A Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of VRN110755 in Patients With Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer (NSCLC)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 315
- 试验地点
- 29
- 主要终点
- Estimate of Maximum Tolerated Dose (MTD) of VRN110755
研究概览
简要总结
This first-in-human, Phase 1/2, multicenter, open-label, non-randomized study evaluates the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of VRN110755, a highly selective oral epidermal growth factor receptor (EGFR) inhibitor, in patients with EGFR-mutant non-small cell lung cancer (NSCLC).
The study includes a Phase 1a dose-escalation portion, a Phase 1b dose-expansion portion, and a Phase 2 evaluation. The study is designed to determine the maximum tolerated dose and recommended Phase 2 dose of VRN110755 and to evaluate preliminary and confirmatory antitumor activity in patients with EGFR-mutant NSCLC, including patients with acquired resistance following EGFR tyrosine kinase inhibitor therapy.
详细描述
This is a Phase 1/2, multicenter, open-label, non-randomized, dose-escalation and dose-expansion clinical trial evaluating VRN110755 administered as oral monotherapy once daily in 28-day treatment cycles.
Phase 1a uses a standard 3+3 dose-escalation design to evaluate safety, tolerability, dose-limiting toxicities, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity and to determine the maximum tolerated dose (MTD).
Phase 1b evaluates safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity across molecularly defined EGFR-mutant NSCLC cohorts and determines the recommended Phase 2 dose (RP2D).
Following determination of the RP2D, selected expansion cohorts will continue into the Phase 2 portion to further evaluate the efficacy, safety, tolerability, and pharmacokinetics of VRN110755. The specific Phase 2 cohorts will be selected based on the safety and efficacy data generated during Phase 1b.
Participants remain on treatment until disease progression, unacceptable toxicity, withdrawal of consent, initiation of another anticancer therapy, death, or study completion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults aged 18 years or older (19 years or older in the Republic of Korea).
- •Able to understand, sign, and provide written informed consent.
- •Histologically or cytologically confirmed advanced, metastatic, or recurrent predominantly nonsquamous non-small cell lung cancer (NSCLC) with a documented epidermal growth factor receptor (EGFR) mutation.
- •At least one measurable extracranial lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.
- •Documented EGFR mutation determined by tumor tissue or liquid biopsy.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Able to swallow oral capsules and comply with study procedures.
- •Women of childbearing potential must have a negative pregnancy test, must not be breastfeeding, and must agree to use effective contraception during the study and for 7 months after the last safety follow-up visit. Men must agree to use effective contraception during the study and for 6 months after the last safety follow-up visit.
- •No appropriate standard treatment options are available or standard treatment is not considered feasible, in the opinion of the investigator.
- •Participants must meet the disease-specific eligibility criteria for one of the following study groups:
- •NSCLC with EGFR activating, resistant, uncommon, or complex mutations, including but not limited to exon 19 deletion (Del19), L858R, C797S, or other uncommon EGFR mutations.
- •Radiographic disease progression following at least 2 cycles of prior EGFR tyrosine kinase inhibitor (TKI) therapy or discontinuation of prior EGFR TKI therapy because of toxicity, with no remaining standard therapy expected to provide clinical benefit.
- •Phase 1b - Cohort A
- •NSCLC with EGFR exon 19 deletion or L858R mutation plus a C797X resistance mutation following disease progression after first-line treatment with a third-generation EGFR TKI (including osimertinib, lazertinib, or aumolertinib).
- •Phase 1b - Cohort B
- •Treatment-naïve NSCLC with common EGFR mutations.
- •Phase 1b - Cohort C
- •NSCLC with atypical or uncommon EGFR mutations (including G719X, L861Q, S768I, E709X, R776H, L747S, or combinations of these mutations) previously treated with at least one systemic therapy, including an EGFR TKI, with no remaining standard therapy expected to provide clinical benefit.
- •Phase 1b - Cohort D
- •Treatment-naïve NSCLC with atypical EGFR mutations.
排除标准
- •Received an investigational anticancer therapy within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment.
- •Unresolved side effects from previous anticancer therapy greater than Grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), except for Grade 2 peripheral neuropathy or alopecia.
- •Pregnant or breastfeeding, or planning to become pregnant during the study.
- •NSCLC with an EGFR or HER2 exon 20 insertion mutation.
- •Another active malignancy within the past 3 years, with the exception of adequately treated cancers considered cured.
- •Inadequate bone marrow, kidney, or liver function based on protocol-defined laboratory criteria.
- •Active infection requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days before the first dose of study treatment.
- •Active hepatitis B or hepatitis C infection, or known human immunodeficiency virus (HIV) infection.
- •Receipt of a live vaccine within 4 weeks before the first dose of study treatment.
- •Use of strong or moderate cytochrome P450 (CYP) 3A inhibitors or inducers, certain herbal supplements, or other prohibited medications within the protocol-defined washout period.
- •Major surgery within 4 weeks before the first dose of study treatment or incomplete recovery from major surgery.
- •Receipt of prior anticancer therapy within the protocol-defined washout period, including systemic therapy, immunotherapy, or radiotherapy.
- •Symptomatic or uncontrolled central nervous system (CNS) metastases or spinal cord compression requiring increasing doses of corticosteroids. Participants with treated and stable CNS metastases or asymptomatic CNS disease may be eligible.
- •Requirement for systemic corticosteroid therapy exceeding the protocol-defined limit.
- •Clinically significant cardiovascular disease, including prolonged QT interval, clinically significant arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, uncontrolled hypertension, reduced left ventricular ejection fraction, or use of medications known to prolong the QT interval.
- •History of interstitial lung disease, noninfectious pneumonitis requiring steroid treatment, or current interstitial lung disease or pneumonitis.
- •Inability to swallow oral capsules or gastrointestinal disorders that may interfere with absorption of study treatment.
- •Known allergy or hypersensitivity to VRN110755 or any of its components.
- •Alcohol or drug abuse within the previous 2 years or any medical, psychological, or social condition that, in the opinion of the investigator, would interfere with study participation or interpretation of study results.
- •Use of proton pump inhibitors, histamine-2 receptor antagonists, or locally acting antacids within the protocol-defined washout period or inability to comply with protocol requirements for acid-reducing medications.
- •For Phase 1b and Phase 2 only: Presence of another targetable oncogenic driver alteration with an approved targeted therapy, including MET or HER2 amplification; ALK, ROS1, NTRK, or RET fusion; or BRAF V600E or KRAS G12X mutation.
研究组 & 干预措施
Phase 1a Dose Escalation
Participants with advanced, metastatic, or recurrent EGFR-mutant non-small cell lung cancer (NSCLC) who have experienced disease progression following prior EGFR tyrosine kinase inhibitor (TKI) therapy and harbor activating, resistant, uncommon, or complex EGFR mutations. Participants receive escalating dose levels of VRN110755 to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity and to determine the maximum tolerated dose (MTD).
干预措施: VRN110755 (Drug)
Phase 1b Cohort A
Participants with EGFR-mutant NSCLC harboring exon 19 deletion or exon 21 L858R mutations and a C797X resistance mutation following progression on first-line third-generation EGFR TKI therapy, including osimertinib, lazertinib, or aumolertinib. Participants receive VRN110755 to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity and to support selection of the recommended Phase 2 dose.
干预措施: VRN110755 (Drug)
Phase 1b Cohort B
Treatment-naïve participants with NSCLC harboring common EGFR mutations. Participants receive VRN110755 to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in patients who have not previously received systemic treatment for EGFR-mutant NSCLC.
干预措施: VRN110755 (Drug)
Phase 1b Cohort C
Participants with NSCLC harboring atypical or uncommon EGFR mutations, including G719X, L861Q, S768I, E709X, R776H, L747S, or combinations thereof, who have previously received at least one prior systemic therapy, including an EGFR TKI, and have no remaining standard treatment options expected to provide clinical benefit. Participants receive VRN110755 to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity.
干预措施: VRN110755 (Drug)
Phase 1b Cohort D
Treatment-naïve participants with NSCLC harboring atypical EGFR mutations. Participants receive VRN110755 to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in patients who have not previously received systemic treatment for EGFR-mutant NSCLC.
干预措施: VRN110755 (Drug)
结局指标
主要结局
Estimate of Maximum Tolerated Dose (MTD) of VRN110755
时间窗: 28 days
This will be based on dose-limiting toxicities (DLTs) observed during the DLT evaluation period.
Number of participants with dose-limiting toxicities (DLTs) following treatment with VRN110755
时间窗: 28 days
Dose-limiting toxicities will be assessed according to protocol-defined DLT criteria during the DLT evaluation period.
Number of participants experiencing treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events leading to discontinuation
时间窗: From first dose until end of study (up to approximately 6 years)
Number of participants with changes in vital signs from baseline following treatment with VRN110755
时间窗: From baseline through End of Treatment (up to approximately 6 years)
Vital signs include blood pressure, pulse rate, respiratory rate, body temperature, and oxygen saturation.
Number of participants with changes in laboratory test results from baseline following treatment with VRN110755
时间窗: From baseline through End of Treatment (up to approximately 6 years)
Laboratory evaluations include hematology, clinical chemistry, coagulation, and urinalysis assessments.
Number of participants with changes in physical examination findings from baseline following treatment with VRN110755
时间窗: From baseline through End of Treatment (up to approximately 6 years)
Physical examinations include complete physical examinations at screening and End of Treatment and symptom-directed physical examinations during study treatment.
Number of participants with changes in ophthalmologic examination findings from baseline following treatment with VRN110755
时间窗: From baseline through End of Treatment (up to approximately 6 years)
Ophthalmologic examinations include best corrected visual acuity, intraocular pressure, slit-lamp examination, spectral-domain optical coherence tomography (SD-OCT), confrontation visual fields, and fundoscopic examination.
Number of participants with changes in electrocardiogram (ECG) parameters from baseline following treatment with VRN110755
时间窗: From baseline through End of Treatment (up to approximately 6 years)
Electrocardiogram assessments include 12-lead ECG parameters, including QT interval corrected using Fridericia's formula (QTcF).
Number of participants with changes in Eastern Cooperative Oncology Group (ECOG) Performance Status from baseline following treatment with VRN110755
时间窗: From baseline through End of Treatment (up to approximately 6 years)
次要结局
- Plasma PK of VRN110755 - Maximum Plasma Concentration (Cmax)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Minimum Plasma Concentration (Cmin)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Area Under the Plasma Concentration-Time Curve Over the Dosing Interval (AUCτ)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Time to Maximum Plasma Concentration (Tmax)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Terminal Elimination Rate Constant (λz)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Apparent Terminal Elimination Half-life (t½)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Apparent Volume of Distribution During the Terminal Phase (Vz/F)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Apparent Total Plasma Clearance (CL/F)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Trough Plasma Concentration (Ctrough)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Mean Residence Time Based on AUClast (MRTlast)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Plasma PK of VRN110755 - Accumulation Ratio (Rac)(Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.)
- Change from Baseline in Circulating Tumor DNA (ctDNA)(Screening, Day 1 of protocol-specified treatment cycles (each cycle is 28 days) and End of Treatment (up to approximately 6 years))
- Objective Response Rate (ORR)(From first dose until end of study (up to approximately 6 years))
- Duration of Response (DOR)(From first dose until end of study (up to approximately 6 years))
- Number of participants with Disease Control Rate (DCR)(From first dose until end of study (up to approximately 6 years))
- Progression-Free Survival (PFS)(From first dose until end of study (up to approximately 6 years))
- Overall Survival (OS)(From first dose until end of study (up to approximately 6 years))
- Intracranial Objective Response Rate (Intracranial ORR)(From first dose until end of study (up to approximately 6 years))
- Intracranial Progression-Free Survival (Intracranial PFS)(From first dose until end of study (up to approximately 6 years))