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

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ClinicalTrials.gov Identifier: NCT02664935
Recruitment Status : Recruiting
First Posted : January 27, 2016
Last Update Posted : March 18, 2019
Sponsor:
Collaborators:
Cancer Research UK
AstraZeneca
Pfizer
Experimental Cancer Medicine Centres
Mirati Therapeutics Inc.
Information provided by (Responsible Party):
University of Birmingham

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer Carcinoma, Squamous Cell Adenocarcinoma Drug: AZD4547 Drug: Vistusertib Drug: Palbociclib Drug: Crizotinib Drug: Selumetinib Drug: Docetaxel Drug: AZD5363 Drug: Osimertinib Drug: Durvalumab Drug: Sitravatinib Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 620 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 2015
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Arm A: AZD4547
AZD4547 - FGFR Inhibitor Route & Formulation: Oral, Tablets Strengths: 20 & 80mg Trial Dose & Schedule: 80 mg BD, Continuous dosing, 21 day cycle
Drug: AZD4547
FGFR Inhibitor

Experimental: Arm B: Vistusertib (AZD2014)
Vistusertib (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.
Drug: Vistusertib
MTORC1/2 Inhibitor
Other Name: AZD2014

Experimental: Arm C: Palbociclib
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.
Drug: Palbociclib
CDK4/6 Inhibitor

Experimental: Arm D: Crizotinib
Crizotinib - ALK Inhibitor Route & Formulation: Oral, Capsules Strengths: 200 & 250mg Trial Dose & Schedule: 250 mg BD, Continuous dosing, 21 day cycle.
Drug: Crizotinib
ALK/MET/ROS1 Inhibitor

Experimental: Arm E: Selumetinib & Docetaxel

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.

Drug: Selumetinib
MEK Inhibitor
Other Name: AZD6244

Drug: Docetaxel
Taxane, anti-mitotic cytotoxic chemotherapy

Experimental: Arm F: AZD5363
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.
Drug: AZD5363
AKT Inhibitor

Experimental: Arm G: Osimertinib (AZD9291)
Osimertinib (AZD9291) - EGFRM+ and T790M+ Inhibitor Route & Formulation: Oral, Tablets Strengths: 80mg Trial Dose & Schedule: 80 mg OD, Continuous dosing, 21 day cycles
Drug: Osimertinib
EGFRm+ T790M+ Inhibitor
Other Name: AZD9291

Experimental: Arm NA: Durvalumab (MEDI4736)
Durvalumab (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.
Drug: Durvalumab
Anti-PDL1
Other Name: MEDI4736

Experimental: Arm H: Sitravatinib
Sitravatinib - VEGFR Inhibitor Route & Formulation: Oral, Capsules Strengths: 10 & 40mg Trial Dose & Schedule: 120 mg OD, Continuous dosing, 21 day cycles
Drug: Sitravatinib
VEGFR Inhibitor
Other Name: MGCD516




Primary Outcome Measures :
  1. Objective response (OR) [ Time Frame: From baseline until disease progression, assessed up to 18 months. ]
    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.

  2. Progression-free survival time (PFS) [ Time Frame: From date of commencement of trial treatment to date of CT scan when progressive disease first recorded or date of death without previously recorded progression, assessed up to 18 months. ]
    Defined as the time from commencement of trial treatment to the date of CT scan when progressive disease first recorded or date of death without previously recorded progression (Primary Outcome for Arm C only). Patients who are alive with no recorded progression at the time of analysis 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.

  3. Durable clinical benefit (DCB) [ Time Frame: From baseline until the first scan after 24 weeks showing the patient free of disease progression. ]
    A patient will be defined as experiencing DCB if they remain free of disease progression at their fourth CT or MRI scan since treatment start date, i.e. approximately 24 weeks, or at any scan after 24 weeks that shows the patient free of disease progression (co-primary outcome for all Trial Arms except Arm C & G)


Secondary Outcome Measures :
  1. Best percentage change in sum of target lesion diameters (PCSD) [ Time Frame: From baseline until disease progression, assessed up to 18 months. ]
    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.

  2. 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. ]
    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.

  3. Overall survival time (OS) [ Time Frame: From time of commencement of trial treatment until date of death, assessed up to 18 months. ]
    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.

  4. 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. ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02664935


Contacts
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Contact: Manita Mehmi 01214147611 lungmatrix@trials.bham.ac.uk
Contact: Joshua S Savage 01214158421 lungmatrix@trials.bham.ac.uk

Locations
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United Kingdom
Belfast City Hospital, Belfast Health and Social Care Trust Recruiting
Belfast, United Kingdom
Principal Investigator: Paula Scullin         
Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust Recruiting
Birmingham, United Kingdom, B15 2GW
Contact: Gary Middleton, MB BS MD FRCP         
Principal Investigator: Gary Middleton, MB BS MD FRCP         
Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust Recruiting
Birmingham, United Kingdom
Principal Investigator: Joyce Thompson         
University Hospitals Bristol NHS Foundation Trust Not yet recruiting
Bristol, United Kingdom
Principal Investigator: Adam Dangoor         
Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust Recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: David Gilligan, BSc (Hons) MB BChir FRCP FRCR       cctc@addenbrookes.nhs.uk   
Principal Investigator: David Gilligan, BSc (Hons) MB BChir FRCP FRCR         
Velindre Cancer Centre, Velindre NHS Trust Recruiting
Cardiff, United Kingdom, CF14 2TL
Contact: Alison Brewster, BSC MB BCh FRCR MD    029 2061 5888      
Principal Investigator: Alison Brewster, BSC MB BCh FRCR MD         
Colchester General Hospital Recruiting
Colchester, United Kingdom
Principal Investigator: Dakshinamoorthy Muthukumar         
Edinburgh Cancer Centre, Western General Hospital Active, not recruiting
Edinburgh, United Kingdom, EH4 2XU
Royal Devon and Exeter Hospital Recruiting
Exeter, United Kingdom
Contact: Elizabeth Toy         
Principal Investigator: Elizabeth Toy         
Cancer Research UK Clinical Trials Unit, Beatson West of Scotland Cancer Centre Recruiting
Glasgow, United Kingdom, G12 0YN
Contact: Noelle O'Rourke, BA MB MCh MA MCRP MD FRCR CCST         
Principal Investigator: Noelle O'Rourke, BA MB MCh MA MCRP MD FRCR CCST         
St. James' University Hospital, Leeds Teaching Hospital NHS Trust Recruiting
Leeds, United Kingdom, LS9 7TF
Contact: Clive Mulatero, BA MB BCh MA PhD FRCP         
Principal Investigator: Clive Mulatero, BA MB BCh MA PhD FRCP         
Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust Recruiting
Leicester, United Kingdom
Contact: Dean Fennell         
Principal Investigator: Dean Fennell         
Royal Marsden Hospital, The Royal Marsden NHS Foundation Trust Recruiting
London, United Kingdom, SW3 6JJ
Contact: Sanjay Popat         
Principal Investigator: Sanjay Popat, BSc MB BS MRCP PhD FRCP         
Charing Cross Hospital, Imperial College Healthcare NHS Trust Recruiting
London, United Kingdom
Contact: Conrad Lewanski         
Principal Investigator: Conrad Lewanski         
Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust Recruiting
London, United Kingdom
Contact: James Spicer         
Principal Investigator: James Spicer         
St Bartholomew's Hospital, Barts Health NHS Trust Recruiting
London, United Kingdom
Contact: John Conibear         
Principal Investigator: John Conibear         
University College Hospital, University College London Hospitals NHS Foundation Trust Recruiting
London, United Kingdom
Principal Investigator: Martin Forster         
The Christie Hospital, The Christie NHS Foundation Trust Recruiting
Manchester, United Kingdom
Contact: Yvonne Summers         
Principal Investigator: Yvonne Summers         
Sir Bobby Robson Cancer Trial Research Centre, The Newcastle upon Tyne Hospitals Recruiting
Newcastle, United Kingdom, NE7 7DN
Contact: Alastair Greystoke         
Principal Investigator: Alastair Greystoke, BSc MBChB MRCP MSc PhD         
Churchill Hospital, Oxford University Hospitals NHS Foundation Trust Recruiting
Oxford, United Kingdom
Contact: Denis Talbot         
Principal Investigator: Denis Talbot         
Weston Park Hospital, Sheffield Teaching Hospitals NHS Foundation Trust Recruiting
Sheffield, United Kingdom
Contact: Sarah Danson         
Principal Investigator: Sarah Danson         
Southampton General Hospital, University Hospital Southampton NHS Foundation Trust Recruiting
Southampton, United Kingdom, SO16 6YD
Contact       clinicaltrials@uhs.nhs.uk   
Principal Investigator: Judith Cave         
Sponsors and Collaborators
University of Birmingham
Cancer Research UK
AstraZeneca
Pfizer
Experimental Cancer Medicine Centres
Mirati Therapeutics Inc.
Investigators
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Principal Investigator: Gary W Middleton University of Birmingham

Additional Information:
Study Data/Documents: Trial Website  This link exits the ClinicalTrials.gov site
ISRCTN Registry  This link exits the ClinicalTrials.gov site
Identifier: ISRCTN38344105

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Responsible Party: University of Birmingham
ClinicalTrials.gov Identifier: NCT02664935     History of Changes
Other Study ID Numbers: RG_14-072
2014-000814-73 ( EudraCT Number )
ISRCTN38344105 ( Other Identifier: ISRCTN )
First Posted: January 27, 2016    Key Record Dates
Last Update Posted: March 18, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by University of Birmingham:
NSCLC
Lung Cancer
Adenocarcinoma
Matrix
SMP2
Umbrella Trial Design
Multi-arm
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Lung Diseases
Adenocarcinoma
Carcinoma, Squamous Cell
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Docetaxel
Durvalumab
Palbociclib
Crizotinib
Osimertinib
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Protein Kinase Inhibitors
Enzyme Inhibitors