AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer
Condition: Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: AZD9291 80 mg/40 mg + placebo; Placebo Erlotinib 150/100mg; Placebo Gefitinib 250 mg; Erlotinib 150/100 mg; Gefitinib 250 mg; Placebo AZD9291 80 mg/ 40 mg
Intervention description: 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.; 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.; 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.; 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 the option to receive open-label AZD9291 (crossover to active AZD9291).; 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 (crossover to active AZD9291).; The initial dose of Placebo AZD9291 80 mg once daily can be reduced to Placebo AZD9291 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.
Intervention MeSH terms: Erlotinib Hydrochloride; Gefitinib; Osimertinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 674.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Advanced Non-Small Cell Lung Cancer; EGFRm+; AZD9291; TKI; Phase III

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 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