Phase III Study of TY-9591 in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLETEO)

Study Overview
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Brief Summary
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To assess the efficacy and safety of TY-9591 versus Osimertinib in patients with locally advanced or Metastatic Non Small Cell Lung Cancer.

Detailed Description
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This is a Phase III, double-blind, randomised study assessing the efficacy and safety of TY-9591 versus Osimertinib in patients with locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) that is known to be EGFR sensitising mutation (EGFRm) positive, treatment-naïve and eligible for first-line treatment with an EGFR-TKI.

Official Title
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A Phase III, Randomised, Double-blind, Multi-center Study to Assess the Efficacy and Safety of TY-9591 Tablets Versus Osimertinib as First Line Treatment in Patients With EGFR-sensitive Mutation, Locally Advanced or Metastatic Non Small Cell Lung Cancer.

Conditions
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NSCLC, EGFR Activating Mutation

Intervention / Treatment
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* Drug: TY-9591
* Drug: placebo Osimertinib
* Drug: Osimertinib
* Drug: placebo TY-9591


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged ≥18 years and <80 years. Locally advanced or metastatic NSCLC diagnosed by histology or cytology. Presence of an activating EGFR-sensitive mutations (including exon 19 deletions, L858R, the above mentioned mutations alone or co-existed with other EGFR-mutated sites). No prior systemic antitumor therapy for locally advanced or metastatic NSCLC. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. The ECOG score is 0-1, and there is no deterioration 2 weeks before the study, and the expected survival is not less than 3 months. Adequate bone marrow reserve function, and no liver, kidney and coagulation dysfunction. Male patients and female patients of reproductive age should take adequate contraceptive measures from signing informed consent to 3 months after the last study drug treatment; Women of childbearing age have negative pregnancy test results within 7 days of the first dose. Patients having recovered from all grade ≤ 1 toxicities related to previous anticancer therapies (CTCAE v 5.0) except for alopecia, platinum-therapy-related neuropathy (where ≤2 is allowed) before first dose of study treatment. Patients can understand and voluntarily sign the informed consent form. Patient able to comply with study requirements. Exclusion Criteria: Any of the following treatment: Previous treatment with EGFR inhibitor; Previous treatment with Systematic antitumor therapy (including targeted therapy, biotherapy and immunodrug therapy, etc.)； Previous treatment with standard chemotherapy with 28 days before the first dose of the study drug, and traditional Chinese medicine antitumor therapy within 7 days before the first dose of the study drug; Receiving radiation to more than 30% of the bone marrow or with a wide field of radiation that had to be completed within 28 days of the first dose of study treatment; Radiotherapy with a limited field of radiation within 7 days of the first dose of study treatment or palliative radiation therapy for bone metastasis; Uncontrollable or poorly controlled pleural and abdominal effusion; Major surgery within 28 days of the first dose of study treatment; Patients currently receiving (or at least within 14 days prior to receiving the first dose )medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 isoenzyme (CYP)3A4; Patients who are receiving and need to continue receiving medications during the study that are known to prolong the QTc interval or may cause tachycardia; Participants in other clinical trials (other than non-interventional clinical trials) within 28 days prior to the first administration of the investigational drug. Pathologically confirmed squamous cell carcinoma or squamous cell component predominance in NSCLC. Symptomatic brain metastases or leptomeningeal metastases. Patients have spinal cord compression caused by tumor. Clinically severe gastrointestinal dysfunction may affect the ingestion, transport or absorption of the study drugs. Cardiac function and disease are consistent with the following: Corrected QT interval(QTc)≥ 470 milliseconds from 3 times of electrocardiograms (ECGs); Any clinically important abnormalities in rhythm; Any factors that increase the risk of QTc prolongation; Left ventricular ejection fraction (LVEF) <50%. Active human immunodeficiency virus (HIV), syphilis, hepatitis c virus (HCV) or hepatitis b virus (HBV) infection, with the exception of asymptomatic chronic hepatitis b or hepatitis c carriers. Previous history of interstitial lung disease(ILD), drug-induced ILD or radiation pneumonitis require steroid treatment, or any evidence of clinically active ILD diseases. Previous allogeneic bone marrow transplant. Pregnant or lactating women. Any other disease or medical condition that is unstable or may affect the safety or study compliance. Hypersensitivity to investigational drug or similar compounds or excipients.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TY-9591+placebo Osimertinib<br>TY-9591 (160mg orally, once daily) plus placebo Osimertinib (80mg orally, once daily), in accordance with the randomization schedule. | Drug: TY-9591<br>* The dose of TY-9591 is 160 mg once daily. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.<br>* Other names: TY-9591 Tablets;Drug: placebo Osimertinib<br>* The dose of placebo Osimertinib is 80 mg once daily. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.<br>* Other names: placebo Tagrisso;|
| Active Comparator: Osimertinib+placebo TY-9591<br>Osimertinib (80mg orally, once daily) plus placebo TY-9591 (160mg orally, once daily), in accordance with the randomization schedule. | Drug: Osimertinib<br>* The dose of Osimertinib is 80 mg once daily. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.<br>* Other names: Tagrisso;Drug: placebo TY-9591<br>* The dose of placebo TY-9591 is 160 mg once daily. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.<br>* Other names: placebo TY-9591 Tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) | PFS is defined as time from randomization until the date of first documented disease progression or death due to any cause | approximately 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) during the study treatment | approximately 18 months | 
| Intracranial Overall Response Rate (iORR) | iORR is defined as the proportion of patients with a best intracranial response of complete response (CR) or partial response (PR) during the study treatment | approximately 18 months | 
| Intracranial Median Progression Free Survival (iPFS) | iPFS is defined as time from randomization until the date of first documented intracranial disease progression or death due to any cause | approximately 18 months | 
| Duration of Response (DoR) | DoR is defined as the time from the date of first documented response (PR or CR) until the date of first documented disease progression or death due to any cause during the study treatment | approximately 18 months | 
| Disease Control Rate (DCR) | DCR is defined as the proportion of patients with a best overall response of complete response (CR) , partial response (PR) or Stable disease (SD) ≥6 weeks during the study treatment | approximately 18 months | 
| Clinical Benefit Rate (CBR) | CBR is defined as the proportion of patients with a best overall response of complete response (CR) , partial response (PR) or Stable disease (SD) ≥24 weeks during the study treatment | approximately 18 months | 
| Depth of Response (DepOR) | The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir compared to baseline, in the absence of new lesions (NLs) or progression of Non-target lesions (NTLs) | approximately 18 months | 
| Time To Progress (TTP) | TTP is defined as the time from randomization until the date of first documented disease progression (excluding death) | approximately 18 months | 
| Overall Survival (OS) | OS is defined as the time from randomization until death from any cause | From the date of first dose until the date of death from any cause or loss to follow-up, whichever comes first, assessed up to 100 months | 
| Assessment of health-related quality of life (FACT-L) | Change in FACT-L scores relative to Baseline | approximately 18 months | 
| Safety variables | Adverse events, clinical symptoms, vital signs, ECG's, clinical laboratory safety tests, ect. | Assessments performed throughout the study period | 
| Plasma Concentrations of TY-9591 | To characterise the pharmacokinetics (PK) of TY-9591 | approximately 18 months | 
| Plasma Concentrations of TY-9591-D1 | To characterise the pharmacokinetics (PK) of TY-9591 metabolite D1 | approximately 18 months | 
| Plasma Concentrations of TY-9591-D2 | To characterise the pharmacokinetics (PK) of TY-9591 metabolite D2 | approximately 18 months |