A Phase III, Double-blind, Randomised Study to Assess the Safety and Efficacy of AZD9291 Versus a Standard of Care Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor as First Line Treatment in Patients With Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non Small Cell Lung Cancer.

Official Summary

To assess the efficacy and safety of AZD9291 versus a standard of care epidermal growth factor receptor tyrosine kinase inhibitor in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 100 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: TRIPLE
• Enrollment: 674 participants

Study Arms

• AZD9291+ placebo (EXPERIMENTAL)
  AZD9291 (80 mg or 40 mg orally, once daily) plus placebo Erlotinib (150mg or 100mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily), in accordance with the randomization schedule.
• Standard of Care + placebo AZD9291 (ACTIVE_COMPARATOR)
  Erlotinib (150 mg or 100 mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily) plus placebo AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomisation schedule. Following objective disease progression according to RECIST 1.1, as per investigator assessment, patients who were randomized to Standard of Care arm may have the option to receive open-label AZD9291 (crossover to active AZD9291).

Interventions

• DRUG: AZD9291 80 mg/40 mg + placebo — The initial dose of AZD9291 80 mg once daily can be reduced to 40 mg once daily under specific circumstances. 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.
• DRUG: Placebo Erlotinib 150/100mg — The initial dose of Placebo Erlotinib 150 mg once daily can be reduced to Placebo 100 mg once daily under specific circumstances. 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.
• DRUG: Placebo Gefitinib 250 mg — 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, as judged by the Investigator, and in the absence of discontinuation criteria.
• DRUG: Erlotinib 150/100 mg — The initial dose of Erlotinib 150mg once daily can be reduced to 10 mg once daily under specific circumstances. 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. Following objective disease progression according to RECIST 1.1, as per investigator assessment, patients who were randomized to Standard of Care arm may have t
• DRUG: Gefitinib 250 mg — The initial dose of Gefitinib 250mg 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, as judged by the Investigator, and in the absence of discontinuation criteria. Following objective disease progression according to RECIST 1.1, as per investigator assessment, patients who were randomized to Standard of Care arm may have the option to receive open-label AZD9291 (cross

Primary Outcomes

• Median Progression Free Survival (PFS) (Months) (At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression)
• Percentage of Participants in Progression Free Survival at 6, 12, and 18 Months (At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression)

Secondary Outcomes

• Objective Response Rate (ORR) (At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression)
• Duration of Response (DoR) (At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression)
• Disease Control Rate (DCR) (At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression)
• Depth of Response (At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression)
• Overall Survival (OS)- Number of Participants With an Event (From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months))

Eligibility Criteria

Inclusion Criteria:

1. Male or female, aged at least 18 years.
2. Pathologically confirmed adenocarcinoma of the lung.
3. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy.
4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R).
5. Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR mutation status.
6. Patients must be treatment-naïve for locally advanced or metastatic NSCLC and eligible to receive first-line treatment with gefitinib or erlotinib as selected by the participating centre. Prior adjuvant and neo-adjuvant therapy is permitted(chemotherapy, radiotherapy, investigational agents).
7. Provision of informed consent prior to any study specific procedures, sampling, and analysis.
8. World Health Organization Performance Status of 0 to 1 with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks

Exclusion Criteria:

1. 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.
2. Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of study drug.
3. 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 AZD9291.
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

Trial Locations

• Research Site, Anaheim, California, United States
• Research Site, Santa Rosa, California, United States
• Research Site, West Hills, California, United States
• Research Site, Tampa, Florida, United States
• Research Site, Atlanta, Georgia, United States
• Research Site, Atlanta, Georgia, United States
• Research Site, Marietta, Georgia, United States
• Research Site, Louisville, Kentucky, United States
• Research Site, Bethesda, Maryland, United States
• Research Site, Boston, Massachusetts, United States
• ...and 10 more locations

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