A Study of VRN110755 in Patients With EGFR-Mutant Non-Small Cell Lung Cancer

Официальное название

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)

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат VRN110755
  VRN110755 is an investigational highly selective oral EGFR inhibitor supplied as capsules for oral administration. The drug is designed to target activating EGFR mutations and selected resistance mutations, including C797S, in patients with EGFR-mutant NSCLC.

Первичные конечные точки

• Estimate of Maximum Tolerated Dose (MTD) of VRN110755 [Срок оценки: 28 days]
• Number of participants with dose-limiting toxicities (DLTs) following treatment with VRN110755 [Срок оценки: 28 days]
• Number of participants experiencing treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events leading to discontinuation [Срок оценки: 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 [Срок оценки: From baseline through End of Treatment (up to approximately 6 years)]
• Number of participants with changes in laboratory test results from baseline following treatment with VRN110755 [Срок оценки: From baseline through End of Treatment (up to approximately 6 years)]
• Number of participants with changes in physical examination findings from baseline following treatment with VRN110755 [Срок оценки: From baseline through End of Treatment (up to approximately 6 years)]
• Number of participants with changes in ophthalmologic examination findings from baseline following treatment with VRN110755 [Срок оценки: From baseline through End of Treatment (up to approximately 6 years)]
• Number of participants with changes in electrocardiogram (ECG) parameters from baseline following treatment with VRN110755 [Срок оценки: From baseline through End of Treatment (up to approximately 6 years)]
• Number of participants with changes in Eastern Cooperative Oncology Group (ECOG) Performance Status from baseline following treatment with VRN110755 [Срок оценки: From baseline through End of Treatment (up to approximately 6 years)]

Вторичные конечные точки (12)

• Plasma PK of VRN110755 - Maximum Plasma Concentration (Cmax) [Срок оценки: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.]
• Plasma PK of VRN110755 - Minimum Plasma Concentration (Cmin) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.]
• Plasma PK of VRN110755 - Time to Maximum Plasma Concentration (Tmax) [Срок оценки: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.]
• Plasma PK of VRN110755 - Terminal Elimination Rate Constant (λz) [Срок оценки: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.]
• Plasma PK of VRN110755 - Apparent Terminal Elimination Half-life (t½) [Срок оценки: 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) [Срок оценки: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.]
• Plasma PK of VRN110755 - Apparent Total Plasma Clearance (CL/F) [Срок оценки: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.]
• Plasma PK of VRN110755 - Trough Plasma Concentration (Ctrough) [Срок оценки: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.]
• Plasma PK of VRN110755 - Mean Residence Time Based on AUClast (MRTlast) [Срок оценки: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.]
• Plasma PK of VRN110755 - Accumulation Ratio (Rac) [Срок оценки: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.]

Критерии участия

Критерии включения

• 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 1.1.
• Documented EGFR mutation determined by tumor tissue or liquid biopsy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• 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:

• Phase 1a

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

South Korea · 5 центров

• Seoul National University Bundang Hospital — Seongnam-si
• The Catholic University of Korea, St. Vincent's Hospital — Suwon
• Chungbuk National University Hospital — Cheongju-si
• Severance Hospital Yonsei University Health System — Seoul
• Samsung Medical Center — Seoul

Тайвань · 5 центров

• Kaohsiung Medical University Chung-Ho Memorial Hospital — Kaohsiung City
• Taichung Veterans General Hospital — Taichung
• National Taiwan University Hospital — Taipei
• Taipei Medical University Hospital — Taipei
• Taipei Veterans General Hospital — Taipei

Малайзия · 4 центра

• Hospital Umum Sarawak — Kuching
• Hospital Kuala Lumpur — Kuala Lumpur
• University Malaya Medical Centre — Kuala Lumpur
• Institut Kanser Negara — Putrajaya

Испания · 4 центра

• ICO Badalona - Hospital Universitari Germans Trias i Pujol — Badalona
• ICO l'Hospitalet - Hospital Duran i Reynals — L'Hospitalet de Llobregat
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Regional Universitario de Málaga - Hospital Civil — Málaga

Австралия · 2 центра

• Southern Oncology Clinical Research Unit — Bedford Park
• Monash Medical Centre Clayton — Clayton

Франция · 2 центра

• AP-HM Hôpital Nord — Marseille
• Centre Georges François Leclerc — Dijon

Гонконг · 2 центра

• Prince of Wales Hospital — Гонконг
• Queen Mary Hospital — Гонконг

Сингапур · 2 центра

• National Cancer Centre Singapore — Singapore
• Tan Tock Seng Hospital — Singapore

Таиланд · 2 центра

• Phramongkutklao Hospital — Thung Phaya Thai
• Songklanagarind Hospital Prince of Songkla University — Hat Yai

Канада · 1 центр

• Princess Margaret Cancer Centre — Toronto

Идентификаторы

NCT: NCT07699328 · VRN110755_01 · 2025-523122-40-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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