Multi-drug phase II trial in non-small cell lung cancer...1 Multi-drug phase II trial in non-small cell lung cancer Sponsor: University of Birmingham Chief Investigator: Gary Middleton

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Multi-drug phase II trial in non-small cell lung cancer

Sponsor: University of Birmingham

Chief Investigator: Gary Middleton

Chief Biostatistician: Lucinda Billingham

Lead Investigators: Sanjay Popat, Timothy Yap, Yvonne Summers, James Spicer

Trial Management Team at CRCTU: Laura Llewellyn, Dee Wherton, Susannah Brown,

Kate Davies, Maria Sharif, Peter Fletcher, Ylenia Vigo, Ian Nutt

SMP2 Team at Cancer Research UK: led by Rowena Sharpe and Catrin Middleton

Trial Management Group: chaired by Sanjay Popat

Trial Steering Committee: chaired by Richard Kaplan

Current Pharma partners: AstraZeneca, Pfizer

Contact: [email protected] Website: www.birmingham.ac.uk/lungmatrix

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Background

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• In the UK, 46,000 people every year are diagnosed with lung cancer (Cancer Research UK Cancer Statistics website)

• Lung cancer is the most common cause of death worldwide with 1.59 million deaths in 2012

• NSCLC is the most common type of lung cancer.

Non-Small Cell Lung Cancer (NSCLC)

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• Traditionally doctors decide on how to treat a cancer by looking at what type of cancer it is, but this doesn’t work for everyone

• The body is made up of trillions of cells, which all have a specific job. DNA is a set of instructions found in the genes inside each cell telling it what to do

• In tumours sometimes the instructions (DNA) can have mistakes. This is particularly true in lung cancer, where changes in the DNA are different from person to person

• By testing a small piece of tumour in the laboratory a change in the DNA sequence can be found in some patients.

Treating NSCLC

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• Doctors look at which DNA change the patient’s cancer has and then select the best drug option for that particular patient

• This is called “precision medicine”, “stratified medicine” or “targeted therapy”

• By testing a small piece of tumour in the laboratory, a change in the DNA sequence can be found in some patients

• Different drugs can target cancers with different DNA changes

The National Lung Matrix Trial

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Trial Design

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We would like to:

• See how well each treatment works

• Find out more information about tumour shrinkage

• Find out more information about the safety of the drugs and associated side effects

• Collect blood samples to look at the tumour DNA present in the blood before, during and after treatment. This may enable us to identify which changes in the tumour DNA are linked to drug resistance

• Collect tissue to help us understand why some people benefit from treatment and others do not.

Aims of the National Lung Matrix Trial

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Trial Treatment

Arm Drug Cohort DNA/gene change

A AZD4547 A1 FGFR or FGFR3 mutation

B Vistusertib

(AZD2014)

B1

B2

TSC1 or TSC2 mutation

STK11/LKB1 mutation or homozygous deletion

C Palbociclib C1

C2

C3

C4

C5

C6

Proficient Rb and homozygous p16 loss

Proficient Rb and homozygous p16 loss

Proficient Rb and CDK4 amplification

Proficient Rb and CCND1 amplification

Proficient Rb, STK11/LKB1 mutation or homozygous

deletion, TSC1/TSC2 mutation, with activated

KRAS/MAPK pathway

Proficient Rb and KRAS mutation

• Patients will be offered a drug depending on the specific gene

(or DNA) change present within their cancer cells

• Patients will be placed into different groups (referred to as arms),

depending on the drug they receive and also into different sub-groups

(referred to as cohorts) depending on the type of NSCLC and gene

change they have:

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Trial Treatment continued…

Arm Drug Cohort DNA change

D Crizotinib D1

D2

D3

MET amplification

ROS1 gene fusions

MET exon 14 mutation or deletion

E Selumetinib &

Docetaxel

E1

E2

E3

NF1 mutation

NF1 mutation

NRAS mutation

F AZD5363 F1

F2

F3

F4

PIK3CA mutation

PIK3CA mutation

PI3K/AKT deregulation

PTEN loss or PTEN mutation

G Osimertinib

(AZD9291)

G1 EGFR mutation and T790M+

NA Durvalumab

(MEDI4736)

NA1 No gene change

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Patients & Hospitals

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Patients aged at least 18 years with:

• Non-small cell lung cancer that is either squamous cell carcinoma or adenocarcinoma

• Cancer that has spread outside of the lung (stage 3) where further surgery or radiotherapy will not be curative, or cancer that has spread to another part of your body (stage 4)

And have:

• Received at least one suitable standard treatment and the cancer has continued to grow

• Consented and given a tumour sample for the Stratified Medicine Programme 2 (SMP2)

(Other more detailed entry criteria apply)

Who can take part in the trial

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Patients with:

• Cancer that has spread to the brain or is pressing on the spinal cord and requires treatment (steroids)

• Any other cancer in the last 3 years (except carcinoma of the cervix or basal cell skin cancer that has been successfully treated)

• Side effects from earlier cancer treatment (except hair loss)

• HIV, hepatitis B or hepatitis C

• Certain heart problems (depending on which treatment you receive)

And have:

• Received major chemotherapy, surgery, radiotherapy or other anti-cancer treatment in the last 4 weeks

(Other more detailed entry criteria apply)

Who cannot take part in the trial

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• There is no guarantee that individual patients will benefit directly from taking part in the trial, however…

• It is possible that the drugs may cause tumour shrinkage and/or prolong some patients lives

• Tests and treatment being used today were developed thanks to the help of patients who took part in research years ago

• Information from the National Lung Matrix trial will help to improve the treatment of other people with NSCLC in the future

Benefits for patients

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Participating Hospitals

• The National Lung Matrix Trial is being run through all 18 UK Experimental Cancer Medicine Centres (ECMC) at 18 hospitals throughout the UK

• 10 additional hospitals have been approved for inclusion in areas of the UK with large populations of lung cancer patients not currently represented in the trial

• See the National Lung Matrix Trial website for up-to-date details on participating hospitals: www.birmingham.ac.uk/lungmatrix

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Trial Recruitment

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• Patients are placed into different groups (arms), depending on the specific drug they receive and also into different sub-groups (cohorts) depending on the type of NSCLC and gene change they have.

• Each cohort aims to recruit up to 30 patients:

• After the first 15 patients have been recruited, their safety data and trial results are reviewed, and the Trial Steering Committee decide whether the trial should continue recruiting in this cohort or stop.

• The overall trial recruitment target is 620 patients (correct at 01-Aug-2017) .

Trial Recruitment Target

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Cumulative & Monthly Recruitment

Data as of 30th June 2017

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Recruitment by Treatment Arm and Cohort

Data as of 30th June 2017

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Trial Management & Milestones

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Sponsor: University of Birmingham

• The company who takes overall responsibility for the quality assurance and conduct of the trial

Clinical Trials Unit: Cancer Research UK Clinical Trials Unit

• Responsible for the design of, and day to day running of the trial, including analysis of trial results

Chief Investigator: Professor Gary Middleton

• A named researcher who is responsible for the design & conduct of the research

Funder: Cancer Research UK

• Provides a grant to the Sponsor and Clinical Trials Unit to enable the trial to run. (Doctors do not receive any payments for recruiting patients)

Drug supply: AstraZeneca & Pfizer

• The current trial arms are testing drugs supplied free of charge by these two pharmaceutical companies

Who is organising and funding the trial

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Operational Management Group:

• Oversight of the day to day management of the trial and decision making

Trial Management Group:

• Monitor all aspects of the conduct and progress of the trial, patient safety and trial quality

• Multidisciplinary group including radiology, pathology, pharmacy & patient representation

Trial Steering Committee:

• Provide overall supervision of the trial, monitor trial progress, safety, and make recommendations to continue, modify or stop the trial

Medicines and Healthcare products Regulatory Agency (MHRA)

• Provide approval to run the trial, review relevant changes to the trial and safety data

Research Ethics Committee

• Independently safeguard the rights, safety, dignity and well-being of research participants

Who is overseeing the trial

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Trial Milestones

Year Milestone

2017 July: Major improvements to trial website www.birmingham.ac,uk/lungmatrix June: 150th patient recruited & funding approved for 2 new cohorts

2016 November: 100th patient recruited June: Approval for funding for further 2 years & 2 new arms from Cancer Research UK March: 50th patient recruited

2015 October: Additional Arm F & G opened to recruitment May: First patient recruited March: First hospital opened to recruitment (Newcastle)

2014 December: MHRA approval received November: Research ethics approval received October: Protocol Version 1 submitted for MHRA & research ethics approval August: Cancer Research UK Grant activated

2013 September: Cancer Research UK Clinical Trials Unit at Birmingham selected to run the trial with Prof Gary Middleton as the Chief Investigator

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• The Cancer Research UK Clinical Trials Unit National Lung Matrix Trial Team

• The Cancer Research UK SMP2 Team

• Members of the National Lung Matrix Trial Management Group & Trial Steering

Committee

• Members of the SMP2 Governance Board

• The NCRI Lung Clinical Studies Group

• All the Lead Investigators, Principal Investigators, clinical teams and research

nurses at all sites

• The patients and their families

With Many Thanks to:

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Thank You