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

NCT ID: NCT02664935

Last Updated: 2025-05-21

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 423 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-05-31
• Study Completion Date: 2025-09-30

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.

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.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A: AZD4547

AZD4547 - FGFR Inhibitor Route \& Formulation: Oral, Tablets Strengths: 20 \& 80mg Trial Dose \& Schedule: 80 mg BD, Continuous dosing, 21 day cycle.

Group Type: EXPERIMENTAL

AZD4547

Intervention Type: DRUG

FGFR Inhibitor

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.

Group Type: EXPERIMENTAL

Vistusertib

Intervention Type: DRUG

MTORC1/2 Inhibitor

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.

Group Type: EXPERIMENTAL

Palbociclib

Intervention Type: DRUG

CDK4/6 Inhibitor

Arm D: Crizotinib

Crizotinib - ALK Inhibitor Route \& Formulation: Oral, Capsules Strengths: 200 \& 250mg Trial Dose \& Schedule: 250 mg BD, Continuous dosing, 21 day cycle.

Group Type: EXPERIMENTAL

Crizotinib

Intervention Type: DRUG

ALK/MET/ROS1 Inhibitor

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.

Group Type: EXPERIMENTAL

Selumetinib

Intervention Type: DRUG

MEK Inhibitor

Docetaxel

Intervention Type: DRUG

Taxane, anti-mitotic cytotoxic chemotherapy

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.

Group Type: EXPERIMENTAL

AZD5363

Intervention Type: DRUG

AKT Inhibitor

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.

Group Type: EXPERIMENTAL

Osimertinib

Intervention Type: DRUG

EGFRm+ T790M+ Inhibitor

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.

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Anti-PDL1

Arm H: Sitravatinib

Sitravatinib - VEGFR Inhibitor Route \& Formulation: Oral, Capsules Strengths: 10 \& 40mg Trial Dose \& Schedule: 120 mg OD, Continuous dosing, 21 day cycles.

Group Type: EXPERIMENTAL

Sitravatinib

Intervention Type: DRUG

VEGFR Inhibitor

Arm J: AZ6738 & Durvalumab

AZD6738 - ATR Inhibitor Route & Formulation: Oral, Tablets Strengths: 20mg, 80mg, 100mg Trial Dose & Schedule: 240 mg twice daily (BD) on days 15-28 of 28 day cycle.

Durvalumab (MEDI4736) - Anti-PDL1 Route & Formulation: IV Infusion, Lyophilized powder for solution for infusion Strengths: Vial containing 500mg Trial Dose & Schedule: 1500mg on day 1 of each 28 day cycle

Group Type: EXPERIMENTAL

Durvalumab

Intervention Type: DRUG

Anti-PDL1

AZD6738

Intervention Type: DRUG

ATR inhibitor

Interventions

AZD4547

FGFR Inhibitor

Intervention Type: DRUG

Vistusertib

MTORC1/2 Inhibitor

Intervention Type: DRUG

Palbociclib

CDK4/6 Inhibitor

Intervention Type: DRUG

Crizotinib

ALK/MET/ROS1 Inhibitor

Intervention Type: DRUG

Selumetinib

MEK Inhibitor

Intervention Type: DRUG

Docetaxel

Taxane, anti-mitotic cytotoxic chemotherapy

Intervention Type: DRUG

AZD5363

AKT Inhibitor

Intervention Type: DRUG

Osimertinib

EGFRm+ T790M+ Inhibitor

Intervention Type: DRUG

Durvalumab

Anti-PDL1

Intervention Type: DRUG

Sitravatinib

VEGFR Inhibitor

Intervention Type: DRUG

AZD6738

ATR inhibitor

Intervention Type: DRUG

Other Intervention Names

AZD2014; AZD6244; AZD9291; MEDI4736; MGCD516

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cancer Research UK

OTHER

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Pfizer

INDUSTRY

Sponsor Role: collaborator

Experimental Cancer Medicine Centres

OTHER

Sponsor Role: collaborator

Mirati Therapeutics Inc.

INDUSTRY

Sponsor Role: collaborator

University of Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gary W Middleton

Role: PRINCIPAL_INVESTIGATOR

University of Birmingham

Locations

Aberdeen Royal Infirmary

Aberdeen, , United Kingdom

Belfast City Hospital, Belfast Health and Social Care Trust

Belfast, , United Kingdom

Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust

Birmingham, , United Kingdom

Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust

Birmingham, , United Kingdom

University Hospitals Bristol NHS Foundation Trust

Bristol, , United Kingdom

Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust

Cambridge, , United Kingdom

Velindre Cancer Centre, Velindre NHS Trust

Cardiff, , United Kingdom

Colchester General Hospital

Colchester, , United Kingdom

Edinburgh Cancer Centre, Western General Hospital

Edinburgh, , United Kingdom

Royal Devon and Exeter Hospital

Exeter, , United Kingdom

Beatson West of Scotland Cancer Centre

Glasgow, , United Kingdom

St. James' University Hospital, Leeds Teaching Hospital NHS Trust

Leeds, , United Kingdom

Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust

Leicester, , United Kingdom

Royal Marsden Hospital, The Royal Marsden NHS Foundation Trust

London, , United Kingdom

Charing Cross Hospital, Imperial College Healthcare NHS Trust

London, , United Kingdom

Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust

London, , United Kingdom

St Bartholomew's Hospital, Barts Health NHS Trust

London, , United Kingdom

University College Hospital, University College London Hospitals NHS Foundation Trust

London, , United Kingdom

Maidstone Hospital

Maidstone, , United Kingdom

The Christie Hospital, The Christie NHS Foundation Trust

Manchester, , United Kingdom

Clatterbridge Cancer Centre

Metropolitan Borough of Wirral, , United Kingdom

Sir Bobby Robson Cancer Trial Research Centre, The Newcastle upon Tyne Hospitals

Newcastle, , United Kingdom

Churchill Hospital, Oxford University Hospitals NHS Foundation Trust

Oxford, , United Kingdom

Weston Park Hospital, Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, , United Kingdom

Southampton General Hospital, University Hospital Southampton NHS Foundation Trust

Southampton, , United Kingdom

Countries

United Kingdom

References

Middleton G, Crack LR, Popat S, Swanton C, Hollingsworth SJ, Buller R, Walker I, Carr TH, Wherton D, Billingham LJ. The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer. Ann Oncol. 2015 Dec;26(12):2464-9. doi: 10.1093/annonc/mdv394. Epub 2015 Sep 25.

Reference Type: BACKGROUND

PMID: 26410619 (View on PubMed)

Middleton G, Fletcher P, Popat S, Savage J, Summers Y, Greystoke A, Gilligan D, Cave J, O'Rourke N, Brewster A, Toy E, Spicer J, Jain P, Dangoor A, Mackean M, Forster M, Farley A, Wherton D, Mehmi M, Sharpe R, Mills TC, Cerone MA, Yap TA, Watkins TBK, Lim E, Swanton C, Billingham L. The National Lung Matrix Trial of personalized therapy in lung cancer. Nature. 2020 Jul;583(7818):807-812. doi: 10.1038/s41586-020-2481-8. Epub 2020 Jul 15.

Reference Type: RESULT

PMID: 32669708 (View on PubMed)

Study Documents

Document Type: Trial Website

View Document

Related Links

https://doi.org/10.1016/j.jtho.2019.08.060

PL02.09 National Lung Matrix Trial (NLMT): First Results from an Umbrella Phase II Trial in Advanced Non-Small Cell Lung Cancer (NSCLC) Middleton, G. et al. Journal of Thoracic Oncology, Volume 14, Issue 10, S7

https://doi.org/10.1016/j.jtho.2023.09.154

MA06. 06 A Phase II Trial of Ceralasertib and Durvalumab in Advanced Non-Small Cell Lung Cancer (NSCLC) with and without RAS Mutations: Results of NLMT Arm J

Other Identifiers

2014-000814-73

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ISRCTN38344105

Identifier Type: OTHER

Identifier Source: secondary_id

RG_14-072

Identifier Type: -

Identifier Source: org_study_id