Clinical trial NCT03046992: Clinical Trial of YH25448 in Patients with EGFR Mutation Positive Advanced NSCLC
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: EGFR Gene Mutation
Keywords: EGFR
Non-Small Cell Lung Cancer
T790M
Brain Metastasis
Lead sponsor: Yuhan Corporation
Sponsor class: INDUSTRY
First posted: 2017-02-08
Enrollment: 224
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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%

Primary outcomes:
measure: Safety and tolerability by Common Terminology Criteria for Adverse Events (CTCAE) v4.03
timeFrame: Safety and tolerability profile will be collected from baseline until 28 days after the last dose, expected average 1 year.
measure: Objective Response Rate (ORR)
timeFrame: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
Secondary outcomes:
measure: Duration of Response (DoR)
timeFrame: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
measure: Disease Control Rate (DCR)
timeFrame: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
measure: Progression-Free Survival (PFS)
timeFrame: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
measure: Overall Survival (OS)
timeFrame: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
measure: Tumor shrinkage
timeFrame: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
measure: Objective Intracranial Response Rate (OIRR)
timeFrame: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
measure: Duration of Intracranial Response (DoIR)
timeFrame: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
measure: Intracranial Progression Free Survival (IPFS).
timeFrame: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.
Other outcomes:
Locations:
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheongbuk-do
city: Bucheon-si
country: Korea, Republic of
facility: The Catholic University of Korea, Bucheon St. Mary's Hospital
state: Gyeonggi-do
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggi-do
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
state: Gyeonggi-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 University of Korea, St. Vincent's Hospital
state: Gyeonggi-do
city: Jinju-si
country: Korea, Republic of
facility: Gyeongsang National University Hospital
state: Gyeongsangnam-do
city: Busan
country: Korea, Republic of
facility: Inje University Haeundae Paik Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Kangbuk Samsung Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: SMG-SNU Boramae Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
Study officials:
affiliation: Clinical Development Department
name: Yuhan Corporation
role: STUDY_DIRECTOR
References:
citation: Kim B, Lee J, Jang H, Lee N, Mehta J, Jang SB. Effects of Acid-Reducing Agents on the Pharmacokinetics of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. Adv Ther. 2022 Oct;39(10):4757-4771. doi: 10.1007/s12325-022-02286-z. Epub 2022 Aug 13.
citation: Cho BC, Han JY, Kim SW, Lee KH, Cho EK, Lee YG, Kim DW, Kim JH, Lee GW, Lee JS, Shim BY, Kim JS, Chun SH, Lee SS, Kim HR, Hong MH, Ahn JS, Sun JM, Lee Y, Lee DH, Kang JA, Lee N, Kwon MJ, Espenschied C, Yablonovitch A, Ahn MJ. A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors. J Thorac Oncol. 2022 Apr;17(4):558-567. doi: 10.1016/j.jtho.2021.11.025. Epub 2021 Dec 24.
citation: Ahn MJ, Han JY, Lee KH, Kim SW, Kim DW, Lee YG, Cho EK, Kim JH, Lee GW, Lee JS, Min YJ, Kim JS, Lee SS, Kim HR, Hong MH, Ahn JS, Sun JM, Kim HT, Lee DH, Kim S, Cho BC. Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1-2 study. Lancet Oncol. 2019 Dec;20(12):1681-1690. doi: 10.1016/S1470-2045(19)30504-2. Epub 2019 Oct 3.
citation: Yun J, Hong MH, Kim SY, Park CW, Kim S, Yun MR, Kang HN, Pyo KH, Lee SS, Koh JS, Song HJ, Kim DK, Lee YS, Oh SW, Choi S, Kim HR, Cho BC. YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2019 Apr 15;25(8):2575-2587. doi: 10.1158/1078-0432.CCR-18-2906. Epub 2019 Jan 22.