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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
315
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.
Southern Oncology Clinical Research Unit
Bedford Park, South Australia, Australia
RECRUITINGMonash Medical Centre Clayton
Clayton, Victoria, Australia
RECRUITINGPrincess Margaret Cancer Centre
Toronto, Ontario, Canada
RECRUITINGAP-HM Hôpital Nord
Marseille, Bouches-du-Rhône, France
Estimate of Maximum Tolerated Dose (MTD) of VRN110755
This will be based on dose-limiting toxicities (DLTs) observed during the DLT evaluation period.
Time frame: 28 days
Number of participants with dose-limiting toxicities (DLTs) following treatment with VRN110755
Dose-limiting toxicities will be assessed according to protocol-defined DLT criteria during the DLT evaluation period.
Time frame: 28 days
Number of participants experiencing treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events leading to discontinuation
Time frame: 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
Vital signs include blood pressure, pulse rate, respiratory rate, body temperature, and oxygen saturation.
Time frame: 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
Laboratory evaluations include hematology, clinical chemistry, coagulation, and urinalysis assessments.
Time frame: 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
Physical examinations include complete physical examinations at screening and End of Treatment and symptom-directed physical examinations during study treatment.
Time frame: 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
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.
Time frame: 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
Electrocardiogram assessments include 12-lead ECG parameters, including QT interval corrected using Fridericia's formula (QTcF).
Time frame: 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
Time frame: From baseline through End of Treatment (up to approximately 6 years)
Plasma PK of VRN110755 - Maximum Plasma Concentration (Cmax)
Maximum observed plasma concentration of VRN110755.
Time frame: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.
Plasma PK of VRN110755 - Minimum Plasma Concentration (Cmin)
Minimum observed plasma concentration of VRN110755.
Time frame: 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)
Area under the plasma concentration-time curve from time zero to the last measurable concentration of VRN110755.
Time frame: 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)
Area under the plasma concentration-time curve over the dosing interval at steady state for VRN110755.
Time frame: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.
Plasma PK of VRN110755 - Time to Maximum Plasma Concentration (Tmax)
Time from dosing to the maximum observed plasma concentration of VRN110755.
Time frame: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.
Plasma PK of VRN110755 - Terminal Elimination Rate Constant (λz)
Terminal elimination rate constant of VRN110755 estimated from the terminal log-linear portion of the plasma concentration-time curve.
Time frame: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.
Plasma PK of VRN110755 - Apparent Terminal Elimination Half-life (t½)
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Centre Georges François Leclerc
Dijon, Côte-d'Or, France
RECRUITINGPrince of Wales Hospital
Hong Kong, Hong Kong
RECRUITINGQueen Mary Hospital
Hong Kong, Hong Kong
RECRUITINGHospital Umum Sarawak
Kuching, Sarawak, Malaysia
RECRUITINGHospital Kuala Lumpur
Kuala Lumpur, Malaysia
RECRUITINGUniversity Malaya Medical Centre
Kuala Lumpur, Malaysia
RECRUITING...and 19 more locations
Apparent terminal elimination half-life of VRN110755 estimated from the terminal elimination phase of the plasma concentration-time curve.
Time frame: 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)
Apparent volume of distribution during the terminal elimination phase of VRN110755 following oral administration.
Time frame: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.
Plasma PK of VRN110755 - Apparent Total Plasma Clearance (CL/F)
Apparent total plasma clearance of VRN110755 following oral administration.
Time frame: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.
Plasma PK of VRN110755 - Trough Plasma Concentration (Ctrough)
Plasma concentration of VRN110755 immediately before the next scheduled dose at steady state.
Time frame: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.
Plasma PK of VRN110755 - Mean Residence Time Based on AUClast (MRTlast)
Mean residence time of VRN110755 in the body calculated based on AUClast.
Time frame: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.
Plasma PK of VRN110755 - Accumulation Ratio (Rac)
Accumulation ratio of VRN110755 following repeated once-daily dosing, calculated using protocol-specified pharmacokinetic parameters.
Time frame: Predose and up to 24 hours postdose on protocol-specified pharmacokinetic sampling days.
Change from Baseline in Circulating Tumor DNA (ctDNA)
Change from baseline in circulating tumor DNA (ctDNA) levels, including EGFR Del19, L858R, Del19/C797S, L858R/C797S, C797S, and other protocol-specified EGFR mutations.
Time frame: 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)
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.
Time frame: From first dose until end of study (up to approximately 6 years)
Duration of Response (DOR)
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.
Time frame: From first dose until end of study (up to approximately 6 years)
Number of participants with Disease Control Rate (DCR)
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.
Time frame: From first dose until end of study (up to approximately 6 years)
Progression-Free Survival (PFS)
Progression-free survival (PFS), defined as the time from the first dose of study treatment until documented disease progression or death from any cause.
Time frame: From first dose until end of study (up to approximately 6 years)
Overall Survival (OS)
Overall survival (OS), defined as the time from the first dose of study treatment until death from any cause.
Time frame: From first dose until end of study (up to approximately 6 years)
Intracranial Objective Response Rate (Intracranial ORR)
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.
Time frame: From first dose until end of study (up to approximately 6 years)
Intracranial Progression-Free Survival (Intracranial PFS)
Intracranial progression-free survival assessed according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria in participants with brain metastases.
Time frame: From first dose until end of study (up to approximately 6 years)