Condition category
Cancer
Date applied
10/06/2015
Date assigned
10/06/2015
Last edited
21/09/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Mrs Dee Wherton

ORCID ID

Contact details

Early Drug Development Team
Cancer Research UK Clinical Trials Unit
School of Cancer Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom

Additional identifiers

EudraCT number

2014-000814-73

ClinicalTrials.gov number

NCT02664935

Protocol/serial number

17746

Study information

Scientific 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

Acronym

Study hypothesis

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. The trial is primarily an enrichment putative biomarker design, including patients who are positive for at least on 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:
1. All amplifications and rearrangements will be treated with targeted agent appropriate to them irrespective of concomitant mutations. This will yield crucial predictive biomarker information.
2. 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 secondary objective of the trial is to provide the opportunity for industrial partners to test novel agents in the cohort of patients who are not positive for any of the actionable targets in the trial, referred to as the no actionable genetic change arm.

Ethics approval

NRES Committee South Central – Oxford C Research Ethics Committee, 18/12/2014, ref: 14/SC/1346

Study design

Non-randomised; Interventional; Design type: Not specified, Treatment

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Topic: Cancer; Subtopic: Lung Cancer; Disease: Lung (non-small cell)

Intervention

As of 21/09/2016:
1. Arm A - FGFR Inhibitor; AZD4547
2. Arm B - MTORC1/2 Inhibitor; AZD2014
3. Arm C - CDK4/6 Inhibitor; Palbociclib
4. Arm D - ALK Inhibitor; Crizotinib
5. Arm E - MEK inhibitor in combination with Docetaxel; Selumetinib and Docetaxel
6. Arm F – AKT Inhibitor; AZD5363
7. Arm G – EGFR mutation positive T790M+ Inhibitor; AZD9291
8. Arm NA Cohort NA1 - Anti-PDL1; MEDI4736
Study Entry : Registration only

Initial:
1. AZD2014, Arm B - MTORC1/2 Inhibitor; AZD4547
2. Arm A - FGFR Inhibitor; Crizotinib
3.Arm D - ALK Inhibitor; MEDI4736
4. Arm NA Cohort NA1 - Anti-PDL1; Palbociclib
5.Arm C - CDK4/6 Inhibitor; Selumetinib and Docetaxel
6. Arm E - MEK inhibitor in combination with Docetaxel
Study Entry : Registration only

Intervention type

Drug

Phase

Phase II

Drug names

1. AZD4547
2. AZD2014
3. Palbociclib
4. Crizotinib
5. Selumetinib
6. Docetaxel
7. MEDI4736
8. AZD5363 (added 21/09/2016)
9. AZD9291 (added 21/09/2016)

Primary outcome measures

Best objective response rate (ORR); Timepoint(s): Patients will have CT scans every 6 weeks from baseline until disease progression.

Secondary outcome measures

1. Best percentage change in sum of target lesion diameters (PCSD)
2. Overall survival time (OS)
3. Progression-free survival time (PFS)
4. Time to Progression (TTP)
5. Toxicity

Overall trial start date

31/03/2015

Overall trial end date

01/03/2020

Reason abandoned

Eligibility

Participant inclusion criteria

As of 21/09/2016:
1. 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)
2. 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
3. Patients will also be eligible without the necessity for first line regimen if they have relapsed within 6 months of completion of definitive chemoradiation
4. Consented and provided an adequate specimen to completely characterise the molecular phenotype of the tumour in the molecular pre-screening (SMP2) according to the molecular exclusion rules
5. 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
6. CT scan of head, chest and abdomen within 28 days of treatment demonstrating measurable disease as per RECIST version 1.1
7. Adequate haematological function within 7 days of treatment
7.1. Haemoglobin ≥ 90 g/L
7.2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
7.3. Platelets ≥ 100 x 109/L
8. 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).
8.1. Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
8.2. Alanine transferase (ALT) ≤ 2.5 x ULN
8.3. Aspartate transferase (AST) ≤ 2.5 x ULN
9. Adequate renal function within 7 days of treatment.
9.1. Creatinine <1.5 times ULN concurrent with creatinine clearance (CLcr) >50 ml/min (measured or calculated by Cockcroft and Gault equation)
10. Age ≥ 18 years
11. 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:
11.1. Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
11.2. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
11.3. 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.
14. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses

Initial:
1. 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)
2. Consented and provided an adequate specimen to completely characterise the molecular phenotype of the tumour in SMP2
3. Histological or cytologically confirmed NSCLC stage III (not suitable for radical radiotherapy or surgery) or stage IV. This includes patients who may not have clear morphology, 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.
4. CT scan of head, chest and abdomen within 28 days of treatment demonstrating measurable disease as per RECIST version 1.1
5. Eastern Cooperative Oncology Group (ECOG) Performance Status =1 with no deterioration over the previous 2 weeks
6. Adequate haematological function within 7 days of treatment
6.1. Haemoglobin = 90 g/L
6.2. Absolute neutrophil count (ANC) = 1.5 x 109/L
6.3 Platelets = 100 x 109/L
7. Adequate hepatic function within 7 days of treatment
7.1. Total serum bilirubin = 1.5 x upper limit of normal (ULN)
7.2. Alanine transferase (ALT) = 2.5 x ULN
7.3. Aspartate transferase (AST) = 2.5 x ULN
8. Adequate renal function within 7 days of treatment
8.1. Creatinine <1.5 times ULN concurrent with creatinine clearance (CLcr) >50 ml/min (measured or calculated by Cockcroft and Gault equation)
9. Age at least 18 years
10. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses
11. Target Gender: Male & Female

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 620; UK Sample Size: 620

Participant exclusion criteria

As of 21/09/2016:
1. Major surgery (excluding placement of vascular access), chemotherapy, radiotherapy, any investigational agents or other anti-cancer therapy within 4 weeks prior to treatment
2. Nausea, vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) that would preclude adequate absorption
3. Any psychological, familial, sociological or geographical condition hampering protocol compliance.
4. 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
5. 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
6. Any unresolved toxicity of grade 2, 3 or 4 from previous treatment (excluding alopecia) at Registration.
7. 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
8. 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
9. 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
10. 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.

Initial:
1. Major surgery (excluding placement of vascular access), chemotherapy, radiotherapy, any investigational agents or other anti-cancer therapy within 4 weeks prior to treatment.
2. Nausea, vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) that would preclude adequate absorption
3. Any psychological, familial, sociological or geographical condition hampering protocol compliance.
4. Concurrent malignancies or invasive cancers diagnosed within past 5 years except for adequately treated basal cell carcinoma of the skin and in situ carcinoma of the uterine cervix
5. 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
6. Any unresolved toxicity of grade 2, 3 or 4 from previous treatment (excluding alopecia) at Registration
7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 28 days prior to registration
8. 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
9. Patients and patients with partners of childbearing potential not willing to use effective contraception during the trial period and for at least 90 days after completion of treatment
10. Female patients of child bearing potential should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to registration
11. Female patients of non-child-bearing potential are excluded unless they fulfil one of the following criteria at screening:
11.1 Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
11.2 Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
11.3 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

Recruitment start date

31/03/2015

Recruitment end date

01/03/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Cancer Research UK Clinical Trials Unit
School of Cancer Sciences University of Birmingham Edgbaston
Birmingham
B15 2TT
United Kingdom

Sponsor information

Organisation

University of Birmingham

Sponsor details

Early Drug Development Team
Cancer Research UK Clinical Trials Unit
School of Cancer Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom

Sponsor type

University/education

Website

www.birmingham.ac.uk/MATRIX

Funders

Funder type

Government

Funder name

AstraZeneca

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

Pfizer

Alternative name(s)

Pfizer Inc.

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United States of America

Results and Publications

Publication and dissemination plan

1. Abstract submitted on 05-Jun-2016 for NCRI 2016: Lucinda Billingham, Dee Wherton, Laura Llewellyn, Susannah Brown, Sarah Johnson, Peter Fletcher, Clive Mulatero, Tim Yap, Yvonne Summers, James Spicer, Rowena Sharpe, Sanjay Popat, Gary Middleton. National Lung Matrix Trial: successful implementation of a phase II umbrella trial testing multiple genetic-marker-directed drugs in advanced non-small cell lung cancer.
2. Poster for World Precision Medicine Congress, May 2016: Gary Middleton, Sanjay Popat, Ian Walker, Clive Mulatero, James Spicer, Yvonne Summers, Timothy A. Yap, Laura Llewellyn, Dee Wherton, Lucinda Billingham. National Lung Matrix Trial: Multi-drug, genetic marker-directed, non-comparative, multi-centre, multi-arm phase II trial in non-small cell lung cancer.
3. Brock K, Yap C, Middleton G and Billingham L. Modelling clinical trial recruitment using poisson processes. Trials, 16(Suppl 2), p.85 – Published abstract for ICTMC 2015
4. 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;26(12):2464-9
5. 1 abstract and 1 poster NCRI 2015
6. 1 abstract for World Conference on Lung Cancer 2015:
Billingham L, Brock K, Crack L, Popat S, Middleton G. Using a Bayesian adaptive phase II trial design to test multiple genetic-marker-directed drugs in the National Lung Matrix Trial. Journal of Thoracic Oncology 2015; Abstract MINI29.14
7. 1 abstract and presentation for BTOG 2015 - January 2015
8. Brock K, Billingham L, Crack L, Popat S, Middleton G. Forecasting patient recruitment for time-to-event analysis in National Lung Matrix Trial. Lung Cancer, 87(Suppl1), p.S69 – January 2015
9. 1 abstract and 1 poster NCRI 2014

Intention to publish date

Participant level data

Available on request

Results - basic reporting

Publication summary

2015 protocol in http://www.ncbi.nlm.nih.gov/pubmed/26410619

Publication citations

Additional files

Editorial Notes

21/09/2016: Added trial and sponsor website details and publication plan. Made changes to interventions, drug names, inclusion and exclusion criteria, trial participating centre and sponsor address (time stamped in relevant field). Changed number of participants from 410 to 620. 30/11/2015: Publication reference added.