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
http://www.birmingham.ac.uk/research/activity/mds/trials/crctu/trials/matrix/investigators.aspx
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; Vistusertib (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; Osimertinib (AZD9291)
8. Arm NA Cohort NA1 - Anti-PDL1; Durvalumab (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
AZD4547, Vistusertib (AZD2014), Palbociclib, Crizotinib, Selumetinib, Docetaxel, Durvalumab (MEDI4736), AZD5363, Osimertinib (AZD9291)
Primary outcome measure
Best objective response (BOR); 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. Adverse events
Added 14/02/2017:
6. Durable clinical benefit (DCB)
Overall trial start date
31/03/2015
Overall trial end date
01/03/2020
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Current inclusion criteria as of 12/12/2016:
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
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). (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)
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). 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
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.
12. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses
Previous inclusion criteria from 02/09/2015 to 12/12/2016:
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.
12. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses
Original inclusion criteria:
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: 610; UK Sample Size: 610
Participant exclusion criteria
Current exclusion criteria as of 12/12/2016:
1. Major surgery (excluding placement of vascular access) 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 local 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 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
9. 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
10. Pregnant or breast-feeding women
Cardiac exclusion criteria, performance status and prior treatment washout periods are detailed within The National Lung Matrix Trial arm-specific eligibility criteria.
Previous exclusion criteria from 02/09/2015 to 12/12/2016:
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.
Original exclusion criteria:
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
Institute of Cancer and Genomic 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
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
Sponsor type
University/education
Website
Funders
Funder type
Industry
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. Middleton G; Does tumour genotyping matter: CRUK SMP2 and MATRIX findings; invited oral plenary presentation at Annual Conference of the British Thoracic Oncology Group, Dublin, January 2017.
2. Middleton G; MATRIX/SMP2; invited oral presentation in BTOG/NCRI Advanced Disease Subgroup Update parallel session at Annual Conference of the British Thoracic Oncology Group, Dublin, January 2017.
3. Billingham L, Wherton D, Llewellyn L, Brown S, Johnson S, Fletcher P, Mulatero C, Yap T, Summers Y, Spicer J, Sharpe R, Popat S, Middleton G; 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. Abstract accepted for oral and poster presentation at NCRI Cancer Conference, Liverpool, November 2016.
4. 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.
5. 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
6. 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
7. 1 abstract and 1 poster NCRI 2015
8. 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
9. 1 abstract and presentation for BTOG 2015 - January 2015
10. 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
11. 1 abstract and 1 poster NCRI 2014
Intention to publish date
Participant level data
Available on request
Basic results (scientific)
Publication list
2015 protocol in http://www.ncbi.nlm.nih.gov/pubmed/26410619