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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients With EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

Conditions
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EGFR Gene Mutation

Intervention / Treatment
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* Drug: YH25448


Participation Criteria
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Eligibility Criteria
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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%

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: YH25448<br>Dose Escalation Phase: Consists of 7 Cohorts Dose Expansion Phase: Consists of 5 Cohorts Dose Extension Phase: Consists of 2 Cohorts | Drug: YH25448<br>* Dose Escalation: YH25448 20mg 320mg, PO Dose Expansion: YH25448 40mg 240mg, PO Dose Extension: Recommended Dose 240mg of YH25448<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 | To assess the safety and tolerability profile of YH25448 by Common Terminology Criteria for Adverse Events (CTCAE) v4.03; vital signs (blood pressure, pulse, weight); laboratory parameters (clinical chemistry, hematology, urinalysis); physical examination; centrally reviewed electrocardiograms (ECGs), echocardiogram or multiple gated acquisition scan and performance status. | Safety and tolerability profile will be collected from baseline until 28 days after the last dose, expected average 1 year. | 
| Objective Response Rate (ORR) | Per Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of Complete Response (CR) or Partial Response (PR) (according to independent review), prior to progression or further anti-cancer therapy. | At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DoR) | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT. | At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year. | 
| Disease Control Rate (DCR) | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT. | At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year. | 
| Progression-Free Survival (PFS) | Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT. Kaplan-Meier plots will be used to summarize the progression-free survival. | At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year. | 
| Overall Survival (OS) | To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1. | At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year. | 
| Tumor shrinkage | To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1. | At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year. | 
| Objective Intracranial Response Rate (OIRR) | To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1. | At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year. | 
| Duration of Intracranial Response (DoIR) | To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1. | At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year. | 
| Intracranial Progression Free Survival (IPFS). | To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1. Kaplan-Meier plots will be used to summarize the progression-free survival. | At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR, Non-Small Cell Lung Cancer, T790M, Brain Metastasis