Clinical Trials /

AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer

NCT02296125

Description:

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

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer
  • Official Title: 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.

Clinical Trial IDs

  • ORG STUDY ID: D5160C00007
  • SECONDARY ID: 2014-002694-11
  • SECONDARY ID: U1111-1160-2242
  • NCT ID: NCT02296125

Conditions

  • Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
AZD9291 80 mg/40 mg + placeboAZD9291+ placebo
Placebo Erlotinib 150/100mgPlacebo Tarceva 150/100 mgAZD9291+ placebo
Placebo Gefitinib 250 mgPlacebo Iressa 250 mgAZD9291+ placebo
Erlotinib 150/100 mgTarceva 150/100 mgStandard of Care + placebo AZD9291
Gefitinib 250 mgIressa 250mgStandard of Care + placebo AZD9291
Placebo AZD9291 80 mg/ 40 mgStandard of Care + placebo AZD9291

Purpose

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

Detailed Description

      This is a Phase III, double-blind, randomised study assessing the efficacy and safety of
      AZD9291 (80 mg orally, once daily) versus a standard of care (SoC) Epidermal Growth Factor
      Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) (either gefitinib [250 mg orally, once daily]
      or erlotinib [150 mg orally, once daily]) in patients with locally advanced or metastatic
      Non-small Cell Lung Cancer (NSCLC) that is known to be EGFR sensitising mutation (EGFRm)
      positive, treatment-naïve and eligible for first-line treatment with an EGFR-TKI.
    

Trial Arms

NameTypeDescriptionInterventions
AZD9291+ placeboExperimentalAZD9291 (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.
  • AZD9291 80 mg/40 mg + placebo
  • Placebo Erlotinib 150/100mg
  • Placebo Gefitinib 250 mg
Standard of Care + placebo AZD9291Active ComparatorErlotinib (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).
  • Erlotinib 150/100 mg
  • Gefitinib 250 mg
  • Placebo AZD9291 80 mg/ 40 mg

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
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Median Progression Free Survival (PFS) (Months)
Time Frame:At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
Safety Issue:
Description: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 or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent osimertinib compared with SoC EGFR-TKI therapy as measured by PFS. The primary endpoint of PFS was based on Investigator assessment.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
Safety Issue:
Description:ORR was defined as the number (%) of participants 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 osimertinib compared with SoC EGFR-TKI therapy. ORR was based on Investigator assessment.
Measure:Duration of Response (DoR)
Time Frame:At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression
Safety Issue:
Description: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 osimertinib compared with SoC EGFR-TKI therapy.
Measure:Disease Control Rate (DCR)
Time Frame:At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression
Safety Issue:
Description: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 osimertinib compared with SoC EGFR-TKI therapy.
Measure:Depth of Response
Time Frame:At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression
Safety Issue:
Description: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 (NTLs), compared to baseline and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy
Measure:Overall Survival (OS)- Number of Participants With an Event
Time Frame:From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months)
Safety Issue:
Description: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 osimertinib compared with SoC EGFR-TKI therapy
Measure:Plasma Concentrations of AZD9291
Time Frame:Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)
Safety Issue:
Description:To characterise the pharmacokinetics (PK) of osimertinib
Measure:Plasma Concentrations of Metabolites AZ5104
Time Frame:Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)
Safety Issue:
Description:To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ5104.
Measure:Plasma Concentrations of Metabolite AZ7550
Time Frame:Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)
Safety Issue:
Description:To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ7550.
Measure:Participants Reported Outcome by Cancer Therapy Satisfaction Questionnaire 16 Items (CTSQ-16 Questionnaire)
Time Frame:Questionnaire completed in cycle 2 and 3, prior to Week 6 scan (approximately 2 months)
Safety Issue:
Description:The CTSQ-16 was a 16-item questionnaire measuring 3 domains related to participant's satisfaction with cancer therapy: Expectations of therapy, Feelings about side effects, and Satisfaction with therapy. Scores ranged from 0 to 100 for each domain, with a higher score associated with the best outcome on each domain. The three domains of interest were separately analysed using an ANCOVA stratified by race (Asian versus Non-Asian) and mutation type (Ex19del versus L858R). The results of the analyses were presented in terms of mean together with standard deviation.
Measure:Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)
Time Frame:Questionnaires completed at baseline, first 9 months, and at week 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 and 36
Safety Issue:
Description:The EORTC QLQ-LC13 was a lung-cancer-specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, and site-specific pain); treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia); and pain medication. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items. Higher scores on the global health status/QoL and functioning scales indicated better health status/QoL and function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.
Measure:Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30)
Time Frame:Questionnaires completed at baseline, first 9 months, and at week 6, 12, 18, 24, 30, and 36.
Safety Issue:
Description:The EORTC QLQ-C30 cancer-specific questionnaire consisted of 30 questions, combined to produce 5 functional scales, 3 symptom scales, 6 individual items, and a global measure of health status/QoL. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, the functional scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and functioning scales indicated better health status/function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Advanced Non-Small Cell Lung Cancer; EGFRm+; AZD9291; TKI; Phase III

Last Updated

March 11, 2021