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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03944772
Recruitment Status : Recruiting
First Posted : May 10, 2019
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE April 29, 2019
First Posted Date  ICMJE May 10, 2019
Last Update Posted Date November 17, 2020
Actual Study Start Date  ICMJE June 25, 2019
Estimated Primary Completion Date November 29, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
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 ]
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2020)
  • Progression-free survival (PFS) [ Time Frame: Measured from first dose until progression. For each patient this is expected to be 6 months on average ]
    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).
  • Duration of response (DoR) [ Time Frame: Measured from response until progression. For each patient this is expected to be 6 months on average ]
    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).
  • 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 20 months on average ]
    The time from the date of the first dose of study treatment until death due to any cause.
  • Plasma concentrations of therapeutic agents [ Time Frame: Pre-dose and 1 hour post-dose blood samples on Day 1 of Cycles 1, 3 (Cycle 2 for durvalumab), 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). ]
    Blood samples will be collected at various timepoints to evaluate the sparse pharmacokinetics of study therapeutic agents.
  • Plasma concentrations of therapeutic agents [ Time Frame: Pre-dose and serial post-dose blood samples (1 hour, 2 hours, 4 hours, 6 hours, 8 hours) on Day 15 of Cycle 1 for alectinib and selpercatinib only. ]
    Blood samples will be collected at various timepoints to evaluate the serial pharmacokinetics of study therapeutic agents
  • 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) ]
    To evaluate safety and tolerability of each study treatment
Original Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
  • Progression-free survival (PFS) [ Time Frame: Measured from first dose until progression. For each patient this is expected to be 18 months on average ]
    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).
  • Duration of response (DoR) [ Time Frame: Measured from response until progression. For each patient this is expected to be 15 months on average ]
    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).
  • 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 ]
    The time from the date of the first dose of study treatment until death due to any cause.
  • 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) ]
    Blood samples will be collected at various timepoints to evaluate the pharmacokinetics of study therapeutic agents.
  • 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) ]
    To evaluate safety and tolerability of each study treatment
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD)
Official Title  ICMJE A Biomarker-directed Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy.
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Phase 2 platform study in patients with advanced Non-Small Lung Cancer harbouring an epidermal growth factor receptor (EGFR)-sensitizing mutation with evidence of radiological progression following first-Line osimertinib therapy. This study is modular in design, allowing evaluation of the efficacy, safety and tolerability of multiple study treatments. The study will be conducted in three groups (Groups A, B and C). Patient allocation to a study treatment within each group will be based on tumour molecular profile. Biomarker positive patients will be allocated to a biomarker-matched study treatment in Group A, patients without a biomarker will be allocated to a study treatment in Group B and patients with histological transformed disease or a biomarker amenable to therapies not currently available in ORCHARD will be allocated to Group C (observational; patients managed in accordance with local practice).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non-Small Cell Lung Cancer
Intervention  ICMJE
  • Drug: Osimertinib
    Osimertinib given orally at 80 mg once daily
    Other Name: TAGRISSO
  • Drug: Savolitinib
    Savolitinib will be given orally at 300 mg or 600mg once daily
  • Drug: Gefitinib
    Gefitinib given orally at 250 mg once daily
    Other Name: Iressa
  • Drug: Necitumumab
    Necitumumab given IV at 800 mg on Day 1 and Day 8 of every 3-week cycle
    Other Name: Portrazza
  • Drug: Durvalumab
    Durvalumab given IV at 1500 mg on Day 1 of every cycle
    Other Name: IMFINZI
  • Drug: Carboplatin
    Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles
  • Drug: Pemetrexed
    Pemetrexed given IV at 500 mg/m2 body BSA on Day 1 of every cycle
  • Drug: Alectinib
    Alectinib given orally at 600mg twice daily and for Japanese patients at 300mg twice daily.
    Other Name: Alecensa
  • Drug: Selpercatinib
    Selpercatinib given orally at 160mg twice daily
    Other Name: Loxo-292
Study Arms  ICMJE
  • Experimental: Module 1: Osimertinib + Savolitinib
    The patients in this group will receive osimertinib taken in combination with savolitinib
    Interventions:
    • Drug: Osimertinib
    • Drug: Savolitinib
  • Experimental: Module 2: Osimertinib + Gefitinib
    The patients in this group will receive osimertinib taken in combination with gefitinib
    Interventions:
    • Drug: Osimertinib
    • Drug: Gefitinib
  • Experimental: Module 3: Osimertinib + Necitumumab
    The patients in this group will receive osimertinib taken in combination with necitumumab
    Interventions:
    • Drug: Osimertinib
    • Drug: Necitumumab
  • Experimental: Module 4: Carboplatin + Pemetrexed + Durvalumab)
    The patients in this group will receive platinum-containing doublet (carboplatin + pemetrexed) taken in combination with durvalumab.
    Interventions:
    • Drug: Durvalumab
    • Drug: Carboplatin
    • Drug: Pemetrexed
  • No Intervention: Observational Cohort: No study drug

    Patients 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.

  • Experimental: Module 5: Osimertinib + Alectinib
    The patients in this group will receive osimertinib taken in combination with alectinib
    Interventions:
    • Drug: Osimertinib
    • Drug: Alectinib
  • Experimental: Module 6: Osimertinib + Selpercatinib
    The patients in this group will receive osimertinib taken in combination with selpercatinib
    Interventions:
    • Drug: Osimertinib
    • Drug: Selpercatinib
Publications * Schmid S, Früh M, Peters S. Targeting MET in EGFR resistance in non-small-cell lung cancer-ready for daily practice? Lancet Oncol. 2020 Mar;21(3):320-322. doi: 10.1016/S1470-2045(19)30859-9. Epub 2020 Feb 3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 24, 2020)
182
Original Estimated Enrollment  ICMJE
 (submitted: May 8, 2019)
150
Estimated Study Completion Date  ICMJE November 29, 2023
Estimated Primary Completion Date November 29, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 epidermal growth factor receptor (EGFR) mutation(s) known to be associated with 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.
  • A minimum life expectancy of 12 weeks.
  • Ability to swallow and retain oral medication and have adequate venous access.
  • Provision of archival tumour tissue for exploratory research (if such tissue/sample is available, its provision is mandatory).
  • Ability and willingness to comply with the study and follow-up.
  • Adequate coagulation parameters, defined as: International Normalisation Ratio (INR) <1.5 × upper limit of normal (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 must not have discontinued osimertinib >60 days prior to the first dose of study treatment
  • Prior or concurrent treatment with any systemic anticancer 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:

    • 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
  • As judged by the investigator, any evidence of severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study.
  • 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, and with low potential risk for recurrence.
    • 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 (exceptions apply)
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: Cancer Study Locator (For US sites only) 1-877-400-4656 astrazeneca@emergingmed.com
Listed Location Countries  ICMJE Sweden,   Denmark,   Japan,   Korea, Republic of,   Netherlands,   Norway,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03944772
Other Study ID Numbers  ICMJE D6186C00001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Helena A Yu, MD Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
PRS Account AstraZeneca
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP