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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

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

  • ORG STUDY ID: RG_14-072
  • SECONDARY ID: 2014-000814-73
  • SECONDARY ID: ISRCTN38344105
  • NCT ID: NCT02664935

Conditions

  • Non-Small Cell Lung Cancer
  • Carcinoma, Squamous Cell
  • Adenocarcinoma

Interventions

DrugSynonymsArms
AZD4547Arm A: AZD4547
VistusertibAZD2014Arm B: Vistusertib (AZD2014)
PalbociclibArm C: Palbociclib
CrizotinibArm D: Crizotinib
SelumetinibAZD6244Arm E: Selumetinib & Docetaxel
DocetaxelArm E: Selumetinib & Docetaxel
AZD5363Arm F: AZD5363
OsimertinibAZD9291Arm G: Osimertinib (AZD9291)
DurvalumabMEDI4736Arm NA: Durvalumab (MEDI4736)
SitravatinibMGCD516Arm H: Sitravatinib

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

NameTypeDescriptionInterventions
Arm A: AZD4547ExperimentalAZD4547 - FGFR Inhibitor Route & Formulation: Oral, Tablets Strengths: 20 & 80mg Trial Dose & Schedule: 80 mg BD, Continuous dosing, 21 day cycle
  • AZD4547
Arm B: Vistusertib (AZD2014)ExperimentalVistusertib (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.
  • Vistusertib
Arm C: PalbociclibExperimentalPalbociclib - 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: CrizotinibExperimentalCrizotinib - ALK Inhibitor Route & Formulation: Oral, Capsules Strengths: 200 & 250mg Trial Dose & Schedule: 250 mg BD, Continuous dosing, 21 day cycle.
  • Crizotinib
Arm E: Selumetinib & DocetaxelExperimentalAZD6244 (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: AZD5363ExperimentalAZD5363 - 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: Osimertinib (AZD9291)ExperimentalOsimertinib (AZD9291) - EGFRM+ and T790M+ Inhibitor Route & Formulation: Oral, Tablets Strengths: 80mg Trial Dose & Schedule: 80 mg OD, Continuous dosing, 21 day cycles
  • Osimertinib
Arm NA: Durvalumab (MEDI4736)ExperimentalDurvalumab (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.
  • Durvalumab
Arm H: SitravatinibExperimentalSitravatinib - VEGFR Inhibitor Route & Formulation: Oral, Capsules Strengths: 10 & 40mg Trial Dose & Schedule: 120 mg OD, Continuous dosing, 21 day cycles
  • Sitravatinib

Eligibility Criteria

        Core inclusion and exclusion criteria are presented below. Additional inclusion/exclusion
        criteria apply to each arm and are presented in the relevant arm supplements of the
        protocol.

        Inclusion Criteria:

          -  Prior anti-cancer treatment:

               -  Patients who refuse any standard of care first line therapy, are eligible to
                  receive National Lung Matrix Trial treatment as first line therapy, providing
                  they explicitly consent to this effect.

               -  Patients who have previously consented to and received standard of care first
                  line therapy 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 whose disease has increased in size but is not
                  classed as progressive disease as per RECIST criteria, will be eligible. Patients
                  with no change at all in dimension of disease (i.e. true stability) after first
                  line therapy will not be eligible.

               -  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.

               -  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 or MRI scan of head, chest and abdomen within 28 days of treatment demonstrating
             measurable disease as per RECIST version 1.1 (see Appendix 1: Response Evaluation
             Criteria in Solid Tumours Version 1.1). (The same imaging modality must be used
             throughout treatment).

          -  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). (Note that this will
                  not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
                  hyperbilirubinemia that is predominantly unconjugated in the absence of evidence
                  of haemolysis or hepatic pathology), who may be allowed inclusion at the
                  discretion of the local Investigator).

               -  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 - see Appendix 4: Cockcroft Gault Formula - Creatinine Clearance).
                  If calculated CLcr is <50 ml/min a direct measurement of glomerular filtration
                  rate (GFR) such as EDTA may be performed. If the value is >50 ml/min the patient
                  is eligible.

          -  Age ≥ 18 years.

          -  Females must agree to use adequate contraceptive measures (as defined in Section 6.3),
             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) 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 local 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 - Appendix 3: Common Toxicity Criteria Gradings).

          -  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 local 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 local 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 and lactating patients (patients of childbearing potential must have a
             negative pregnancy test prior to registration).

        Cardiac exclusion criteria, performance status and prior treatment washout periods are
        detailed within the National Lung Matrix Trial arm-specific eligibility criteria.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response (OR)
Time Frame:From baseline until disease progression, assessed up to 18 months.
Safety Issue:
Description:CT scans every 6 weeks from baseline until disease progression (Primary outcome for all Trial Arms except Arm C). Investigators expect patients to participate in the study for a maximum of 18 months, however cannot guarantee that some patients may participate over 18 months.

Secondary Outcome Measures

Measure:Best percentage change in sum of target lesion diameters (PCSD)
Time Frame:From baseline until disease progression, assessed up to 18 months.
Safety Issue:
Description:At each evaluation, the longest diameters of all selected target lesions will be measured and summed and the percentage change from the baseline measurement will be calculated. The best percentage change is the one that reflects either the greatest decrease or the least increase over the whole period of assessment. Investigators expect patients to participate in the study for a maximum of 18 months, however cannot guarantee that some patients may participate over 18 months.
Measure:Time to Progression (TTP)
Time Frame:The time from commencement of trial treatment to the date of the CT scan when progressive disease first recorded, assessed up to 18 months.
Safety Issue:
Description:This is defined as the time from commencement of trial treatment to the date of the CT scan when progressive disease first recorded. Patients with no recorded progression at the time of analysis or who die without recorded progression will be censored at the date of the CT scan when they were last recorded with an evaluable measure that was not progression. Investigators expect patients to participate in the study for a maximum of 18 months, however cannot guarantee that some patients may participate over 18 months.
Measure:Overall survival time (OS)
Time Frame:From time of commencement of trial treatment until date of death, assessed up to 18 months.
Safety Issue:
Description:This is defined as the time of commencement of trial treatment to the date of death. Patients who are alive at the time of analysis will be censored at the date last seen alive. Investigators expect patients to participate in the study for a maximum of 18 months, however cannot guarantee that some patients may participate over 18 months.
Measure:Adverse Events (AE)
Time Frame:From date of informed consent to trial treatment until 28 days after the last administration of the last treatment, assessed up to 18 months.
Safety Issue:
Description:Adverse events will be recorded in relation to each cycle of treatment and graded according to Common Terminology Criteria for Adverse Events (CTCAE). The incidence of each adverse event (all grades and grade 3/4) will be reported as a per-patient-cycle rate and as a per-patient rate. Investigators expect patients to participate in the study for a maximum of 18 months, however cannot guarantee that some patients may participate over 18 months.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Birmingham

Trial Keywords

  • NSCLC
  • Lung Cancer
  • Adenocarcinoma
  • Matrix
  • SMP2
  • Umbrella Trial Design
  • Multi-arm

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