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National Lung Matrix Trial: Multi-drug Phase II Trial in Non-Small Cell Lung Cancer

NCT02664935

Description:

The trial consists of a series of parallel multi-centre single arm phase II trial arms, each testing an experimental targeted drug in a population stratified by multiple pre-specified actionable target putative biomarkers. The primary objective is to evaluate whether there is a signal of activity in each drug-(putative)biomarker cohort separately. A Bayesian adaptive design is adopted to achieve this objective and statistical details are given in the Protocol.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

National Lung Matrix Trial: Multi-drug Phase II Trial in Non-Small Cell Lung Cancer

Title

  • Brief Title: National Lung Matrix Trial: Multi-drug Phase II Trial in Non-Small Cell Lung Cancer
  • Official Title: National Lung Matrix Trial: Multi-drug, Genetic Marker-directed, Non-comparative, Multi-centre, Multi-arm Phase II Trial in Non-small Cell Lung Cancer
  • Clinical Trial IDs

    NCT ID: NCT02664935

    ORG ID: RG_14-072

    NCI ID: 2014-000814-73

    Trial Conditions

    Non-Small Cell Lung Cancer

    Carcinoma, Squamous Cell

    Adenocarcinoma

    Trial Interventions

    Drug Synonyms Arms
    AZD4547 Arm A: AZD4547
    AZD2014 Arm B: AZD2014
    Palbociclib Arm C: Palbociclib
    Crizotinib Arm D: Crizotinib
    Selumetinib AZD6244 Arm E: Selumetinib & Docetaxel
    Docetaxel Arm E: Selumetinib & Docetaxel
    AZD5363 Arm F: AZD5363
    AZD9291 Arm G: AZD9291
    MEDI4736 Durvalumab Arm NA Cohort NA1: MEDI4736

    Trial Purpose

    The trial consists of a series of parallel multi-centre single arm phase II trial arms, each
    testing an experimental targeted drug in a population stratified by multiple pre-specified
    actionable target putative biomarkers. The primary objective is to evaluate whether there is
    a signal of activity in each drug-(putative)biomarker cohort separately. A Bayesian adaptive
    design is adopted to achieve this objective and statistical details are given in the
    Protocol.

    Detailed Description

    The trial is primarily an enrichment putative biomarker design, including patients who are
    positive for at least one of the actionable targets included in the trial. Patients who are
    positive for just one putative biomarker will receive the experimental targeted drug
    specific for that putative biomarker. Putative biomarkers within each drug cohort have been
    chosen such that in the majority of cases it is not expected that patients will be positive
    for two or more putative biomarkers within the same drug. In the rare situation that
    patients are positive for two or more putative biomarkers relevant across different drugs,
    treatment will be allocated in accordance with the following strategy:

    - All amplifications and rearrangements will be treated with targeted agent appropriate
    to them irrespective of concomitant mutations. This will yield crucial predictive
    biomarker information.

    - For concomitant mutations decisions will be made by the Chief Investigator on a
    case-by-case basis and based on close consideration of pathway preference and likely
    dominance of one signal pathway over another together with any pre-clinical efficacy
    studies that address the activity of the drugs in the presence of concomitant
    mutations. A trumping strategy has been devised for this purpose.

    Trial Arms

    Name Type Description Interventions
    Arm A: AZD4547 Experimental AZD4547 - FGFR Inhibitor Route & Formulation: Oral, Tablets Strengths: 20 & 80mg Trial Dose & Schedule: 80 mg BD, Continuous dosing, 21 day cycle AZD4547
    Arm B: AZD2014 Experimental AZD2014 - MTORC1/2 Inhibitor Route & Formulation: Oral, Tablets Strengths: 25mg Trial Dose & Schedule: 125 mg BD, Intermittent dosing (2 continuous days in 7), 28 day cycle. AZD2014
    Arm C: Palbociclib Experimental Palbociclib - CDK4/6 Inhibitor Route & Formulation: Oral, Capsules Strengths: 75, 100 & 125mg Trial Dose & Schedule: 125 mg OD, Intermittent dosing (21 days on, 7 days off), 28 day cycle. Palbociclib
    Arm D: Crizotinib Experimental Crizotinib - ALK Inhibitor Route & Formulation: Oral, Capsules Strengths: 200 & 250mg Trial Dose & Schedule: 250 mg BD, Continuous dosing, 21 day cycle. Crizotinib
    Arm E: Selumetinib & Docetaxel Experimental AZD6244 (Selumetinib) - MEK Inhibitor Route & Formulation: Oral, Capsules Strengths: 25mg Trial Dose & Schedule: 75 mg BD, Continuous dosing, 21 day cycle. Docetaxel - Chemotherapy Route & Formulation: IV infusion over 30-60 minutes, concentrate for solution for infusion. Trial Dose & Schedule: 75 mg/m2, 3-weekly, 21 day cycle. Selumetinib, Docetaxel
    Arm F: AZD5363 Experimental AZD5363 - AKT Inhibitor Route & Formulation: Oral, Tablets Strengths: 80 & 200mg Trial Dose & Schedule: 480 mg BD, Intermittent dosing (4 days on, 3 days off), 28 day cycles. AZD5363
    Arm G: AZD9291 Experimental AZD9291 - EGFRM+ and T790M+ Inhibitor Route & Formulation: Oral, Tablets Strengths: 80mg Trial Dose & Schedule: 80 md OD, Continuous dosing, 21 day cycles AZD9291
    Arm NA Cohort NA1: MEDI4736 Experimental MEDI4736 - Anti-PDL1 Route & Formulation: IV Infusion, Lyophilized powder for solution for infusion Strengths: Vial containing 200mg Trial Dose & Schedule: 10 mg/kg IV, 2-weekly. MEDI4736

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have completed all standard of care therapy that the treating
    oncologist thinks is appropriate. As a minimum patients must have failed one or more
    lines of treatment (either radiological documentation of disease progression or due
    to toxicity).

    - Patients who have progressed after surgical resection and adjuvant therapy will be
    eligible for entry without the need for the administration of first line metastatic
    therapy, if they have progressed within 6 months of completing their adjuvant
    treatment.

    - Patients will also be eligible without the necessity for first line regimen if they
    have relapsed within 6 months of completion of definitive chemoradiation.

    - Consented and provided an adequate specimen to adequately characterise the molecular
    genotype of the tumour in the molecular pre-screening according to the molecular
    exclusion rules (see section 6.4 for definition of an adequate sample).

    - Histological or cytologically confirmed NSCLC stage III (not suitable for radical
    radiotherapy or surgery) or stage IV. This includes patients who may have abnormal
    histology, but IHC strongly support either squamous cell carcinoma (p63 positivity)
    or adenocarcinoma (Thyroid transcription factor 1 [TTF1] positivity). If a physician
    and pathologist are convinced after multi-disciplinary review that the patient has
    stage III or IV NSCLC but where all the IHC is negative and the morphology does not
    distinguish a specific sub-type, these patients will be eligible for non-histology
    specific cohorts.

    - CT scan of head, chest and abdomen within 28 days of treatment demonstrating
    measurable disease as per RECIST version 1.1.

    - Adequate haematological function within 7 days of treatment.

    - Haemoglobin 90 g/L.

    - Absolute neutrophil count (ANC) 1.5 x 109/L.

    - Platelets 100 x 109/L.

    - Adequate hepatic function within 7 days of treatment in patients with no liver
    metastasis (see arm specific entry criteria for adequate hepatic function in patients
    with liver metastases).

    - Total serum bilirubin 1.5 x upper limit of normal (ULN).

    - Alanine transferase (ALT) 2.5 x ULN.

    - Aspartate transferase (AST) 2.5 x ULN.

    - Adequate renal function within 7 days of treatment.

    - Creatinine clearance (CLcr) >50 ml/min (measured or calculated by Cockcroft and
    Gault equation).

    - Age 18 years.

    - Females must agree to use adequate contraceptive measures, should not be breast
    feeding and must have a negative pregnancy test prior to start of dosing if of
    child-bearing potential or must have evidence of non-child-bearing potential by
    fulfilling one of the following criteria at screening:

    - Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least
    12 months following cessation of all exogenous hormonal treatments

    - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
    oophorectomy or bilateral salpingectomy but not tubal ligation.

    - Women aged under 50 years old would be consider postmenopausal if they have been
    amenorrhoeic for 12 months or more following cessation of exogenous hormonal
    treatments and with luteinizing hormone (LH) and follicle stimulating hormone
    (FSH) levels in the post-menopausal range for the institution.

    - Provision of signed and dated, written informed consent prior to any study specific
    procedures, sampling and analyses.

    Exclusion Criteria:

    - Major surgery (excluding placement of vascular access), chemotherapy, radiotherapy,
    any investigational agents or other anti-cancer therapy within 4 weeks prior to
    treatment.

    - Nausea, vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease)
    that would preclude adequate absorption.

    - Any psychological, familial, sociological or geographical condition hampering
    protocol compliance.

    - Concurrent malignancies or invasive cancers diagnosed within past 3 years except for
    adequately treated basal cell carcinoma of the skin and in situ carcinoma of the
    uterine cervix.

    - Judgement by the investigator that the patient should not participate in the study if
    the patient is unlikely to comply with study procedures, restrictions and
    requirements.

    - Any unresolved toxicity of grade 2, 3 or 4 from previous treatment (excluding
    alopecia) at Registration (see CTCAE).

    - Patients who have previous symptomatic brain metastases or spinal cord compression
    are excluded unless they have had adequate treatment, no evidence of progression or
    symptoms, and have had no requirement for steroid treatment in the previous 28 days
    before commencement of trial treatment.

    - Patients with asymptomatic brain metastases picked up at screening CT scan are not
    excluded providing that in the view of the investigator they do not require immediate
    radiotherapy or surgical intervention, and have had no requirement for steroid
    treatment in the previous 28 days before commencement of trial treatment.

    - As judged by the investigator, any evidence of severe or uncontrolled systemic
    diseases, including active bleeding diatheses, or active infection including
    hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic
    conditions is not required.

    - Pregnant or breast-feeding women

    Cardiac exclusion criteria and performance status eligibility criteria are detailed within
    The National Lung Matrix Trial arm-specific eligibility criteria.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Best objective response rate (ORR)

    Progression-free survival time (PFS)

    Secondary Outcome Measures

    Best percentage change in sum of target lesion diameters (PCSD)

    Time to Progression (TTP)

    Overall survival time (OS)

    Toxicity (Adverse Event as per CTCAE criteria)

    Trial Keywords

    NSCLC

    Lung Cancer

    Adenocarcinoma

    Matrix

    SMP2

    Umbrella Trial Design

    Multi-arm