Assessing an Oral EGFR Inhibitor,YK-209A in Patients Who Have Advanced Non-small Cell Lung Cancer With EGFR

Study Overview
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Brief Summary
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This study aimed to evaluate the safety and preliminary efficacy of YK-029A, a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in treated or untreated patients with advanced non-small cell lung cancer (NSCLC).

Detailed Description
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This phase 1/2 study will evaluate the safety, pharmacokinetics, and anti-tumor activity of oral EGFR Inhibitor YK-209A in participants with NSCLC and anti-tumor activity of YK-029A in participants with solid tumors other than NSCLC harboring ex20ins, T790M or rare mutations. The trial will be conducted in three parts: a dose escalation (Part 1), expansion phase (Part 2), followed by an extension phase (Part 3). The objectives of the dose escalation phase (Part 1), is to determine the safety profile of orally administered YK-029A, including the MTD, DLTs, RP2D, pharmacokinetic profile. The primary goal of the expansion component of the trial is to evaluate the anti-tumor activity of YK-029A in nine histologically and molecularly defined cohorts at the RP2D (determined based on dose escalation phase of the trial).

Official Title
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Safety and Preliminary Efficacy of YK-029A, a Novel EGFR TKI, in Patients With Advanced NSCLC Harboring ex20ins, T790M or Rare Mutations

Conditions
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Treatment, Treatment Side Effects

Intervention / Treatment
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* Drug: YK-029A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General Inclusion Criteria all cohorts: dose escalation, dose expansion, and dose extension: Have histologically or cytologically confirmed locally advanced or metastatic NSCLC disease (Stage IIIB or IV) . Male or femal adult，be able to provide a signed and dated, written informed consent. Must have measurable disease by response evaluation criteria in solid tumors (RECIST) v1.1. Minimum life expectancy of 3 months or more. Adequate organ function at baseline. Normal QT interval on screening electrocardiogram (ECG), defined as QT interval corrected (Fridericia) (QTcF) of less than or equal to (≤ ) 450 millisecond (ms) in males or ≤ 470 ms in females. Part 1: Dose Escalation Cohort Specific Inclusion Criteria: Refractory to standard available therapies. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. aged 18-65 years old. previously treated NSCLC patients with EGFR T790M. Part 2: Expansion Cohort 1、2、3 Specific Inclusion Criteria: previously treated NSCLC patients with EGFR T790M. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. aged 18-75 years old. Part 2: Expansion Cohort 4、5 Specific Inclusion Criteria: previously treated NSCLC patients with EGFR exton 20ins. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. aged 18-75 years old. Part 3: Expansion Cohort 6 Specific Inclusion Criteria: previously untreated NSCLC patients with EGFR exton 20ins. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. aged 18-75 years old. Part 3: Expansion Cohort 7、8 Specific Inclusion Criteria: previously treated NSCLC patients with EGFR rare mutation(（G719X、L861Q、S768I). Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. aged 18-75 years old. Part 3: Expansion Cohort9 Specific Inclusion Criteria: previously treated NSCLC patients with EGFR exton 20ins. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. aged 18-75 years old. Exclusion Criteria: Any cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days before screening. Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose or with a wide field of radiation which must be completed within 4 weeks before screening. NSCLC patients with EGFR T790M mutation previously treated with third-generation EGFR-TKIs (such as AZD9291, CO-1686, HM61713, EGF816, PF-06747775, vometinib, BPI-15086, Ivirtinib maleate, etc.) and their apis or the same drugs in other clinical trials Drug treatment. Patients with NSCLC with EGFR ex20ins mutation had previously received EGFR ex20ins inhibitors and/or EGFR-cMET double antibodies (including but not limited to TAK-788, bociotinib, JNJ-61186372, DZD9008, vometinib, PLB1004, and AZD9291 in excess of the clinically approved dose (cohort 9 prohibited AZD9291 at any dose) and Drug substance or other similar drug treatment in the clinical trial stage. NSCLC patients with rare EGFR mutations have previously been treated with third-generation EGFR-Tkis (such as AZD9291, etc.) and their apis or other similar drugs in clinical trials. Received a moderate or strong CYP4503A inhibitor or moderate or strong CYP3A inducer within 10 days prior to first dose of YK-029A. Have significant, uncontrolled, or active cardiovascular disease. Have a known history of uncontrolled hypertension. Participants with hypertension should be under treatment on study entry to control blood pressure. Have prolonged QTcF interval, or being treated with medications known to be associated with the development of torsades de pointes. Have an ongoing or active infection, including but not limited to, the requirement for intravenous (IV) antibiotics, or a known history of human immunodeficiency virus, hepatitis B virus (HBV), or hepatitis C virus (HCV). Testing is not required in the absence of history. Currently have or have a history of interstitial lung disease, radiation pneumonitis that required steroid treatment, or drug-related pneumonitis. Female participants who are lactating and breastfeeding or have a positive urine or serum pregnancy test during the screening period. Note: Female participants who are lactating will be eligible if they discontinue breastfeeding. Have gastrointestinal illness or disorder that could affect oral absorption of YK-029A. Have any condition or illness that, in the opinion of the investigator, might compromise participant safety or interfere with the evaluation of the safety of the drug. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation Component<br>In dose-escalation phase, previously treated patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50, 100, 150, 200 to 250 mg/day (3+3 design). | Drug: YK-029A<br>* Daily dose of YK-029A<br>|
| Experimental: Part 2: Expansion Cohort 1<br>In dose-escalation phase, previously treated patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50mg/day and who have no active, measurable central nervous system (CNS) metastases. | Drug: YK-029A<br>* Daily dose of YK-029A<br>|
| Experimental: Part 2: Expansion Cohort 2<br>In dose-escalation phase, previously treated patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 100mg/day and who have no active, measurable central nervous system (CNS) metastases. | Drug: YK-029A<br>* Daily dose of YK-029A<br>|
| Experimental: Part 2: Expansion Cohort 3<br>In dose-escalation phase, previously treated patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 150mg/day and who have no active, measurable central nervous system (CNS) metastases. | Drug: YK-029A<br>* Daily dose of YK-029A<br>|
| Experimental: Part 3: ExTension Cohort 4<br>In dose-extension phase, previously treated patients with EGFR exon 20ins mutation were enrolled. YK-029A was given at doses of 150mg/day and who have no active, measurable central nervous system (CNS) metastases. | Drug: YK-029A<br>* Daily dose of YK-029A<br>|
| Experimental: Part 3: ExTension Cohort 5<br>In dose-extension phase, previously treated patients with EGFR exon 20ins mutation were enrolled. YK-029A was given at doses of 200mg/day and who have no active, measurable central nervous system (CNS) metastases. | Drug: YK-029A<br>* Daily dose of YK-029A<br>|
| Experimental: Part 3: ExTension Cohort 6<br>In dose-extension phase, previously untreated patients with EGFR exon 20ins mutation were enrolled. YK-029A was given at doses of 200mg/day and who have no active, measurable central nervous system (CNS) metastases. | Drug: YK-029A<br>* Daily dose of YK-029A<br>|
| Experimental: Part 3: ExTension Cohort 7<br>In dose-extension phase, previously treated patients with EGFR rare mutation （G719X、L861Q、S768I etal.)were enrolled. YK-029A was given at doses of 150mg/day and who have no active, measurable central nervous system (CNS) metastases. | Drug: YK-029A<br>* Daily dose of YK-029A<br>|
| Experimental: Part 3: ExTension Cohort 8<br>In dose-extension phase, previously treated patients with EGFR rare mutation （G719X、L861Q、S768I etal.)were enrolled. YK-029A was given at doses of 200mg/day and who have no active, measurable central nervous system (CNS) metastases. | Drug: YK-029A<br>* Daily dose of YK-029A<br>|
| Experimental: Part 3: ExTension Cohort 9<br>In dose-extension phase, previously untreated patients with EGFR exon 20ins mutation were enrolled. YK-029A was given at doses of 150mgBID and who have no active, measurable central nervous system (CNS) metastases. | Drug: YK-029A<br>* Daily dose of YK-029A<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants that Experience Adverse Events (AEs) and Serious Adverse Events (SAEs) . | To investigate the safety and tolerability of YK-029A when given orally to patients with advanced NSCLC with EGFR T790M. | Cycle 1 (Cycle length is equal to [=] 28 days) | 
| Part 1: Number of Participants with Clinically Significant Abnormal Laboratory Values. | To investigate the safety and tolerability of YK-029A when given orally to patients with advanced NSCLC with EGFR T790M. | Cycle 1 (Cycle length is equal to [=] 28 days) | 
| Part 1: Number of Participants with First Cycle Dose-Limiting Toxicities (DLTs). | To establish Maximum Tolerated Dose (MTD) (if possible) and Recommended Phase 2 Dose (PR2D) of YK-029A when given orally in patients with advanced NSCLC with EGFR T790M mutations. | Cycle 1 (Cycle length is equal to [=] 28 days) | 
| Part 1: DLTs of Orally Administered YK-029A. | Toxicity will be Evaluated According to the NCI CTCAE, Version 5.00. DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications. | Cycle 1 (Cycle length is equal to [=] 28 days) | 
| Part 1: Number of Participants with First Cycle Dose-Limiting Toxicities (DLTs). | Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.00. DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications. | Cycle 1 (Cycle length is equal to [=] 28 days) | 
| Part 1: Maximum Tolerated Dose (MTD) of Orally Administered YK-029A | The MTD is the highest dose level at which the participant tolerates treatment without dose-limiting toxicities. | Cycle 1 (Cycle length is equal to [=] 28 days) | 
| Part 2: Objective Response Rate (ORR) according to RECIST 1.1 by IRC | Expansion Cohorts 1、2、3 : Confirmed Objective Response Rate (ORR) Assessed by the Independent Review Committee (IRC) | Up to 36 months after first dose | 
| Part 3: Objective Response Rate (ORR) according to RECIST 1.1 by IRC | xpansion Cohorts 4、5、6、7、8、9 : Confirmed Objective Response Rate (ORR) Assessed by the Independent Review Committee (IRC) | Up to 36 months after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1:Cmax: Maximum Plasma Concentration for YK-029A and its Active Metabolites after a Single Oral Dose. |  | Up to 24 hours; Pre-dose and multiple time points post-dose on Cycle 1 Day 1 (C1D1) | 
| Part1:Tmax: Time to Cmax for YK-029A and its Active Metabolites after a Single Oral Dose. |  | Up to 24 hours; Pre-dose and multiple time points post-dose on C1D1 | 
| Part1:AUC24: Area Under the Plasma Concentration-Time Curve from Time 0 to 24 hours for YK-029A and its Active Metabolites after a Single Oral Dose |  | Up to 24 hours; Pre-dose and multiple time points post-dose on C1D1 | 
| Part1:AUClast: Area Under the Plasma Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for YK-029A and its Active Metabolites after a Single Oral Dose. |  | Up to 24 hours; Pre-dose and multiple time points post-dose on C1D1 | 
| Part1:Cmax, ss: Maximum Plasma Concentration for YK-029A and its Active Metabolites at Steady State after Multiple Oral Doses. |  | Up to approximately 168 days; Pre-dose and multiple time points post-dose. | 
| Part1:Tmax, ss: Time to Cmax for YK-029A and its Active Metabolites at Steady State after Multiple Oral Doses. |  | Up to approximately 168 days; Pre-dose and multiple time points post-dose. | 
| AUC24, ss: Area Under the Plasma Concentration-Time Curve from Time 0 to 24 hours for YK-029A and its Active Metabolites at Steady State after Multiple Oral Doses. |  | Up to approximately 168 days; Pre-dose and multiple time points post-dose. | 
| Part2、3：Overall Response Rate (ORR) as Assessed by the investigator. |  | Up to 36 months after first dose. | 
| Part2、3：Duration of Response (DOR) | Duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that PD is objectively documented. | Up to 36 months after first dose. | 
| Part2、3：Disease Control Rate (DCR) | DCR is defined as the percentage of participants who have achieved CR, PR, or stable disease (SD) (in the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 42 days) after the initiation of study drug. | Up to 36 months after first dose. | 
| Part2、3：Progression Free Survival (PFS) | PFS is defined as the time interval from the date of randomization until the first date at which the criteria for progressive disease (PD) according to RECIST version 1.1 are met or death, whichever occurs first. | Up to 36 months after first dose. | 
| Part2、3：Overall Survival (OS) | OS is defined as the interval from the date of randomization until death. OS is defined as the interval from the date of randomization until death. OS is defined as the interval from the date of randomization until death. | Up to 36 months after first dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC