AZD9291 Versus Placebo in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy.

Study Overview
=================
Brief Summary
-----------------
To assess the efficacy and safety of AZD9291 versus Placebo, in patients with Epidermal Growth Factor Receptor Mutation Positive stage IB-IIIA non-small cell lung carcinoma, following complete tumour resection with or without adjuvant chemotherapy

Detailed Description
-----------------
This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of AZD9291 versus placebo in patients with stage IB-IIIA non-small cell lung cancer (NSCLC) with centrally confirmed, most common sensitising EGFR mutations (Ex19Del and L858R) either alone or in combination with other EGFR mutations as confirmed by a central test, who have had complete tumour resection, with or without postoperative adjuvant chemotherapy. Adjuvant chemotherapy should have consisted of a platinum based doublet given for a maximum of 4 cycles.

Official Title
-----------------
A Phase III, Double-blind, Randomized, Placebo-controlled Multi-centre, Study to Assess the Efficacy and Safety of AZD9291 Versus Placebo, in Patients With Epidermal Growth Factor Receptor Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (ADAURA).

Conditions
-----------------
Stage IB-IIIA Non-small Cell Lung Carcinoma

Intervention / Treatment
-----------------
* Drug: AZD9291 80 mg/40 mg
* Drug: Placebo AZD9291 80 mg/40 mg
* Drug: Open-label AZD9291 80 mg/40 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, aged at least 18 years. Histologically confirmed diagnosis of primary non small lung cancer (NSCLC) on predominantly non-squamous histology MRI or CT scan of the brain must be done prior to surgery as it is considered standard of care. Patients must be classified post-operatively as Stage IB, II or IIIA on the basis of pathologic criteria. Confirmation by the central laboratory that the tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M. Complete surgical resection of the primary NSCLC is mandatory. All gross disease must have been removed at the end of surgery. All surgical margins of resection must be negative for tumour. Complete recovery from surgery and standard post-operative therapy (if applicable) at the time of randomization. World Health Organization Performance Status of 0 to 1. Female patients should be using adequate contraceptive measures, should not be breast feeding, and must have a negative pregnancy test prior to first dose of study drug; or female patients must have an evidence of non-child-bearing potential. Exclusion Criteria: Treatment with any of the following: Pre-operative or post-operative or planned radiation therapy for the current lung cancer Pre-operative (neo-adjuvant) platinum based or other chemotherapy Any prior anticancer therapy Prior treatment with neoadjuvant or adjuvant EGFR-TKI at any time Major surgery (including primary tumour surgery, excluding placement of vascular access) 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 Treatment with an investigational drug within five half-lives of the compound or any of its related material. Patients who have had only segmentectomies or wedge resections History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer, or other solid tumours curatively treated with no evidence of disease for > 5 years following the end of treatment. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy. 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). Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9291. 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 QTc value. Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG. 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. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. Inadequate bone marrow reserve or organ function.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD9291<br>AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomization schedule. | Drug: AZD9291 80 mg/40 mg<br>* The initial dose of AZD9291 80 mg once daily can be reduced to 40 mg once daily.<br>Drug: Open-label AZD9291 80 mg/40 mg<br>* Eligible patients will be offered open-label osimertinib upon recurrence and in the absence of intervening systemic anti-cancer therapy.<br>|
| Placebo Comparator: Placebo AZD9291<br>Matching placebo for AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomization schedule. | Drug: Placebo AZD9291 80 mg/40 mg<br>* The initial dose of Placebo AZD9291 80 mg once daily can be reduced to 40 mg once daily.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the Efficacy of AZD9291 Compared to Placebo as Measured by Disease Free Survival (DFS). | Defined as the time from the date of randomization until the date of disease recurrence or death (by any cause in the absence of recurrence) | From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence), up to approximately 4 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) Rate at 2, 3 and 5 Years | Defined as the percentage of patients alive and disease free at 2, 3 and 5 years, respectively, estimated from Kaplan Meier plots of the primary endpoint of DFS at the time of the primary analysis | From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence), up to approximately 4 years. Assessed at 2 years and 3 years. | 
| Overall Survival (OS) | Defined as the time from the date of randomization until date of death due to any cause. | From date of randomization until date of death due to any cause, up to approximately 4 years. | 
| Overall Survival (OS) | Defined as the time from the date of randomization until date of death due to any cause | From date of randomization until date of death due to any cause, up to approximately 4 years. | 
| Overall Survival Rate at 2, 3 and 5 Years | Defined as the percentage of patients alive at 2, 3 and 5 years, respectively, estimated from a Kaplan Meier plot of OS at the time of the primary analysis | From date of randomization until date of death due to any cause, up to approximately 4 years. Assessed at 2 years and 3 years. | 
| Patient Health-related Quality of Life and Symptoms (HRQoL) by SF-36v2 Health Survey. | Change from baseline will be calculated for each domain and summary scale at each scheduled post-baseline assessment. The SF-36 includes eight domains: Physical Functioning (PF); Role Limitations-Physical (RP), Vitality (VT), General Health Perceptions (GH), Bodily Pain (BP), Social Function (SF), Role Limitations-Emotional (RE), and Mental Health (MH) and two summary scores: The Physical Component Summary (PCS) and Mental Component Summary (MCS). Final scores for each scale range from 0-100 with higher scores indicating better health. | Measured by SF-36 Questionnaire at baseline, 12 week, 24 week and then every 24 weeks until study complete, disease recurrence or other discontinuation criteria met, up to approximately 3 years. | 
| Plasma Concentrations of AZD9291 | The pharmacokinetics exposure parameters derived from plasma concentrations of AZD9291 | Collected at pre-dose, 0.5-1.5hours and 2-4hours post-dose up to 96 weeks (approximately 24 months) | 
| Plasma Concentrations of AZ5104 Metabolites | The pharmacokinetics exposure parameters derived from plasma concentrations of AZ5104 metabolites | From date of dosing to week 96 (approximately 24 months) | 
| Plasma Concentrations of AZ7550 Metabolites | The pharmacokinetics exposure parameters derived from plasma concentrations of AZ7550 metabolites | From date of dosing to week 96 (approximately 24 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stage IB-IIA-IIIA Non-Small Cell Lung Cancer; EGFRm+; Ex19Del; L858R; AZD9291; Phase III, adjuvant chemotherapy; complete tumour resection; EGFR-TKI