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).

Official 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

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 130 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: TRIPLE
• Enrollment: 682 participants

Study Arms

• AZD9291 (EXPERIMENTAL)
  AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomization schedule.
• Placebo AZD9291 (PLACEBO_COMPARATOR)
  Matching placebo for AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomization schedule.

Interventions

• DRUG: AZD9291 80 mg/40 mg — The initial dose of AZD9291 80 mg once daily can be reduced to 40 mg once daily.
• DRUG: Placebo AZD9291 80 mg/40 mg — The initial dose of Placebo AZD9291 80 mg once daily can be reduced to 40 mg once daily.
• DRUG: Open-label AZD9291 80 mg/40 mg — Eligible patients will be offered open-label osimertinib upon recurrence and in the absence of intervening systemic anti-cancer therapy.

Primary Outcomes

• Assess the Efficacy of AZD9291 Compared to Placebo as Measured by Disease Free Survival (DFS). (Up to approximately 5 years after the first patient is randomized (maximum follow up of 70 months))

Secondary Outcomes

• Disease Free Survival (DFS) Rate at 2, 3 and 5 Years (Up to approximately 5 years after the first patient is randomized (maximum follow up of 70 months). DFS rate at 2 years (%), 3 years (%) and 5 years (%) are presented.)
• Overall Survival (OS) (Up to approximately 7 years after the first patient is randomized (maximum follow up of 86 months))
• Overall Survival Rate at 2, 3 and 5 Years (Up to approximately 7 years after the first patient is randomized (maximum follow up of 86 months). OS rate at 2 years (%), 3 years (%) and 5 years (%) are presented.)
• Patient Health-related Quality of Life and Symptoms (HRQoL) by SF-36v2 Health Survey. (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 3 years.)
• Plasma Concentrations of AZD9291 (Collected at pre-dose, 0.5-1.5hours and 2-4hours post-dose up to 96 weeks (approximately 24 months))

Eligibility Criteria

Inclusion Criteria:

1. Male or female, aged at least 18 years.
2. Histologically confirmed diagnosis of primary non small lung cancer (NSCLC) on predominantly non-squamous histology
3. MRI or CT scan of the brain must be done prior to surgery as it is considered standard of care.
4. Patients must be classified post-operatively as Stage IB, II or IIIA on the basis of pathologic criteria.
5. 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.
6. 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.
7. Complete recovery from surgery and standard post-operative therapy (if applicable) at the time of randomization.
8. World Health Organization Performance Status of 0 to 1.
9. 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:

1. 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.
2. Patients who have had only segmentectomies or wedge resections
3. 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.
4. 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.
5. 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).
6. 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.
7. 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.
8. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
9. Inadequate bone marrow reserve or organ function.

Trial Locations

• Research Site, Los Angeles, California, United States
• Research Site, Santa Monica, California, United States
• Research Site, Santa Rosa, California, United States
• Research Site, Torrance, California, United States
• Research Site, Grand Junction, Colorado, United States
• Research Site, New Haven, Connecticut, United States
• Research Site, Norwalk, Connecticut, United States
• Research Site, Fort Myers, Florida, United States
• Research Site, Pembroke Pines, Florida, United States
• Research Site, St. Petersburg, Florida, United States
• ...and 10 more locations

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