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Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD)

NCT03944772

Description:

Phase 2 Platform Study in Patients with Advanced Non-Small Lung Cancer who progressed on First-Line Osimertinib Therapy. This study is modular in design, allowing evaluation of the efficacy, safety and tolerability of multiple study treatments.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD)
  • Official Title: A Biomarker-directed Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy

Clinical Trial IDs

  • ORG STUDY ID: D6186C00001
  • NCT ID: NCT03944772

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
OsimertinibTAGRISSOModule 1: Osimertinib + Savolitinib
SavolitinibModule 1: Osimertinib + Savolitinib
GefitinibIressaModule 2: Osimertinib + Gefitinib
NecitumumabPortrazzaModule 3: Osimertinib + Necitumumab
DurvalumabIMFINZIModule 4: carboplatin + pemetrexed + durvalumab)
CarboplatinModule 4: carboplatin + pemetrexed + durvalumab)
PemetrexedModule 4: carboplatin + pemetrexed + durvalumab)

Purpose

Phase 2 Platform Study in Patients with Advanced Non-Small Lung Cancer who progressed on First-Line Osimertinib Therapy. This study is modular in design, allowing evaluation of the efficacy, safety and tolerability of multiple study treatments.

Detailed Description

      This is an open-label, multicentre, multi-drug, biomarker-directed Phase 2 platform study in
      patients with advanced non-small cell lung cancer (NSCLC) harbouring an epidermal growth
      factor receptor (EGFR)-sensitizing mutation whose disease has progressed on first-line
      monotherapy with osimertinib.Treatment options for these patients are limited. Novel
      treatments for these patients are urgently required.

      This study is modular in design, allowing evaluation of the efficacy, safety and tolerability
      of multiple study treatments.
    

Trial Arms

NameTypeDescriptionInterventions
Module 1: Osimertinib + SavolitinibExperimentalThe patients in this group will receive Osimertinib taken in combination with savolitinib
  • Osimertinib
  • Savolitinib
Module 2: Osimertinib + GefitinibExperimentalThe patients in this group will receive Osimertinib taken in combination with Gefitinib
  • Osimertinib
  • Gefitinib
Module 3: Osimertinib + NecitumumabExperimentalThe patients in this group will receive Osimertinib taken in combination with Necitumumab
  • Osimertinib
  • Necitumumab
Module 4: carboplatin + pemetrexed + durvalumab)ExperimentalThe patients in this group will receive Platinum-containing doublet (carboplatin + pemetrexed) taken in combination with durvalumab.
  • Durvalumab
  • Carboplatin
  • Pemetrexed
Observational Cohort: No study drugNo InterventionPatients in this group will not receive study treatment but receive further anticancer care (Standard of Care therapy or other experimental therapies) or supportive care, as clinically indicated, in accordance with local practice. With Group C, the aim is to understand the clinical course and/or outcome for the overall clinical population after progression on first-line monotherapy with osimertinib.

    Eligibility Criteria

            Inclusion criteria applicable to all study treatment modules (Groups A/B):
    
              -  Non-Small Cell Lung Cancer (NSCLC) with the following features -
    
                   -  Locally advanced or metastatic disease (i.e., advanced NSCLC) not amenable to
                      curative surgery or radiotherapy at study entry.
    
                   -  Histologically or cytologically confirmed adenocarcinoma of the lung harbouring
                      EGFR mutation(s) known to be associated with epidermal growth factor receptor
                      (EGFR) tyrosine kinase inhibitors (TKI) sensitivity at diagnosis.
    
                   -  Received only 1 line of therapy, with single-agent osimertinib, for advanced
                      NSCLC, with clinical benefit as judged by investigator discretion.
    
                   -  Evidence of radiological disease progression on first-line monotherapy with
                      osimertinib 80mg once daily.
    
              -  Suitable for a mandatory biopsy defined as having an accessible tumour and a stable
                 clinical condition that will allow the patient to tolerate the procedure. The biopsy
                 should be performed within 60 days prior to the planned first dose of study treatment.
    
              -  Patients must have measurable disease per Response Evaluation Criteria In Solid
                 Tumours (RECIST) 1.1.
    
              -  World Health Organisation (WHO) performance status 0 or 1 with no deterioration
                 between screening and the first dose of study treatment and a minimum life expectancy
                 of 12 weeks.
    
              -  Adequate coagulation parameters, defined as: International Normalisation Ratio (INR)
                 <1.5 × ULN and activated partial thromboplastin time <1.5 × ULN unless patients are
                 receiving therapeutic anti-coagulation which affects these parameters.
    
              -  Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically
                 stable on low molecular weight heparin, factor Xa inhibitors or thrombin inhibitors
                 for ≥2 weeks.
    
              -  Willingness to adhere to the study treatment-specific contraception requirements.
    
            Exclusion Criteria applicable to all study treatment modules (Groups A/B):
    
              -  Patients whose disease has progressed within the first 3 months of osimertinib
                 treatment
    
              -  Patients must not have experienced a toxicity(-ies) that led to permanent
                 discontinuation or dose reduction of prior osimertinib or have any unresolved
                 toxicities from prior osimertinib treatment greater than CTCAE (Common Terminology
                 Criteria for Adverse Event) Grade 1 at the time of starting study treatment
    
              -  Patients should not have discontinued osimertinib >60 days prior to the first dose of
                 study treatment
    
              -  Prior or concurrent treatment with any systemic anti-cancer therapy for locally
                 advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or
                 any investigational drug (exceptions do apply)
    
              -  Major surgery within the 28 days prior to the first dose of study treatment except:
    
                 o After minor surgery, at least 7 postoperative days must elapse before study
                 treatment is initiated. After placement of vascular access, this waiting period is not
                 required.
    
              -  Receipt of live attenuated vaccine within 30 days prior to the first dose of study
                 treatment.
    
              -  Treatment with warfarin/coumarin analogues within 7 days prior to the first dose of
                 study treatment
    
              -  Diagnosis of small cell lung cancer (SCLC) or squamous cell carcinoma (SCC)
    
              -  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.
    
              -  Allogenic organ transplantation
    
              -  History of another primary malignancy except for:
    
                   -  Malignancy treated with curative intent and with no known active disease for at
                      least 2 years before the first dose of study treatment.
    
                   -  Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of
                      disease
    
                   -  Adequately treated carcinoma in situ without evidence of disease.
    
                   -  Localised non-invasive primary disease under surveillance.
    
              -  Active infection, including infections with hepatitis B virus, hepatitis C virus, or
                 human immunodeficiency virus
    
              -  Pregnancy or breastfeeding in female patients
    
              -  Any of the following cardiac criteria:
    
                   -  Any clinically important abnormalities in rhythm, conduction, or morphology of
                      resting ECG
    
                   -  Unstable atrial fibrillation or unstable cardiac arrhythmia with a ventricular
                      rate >100 bpm on an ECG at rest.
    
                   -  Uncontrolled hypertension
    
                   -  Uncontrolled angina or acute coronary syndrome within 6 months prior to
                      screening.
    
                   -  At risk for brain perfusion problems or stroke, or transient ischemic attack in
                      the last 6 months prior to screening
    
                   -  Symptomatic heart failure - prior or current cardiomyopathy.
    
                   -  Severe valvular heart disease
    
              -  Inadequate bone marrow reserve or organ function
    
              -  Creatinine clearance <50 mL/min, calculated by Cockcroft-Gault equation
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Months
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Objective response rate (ORR)
    Time Frame:Measured from first dose until confirmed response or progression. For each patient this is expected to be 3 months on average
    Safety Issue:
    Description:The percentage of patients with a confirmed investigator-assessed complete or partial response according to Response Evaluation Criteria In Solid Tumours (RECIST) 1.1. Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST 1.1 defined disease progression or cessation of study treatment (if treating beyond progression).

    Secondary Outcome Measures

    Measure:Progression-free survival (PFS)
    Time Frame:Measured from first dose until progression. For each patient this is expected to be 18 months on average
    Safety Issue:
    Description:The time from first dose until the date of objective disease progression or death (by any cause in the absence of progression). Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST (Response Evaluation Criteria In Solid Tumours)1.1 defined disease progression or cessation of study treatment (if treating beyond progression).
    Measure:Duration of response (DoR)
    Time Frame:Measured from response until progression. For each patient this is expected to be 15 months on average
    Safety Issue:
    Description:The time from the date of first response until date of disease progression or death in the absence of disease progression. Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST 1.1 defined disease progression or cessation of study treatment (if treating beyond progression).
    Measure:Overall survival (OS)
    Time Frame:Measured from first dose until death or final cohort data cut-off. For each patient this is expected to be 30 months on average
    Safety Issue:
    Description:The time from the date of the first dose of study treatment until death due to any cause.
    Measure:Plasma concentrations of therapeutic agents
    Time Frame:Pre-dose and 1 hour post-dose blood samples on Day 1 of Cycles 1, 3, 6 for all therapeutic agents and a sample at the 90-day safety follow up for durvalumab only. (One Cycle = 21 or 28 days, depending on treatment)
    Safety Issue:
    Description:Blood samples will be collected at various timepoints to evaluate the pharmacokinetics of study therapeutic agents.
    Measure:Incidence of Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) as characterized and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event [CTCAE] v5
    Time Frame:Continuously from first dose to end of safety follow up after study treatment discontinuation (approximately up to 21 Months)
    Safety Issue:
    Description:To evaluate safety and tolerability of each study treatment

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:AstraZeneca

    Trial Keywords

    • Non-small cell lung cancer
    • Phase II
    • Platform study
    • Biomarker-directed
    • Durvalumab
    • Osimertinib
    • Savolitinib
    • Gefitinib
    • Necitumumab
    • Platinum-containing doublet
    • Pemetrexed
    • Carboplatin
    • EGFR positive
    • NSCLC

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