ASK120067 Versus Gefitinib as First-line Treatment for EGFRm Locally Advanced or Metastatic NSCLC

Study Overview
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Brief Summary
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To assess the efficacy and safety of ASK120067 versus a standard of care epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

Official Title
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A Phase III,Double-Blind, Randomised Study to Assess the Efficacy and Safety of ASK120067 Versus Gefitinib as First-Line Treatment in Patients With Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Conditions
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Locally Advanced or Metastatic NSCLC

Intervention / Treatment
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* Drug: ASK120067
* Drug: Placebo Gefitinib 250 mg
* Drug: Gefitinib
* Drug: Placebo ASK120067


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged at least 18 years. Pathologically confirmed adenocarcinoma of the lung. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R). Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR mutation status. Patients must be treatment-naïve for locally advanced or metastatic NSCLC and eligible to receive first-line treatment with gefitinib as selected by the participating centre. Prior adjuvant and neo-adjuvant therapy is permitted(chemotherapy, radiotherapy, investigational agents). Provision of informed consent prior to any study specific procedures, sampling, and analysis. ECOG score of 0 to 1 Exclusion Criteria: Treatment with any of the following: Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC. Prior treatment with an EGFR-TKI. Major surgery within 4 weeks of the first dose of study drug. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug. Patients currently receiving medications or herbal supplements known to be potent inducers of cytochrome P450 (CYP) 3A4. Alternative anti-cancer treatment Treatment with an investigational drug within five half-lives of the compound or any of its related material. Spinal cord compression, symptomatic and unstable brain metastases, except for those patients who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids. 4、Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). 5、Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of ASK120067. 6、Any of the following cardiac criteria:Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTcF value.Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.Any patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval. 7、Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. 8、Involvement in the planning and/or conduct of the study

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Triple (Participant, Investigator, Outcomes Assessor)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASK120067+ placebo Gefitinib<br>ASK120067 (80 mg orally, twice daily) plus placebo Gefitinib (250 mg orally, once daily), in accordance with the randomization schedule. | Drug: ASK120067<br>* ASK120067 (80 mg orally twice 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 according to RECIST 1.1, as judged by the Investigator, and in the absence of discontinuation criteria.<br>Drug: Placebo Gefitinib 250 mg<br>* The initial dose of Placebo Gefitinib 250 mg once daily cannot be reduced. 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 according to RECIST 1.1, as judged by the Investigator, and in the absence of discontinuation criteria.<br>* Other names: Placebo Iressa 250 mg;|
| Active Comparator: Gefitinib + placebo ASK120067<br>Gefitinib (250 mg orally, once daily) plus placebo ASK120067 (80 mg orally, twice daily), in accordance with the randomization schedule. | Drug: Gefitinib<br>* Gefitinib (250 mg orally, 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 acording to RECIST 1.1, as judged by the Investigator, and in the absence of discontinuation criteria.<br>Drug: Placebo ASK120067<br>* Placebo ASK120067orally 80mg twice 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 according to RECIST 1.1, as judged by the Investigator, and in the absence of discontinuation criteria.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) | Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy prior to progression and was used to assess the efficacy of single agent ASK120067 compared with Gefitinib as measured by PFS. | CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was defined as the number (%) of patients with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of ASK120067 compared with Gefitinib defined as the number (%) of patients with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of ASK120067 compared with Gefitinib | CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years | 
| Duration of Response (DoR) | Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of ASK120067 compared with Gefitinib | CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years | 
| Disease Control Rate (DCR) | The DCR was defined as the percentage of participants who had a best overall response (BOR) of Complete response (CR), Partial response (PR) or Stable disease (SD) ≥6 weeks prior to any Progressive disease (PD) event and was used to further assess the efficacy of ASK120067 compared with Gefitinib | CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years | 
| Depth of Response | 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, in the absence of new lesions (NLs) or progression of Non-target lesions | CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years | 
| Overall Survival (OS)- Number of Participants With an Event | Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of ASK120067 compared with Gefitinib | Time from treatment start to the time of death due to any cause or withdrawal from study,whichever came first, assessed up to approximately 5 years |