EGFR-Mutant Non-Small Cell Lung Cancer
Conditions
Keywords
NSCLC, EGFR, Epidermal Growth Factor Receptor, Non-Small Cell Lung Cancer, EGFR Mutation, C797S, EGFR Tyrosine Kinase Inhibitor Resistance
Brief summary
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.
Detailed description
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.
Interventions
DRUGVRN110755
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.
Sponsors
Voronoi, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will enroll sequentially into Phase 1a dose-escalation cohorts followed by Phase 1b dose-expansion cohorts and Phase 2 cohorts.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimate of Maximum Tolerated Dose (MTD) of VRN110755 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | From baseline through End of Treatment (up to approximately 6 years) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma PK of VRN110755 - Maximum Plasma Concentration (Cmax) | Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days. | Maximum observed plasma concentration of VRN110755. |
| Plasma PK of VRN110755 - Minimum Plasma Concentration (Cmin) | Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days. | Minimum observed plasma concentration of VRN110755. |
| 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. | Area under the plasma concentration-time curve from time zero to the last measurable concentration of VRN110755. |
| 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. | Area under the plasma concentration-time curve over the dosing interval at steady state for VRN110755. |
| Plasma PK of VRN110755 - Time to Maximum Plasma Concentration (Tmax) | Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days. | Time from dosing to the maximum observed plasma concentration of VRN110755. |
| Plasma PK of VRN110755 - Terminal Elimination Rate Constant (λz) | Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days. | Terminal elimination rate constant of VRN110755 estimated from the terminal log-linear portion of the plasma concentration-time curve. |
| Plasma PK of VRN110755 - Apparent Terminal Elimination Half-life (t½) | Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days. | Apparent terminal elimination half-life of VRN110755 estimated from the terminal elimination phase of the plasma concentration-time curve. |
| 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. | Apparent volume of distribution during the terminal elimination phase of VRN110755 following oral administration. |
| Plasma PK of VRN110755 - Apparent Total Plasma Clearance (CL/F) | Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days. | Apparent total plasma clearance of VRN110755 following oral administration. |
| Plasma PK of VRN110755 - Trough Plasma Concentration (Ctrough) | Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days. | Plasma concentration of VRN110755 immediately before the next scheduled dose at steady state. |
| Plasma PK of VRN110755 - Mean Residence Time Based on AUClast (MRTlast) | Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days. | Mean residence time of VRN110755 in the body calculated based on AUClast. |
| Plasma PK of VRN110755 - Accumulation Ratio (Rac) | Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days. | Accumulation ratio of VRN110755 following repeated once-daily dosing, calculated using protocol-specified pharmacokinetic parameters. |
| 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) | Change from baseline in circulating tumor DNA (ctDNA) levels, including EGFR Del19, L858R, Del19/C797S, L858R/C797S, C797S, and other protocol-specified EGFR mutations. |
| Objective Response Rate (ORR) | From first dose until end of study (up to approximately 6 years) | The proportion of participants whose best overall response is a confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. |
| Duration of Response (DOR) | From first dose until end of study (up to approximately 6 years) | Duration of response (DOR), defined as the time from the first documented confirmed complete response or confirmed partial response until disease progression or death from any cause. |
| Number of participants with Disease Control Rate (DCR) | From first dose until end of study (up to approximately 6 years) | Disease control rate (DCR), defined as the proportion of participants achieving confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) according to RECIST Version 1.1. |
| Progression-Free Survival (PFS) | From first dose until end of study (up to approximately 6 years) | Progression-free survival (PFS), defined as the time from the first dose of study treatment until documented disease progression or death from any cause. |
| Overall Survival (OS) | From first dose until end of study (up to approximately 6 years) | Overall survival (OS), defined as the time from the first dose of study treatment until death from any cause. |
| Intracranial Objective Response Rate (Intracranial ORR) | From first dose until end of study (up to approximately 6 years) | The proportion of participants with brain metastases who achieve a confirmed intracranial complete response or partial response according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. |
| Intracranial Progression-Free Survival (Intracranial PFS) | From first dose until end of study (up to approximately 6 years) | Intracranial progression-free survival assessed according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria in participants with brain metastases. |
Countries
Australia, Canada, France, Hong Kong, Malaysia, Singapore, South Korea, Spain, Taiwan, Thailand
Contacts
CONTACTSomi Lee
STUDY_DIRECTORHongryul Jung, PhD
Voronoi, Inc
Outcome results
None listed