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A Global Study to Assess the Effects of Osimertinib Following Chemoradiation in Patients With Stage III Unresectable Non-small Cell Lung Cancer (LAURA)

NCT03521154

Description:

A global study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable Epidermal Growth Factor Receptor Mutation Positive non-small cell lung cancer

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

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Global Study to Assess the Effects of Osimertinib Following Chemoradiation in Patients With Stage III Unresectable Non-small Cell Lung Cancer (LAURA)
  • Official Title: A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study of Osimertinib as Maintenance Therapy in Patients With Locally Advanced, Unresectable EGFR Mutation-positive Non-Small Cell Lung Cancer (Stage III) Whose Disease Has Not Progressed Following Definitive Platinum-based Chemoradiation Therapy (LAURA)

Clinical Trial IDs

  • ORG STUDY ID: D5160C00048
  • NCT ID: NCT03521154

Conditions

  • Non Small Cell Lung Cancer (Stage III)

Interventions

DrugSynonymsArms
Osimertinib 80mg/40mgOsimertinib
Placebo Osimertinib 80mg/40mgPlacebo Osimertinib

Purpose

A global study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable Epidermal Growth Factor Receptor Mutation Positive non-small cell lung cancer

Detailed Description

      This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy
      and safety of osimertinib following chemoradiation in patients with stage III unresectable
      EGFR mutation-positive NSCLC, including the most common EGFR sensitising mutations (Ex19Del
      and L858R), either alone or in combination with other EGFR mutations. Chemoradiation may have
      been given either given concurrently or sequentially. Patients whose disease has not
      progressed following chemoradiation will be randomised within 6 weeks of completion of
      chemoradiation to receive osimertinib or placebo in a 2:1 ratio, and treatment will be
      continued until disease progression, unacceptable toxicity or other discontinuation criteria
      are met.
    

Trial Arms

NameTypeDescriptionInterventions
OsimertinibExperimentalOsimertinib (80mg or 40mg orally, once daily), in accordance with the randomization schedule.
  • Osimertinib 80mg/40mg
Placebo OsimertinibPlacebo ComparatorMatching placebo for Osimertinib (80mg or 40mg orally, once daily), in accordance with the randomization schedule
  • Placebo Osimertinib 80mg/40mg

Eligibility Criteria

        Inclusion Criteria

          1. Male or female aged at least 18 years.

          2. Patients with histologically documented NSCLC of predominantly non-squamous Pathology
             who present with locally advanced, unresectable (Stage III) disease (according to
             Version 8 of the International Association for the Study of Lung Cancer [IASLC]
             Staging Manual in Thoracic Oncology).

          3. The tumor harbours one of the two common EGFR mutations known to be associated with
             EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR
             mutations, assessed by cobas® EGFR Mutation Test v2 (Roche Diagnostics) in a CLIA
             certified (USA sites) or an accredited local laboratory (sites outside of the USA) or
             by central testing.

          4. Patients must have received either concurrent chemoradiation or sequential
             chemoradiation including at least 2 cycles of platinum based chemotherapy and a total
             dose of radiation of 60 Gy ±10% (54 to 66 Gy).

          5. Chemoradiation must be completed ≤6 weeks prior to randomization.

          6. Patients must not have had disease progression during or following definitive
             platinum-based, chemoradiation therapy.

          7. World Health Organization (WHO) performance status of 0 or 1.

          8. Life expectancy >12 weeks at Day 1.

          9. Female patients who are not abstinent (in line with the preferred and usual lifestyle
             choice) must be using adequate contraceptive measures, must 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-childbearing potential.

        Exclusion Criteria

          1. Mixed small cell and non-small cell lung cancer histology

          2. History of interstitial lung disease (ILD) prior to chemoradiation

          3. Symptomatic pneumonitis following chemoradiation

          4. Any unresolved toxicity Common Terminology Criteria for Adverse Events (CTCAE) > Grade
             2 from the prior chemoradiation therapy

          5. Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs

               -  Any clinically important abnormalities in rhythm, conduction, or morphology of
                  resting ECG

               -  Patient with any factors that increase the risk of QTc prolongation or risk of
                  arrhythmic events such as heart failure, hypokalaemia, congenital long QT
                  syndrome, family history of long QT syndrome, or unexplained sudden death under
                  40 years of age in first-degree relatives or any concomitant medication known to
                  prolong the QT interval and cause Torsades de Pointes

          6. Inadequate bone marrow reserve or organ function

          7. History of other malignancies, except: adequately treated non-melanoma skin cancer or
             lentigo maligna , curatively treated in-situ cancer, or other solid tumors curatively
             treated with no evidence of disease for > 5 years following the end of treatment and
             which, in the opinion of the treating physician, do not have a substantial risk of
             recurrence of the prior malignancy.

          8. 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).

          9. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
             swallow the formulated product, or previous significant bowel resection that would
             preclude adequate absorption of osimertinib

         10. Prior treatment with any prior chemotherapy, radiation therapy, immunotherapy or
             investigational agents for NSCLC outside of that received in the definitive setting
             for Stage III disease (chemotherapy and radiotherapy in SCRT and CCRT regimens is
             allowed for treatment of Stage III disease).

         11. Prior treatment with EGFR-TKI therapy

         12. Major surgery as defined by the investigator within 4 weeks of the first dose of study
             drug.

         13. Patients currently receiving (unable to stop use prior to receiving the first dose of
             study treatment) medications or herbal supplements known to be strong inducers of
             CYP3A4 (at least 3 weeks prior to receiving the first dose of study drug).

         14. Contraindication to MRI, including but not limited to, claustrophobia, pace makers,
             metal implants, intracranial surgical clips and metal foreign bodies
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on blinded independent central review assessment according to RECIST 1.1

Secondary Outcome Measures

Measure:PFS in patients with EGFR Ex19del or L858R mutation
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.' based on blinded independent central review assessment according to RECIST 1.1
Measure:PFS in patients with EGFR mutations Ex19del or L858R detectable in plasma-derived ctDNA
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.' based on blinded independent central review assessment according to RECIST 1.1
Measure:Time to CNS PFS
Time Frame:MRI Brain Scan- Approximately 13 months
Safety Issue:
Description:Defined as earlier event of CNS progression or death based on blinded independent central review assessment according to RECIST 1.1
Measure:Overall survival (OS)
Time Frame:Approximately 45 months
Safety Issue:
Description:Defined as the time from randomization until death from any cause
Measure:Objective response rate (ORR)
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as the number (%) of patients with measurable disease with at least 1 visit response of CR (Complete response) or PR (Partial response) based on blinded independent central review assessment according to RECIST 1.1
Measure:Duration of response (DoR)
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as the time from the date of first documented response (i.e., subsequently confirmed) until the date of documented progression or death in the absence of disease progression based on blinded independent central review assessment according to RECIST 1.1
Measure:Disease control rate (DCR)
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as Disease control rate is defined as the percentage of subjects who have a best overall response of CR or PR or SD based on blinded independent central review assessment according to RECIST 1.1
Measure:Tumor shrinkage
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline based on blinded independent central review assessment according to RECIST 1.1
Measure:Time to death or distant metastases (TTDM)
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as the time from the date of randomization until the first date of distant metastasis or date of death in the absence of distant metastasis based on blinded independent central review assessment according to RECIST 1.1
Measure:Time to treatment discontinuation
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as the time from randomization to the earlier of the date of study treatment discontinuation (regardless of the reason for study treatment discontinuation) or death
Measure:Second progression free survival on a subsequent treatment (PFS2)
Time Frame:Assessed by investigator in accordance with clinical practice-approximately 21 months
Safety Issue:
Description:Time from randomisation to second progression (PFS2) is defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PFS or date of death after starting subsequent anti-cancer treatment.
Measure:Time to first subsequent therapy (TFST)
Time Frame:Approximately 13 months
Safety Issue:
Description:Defined as the time from the date of randomization to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death
Measure:Time to second subsequent therapy (TSST)
Time Frame:Approximately 21 months
Safety Issue:
Description:Defined as the time from the date of randomization to the earlier of the date of second subsequent anti-cancer therapy start date following study drug discontinuation or death.
Measure:Patients reported disease-related symptoms and HRQoL by EORTC QLQ-LC13 and EORTC QLQ-30 questionnaires
Time Frame:Approximately 21 months
Safety Issue:
Description:Change in symptoms from baseline
Measure:Incidence of Adverse Events (AEs)
Time Frame:Approximately 14 months
Safety Issue:
Description:AEs graded by CTCAE version 5.0
Measure:Plasma concentrations of osimertinib and AZD5104
Time Frame:Trough concentrations at Week 4,12 and 24
Safety Issue:
Description:The pharmacokinetics exposure parameters derived from plasma concentrations of osimertinib and AZD5104

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Phase III
  • Osimertinib
  • Non Small Cell Lung Cancer (Stage III)
  • Unresectable NSCLC
  • EGFR
  • chemoradiation therapy

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