months.
* At least one measurable extracranial lesion, not previously irradiated and not chosen biopsy during the study screening period.
* Prior to enrolling in the study, patients must have central confirmation of T790M+ mutation status from a sample taken after documented progression on the EGFR-TKIs therapy according to cohort.

Exclusion Criteria:

* Spinal cord compression.
* Brain metastases with symptomatic and/or requiring steroid for at least 2 weeks prior to start of study treatment.
* Known intracranial hemorrhage which is unrelated to tumor.
* Central Nervous System (CNS) complications that require urgent neurosurgical intervention (e.g. resection or shunt placement).
* Leptomeningeal metastasis prior to study treatment.
* Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
* Any cardiovascular disease as followed.

  * History of symptomatic congestive heart failure (CHF) or serious cardiac arrhythmia requiring treatment
  * History of myocardial infarction or unstable angina within 6 months of the first dose of study treatment
  * Left ventricular ejection fraction (LVEF) \< 50%