A study to determine the feasibility of molecular selection of therapy in patients with metastatic colorectal cancer

Lead Research Organisation: Cardiff University
Department Name: School of Biosciences

Abstract

When cancer of the bowel is not completely removable by surgery, or when the cancer has spread to somewhere else in the body, chemotherapy, a form of drug treatment which aims to kill cancer cells, may be given. Usually, the specific chemotherapy that is offered to a patient is chosen on how well it works on average in patients.
There are in all five types of medicine which have been shown to work in colorectal cancer. The most commonly used chemotherapy for bowel cancer is called ?5FU?, which is also known as ?fluorouracil?.
Our previous study (called FOCUS) showed that the combination of 5FU and irinotecan, a new drug, gave the best results, so this is being used as the standard treatment in this research. This will allow us to compare the usual treatment against different combinations of medicines.
In recent years two new treatments have been developed which are not standard chemotherapy. These are called cetuximab and bevacizumab (monoclonal antibodies), which specifically act on special proteins associated with the growth of the cancer. In this trial we will be comparing ways of using all these drugs in the best way by testing the treatments that we think will work best for the type of tumour that participants have, according to molecular testing. These tests will identify the cancer as one of four ?types?.
For each type of cancer, we will be comparing the effects of different treatment plans. Patients will be randomly allocated to three different treatments to discover which is best; one is the usual course of treatment that would be offered. The other two plans are those which the tumour sample tests suggest might be better than the usual treatment for that particular type of bowel cancer.
The treatment is given on a regular basis, every two weeks and continues for at least six months, provided the cancer remains under good control and there are no unpleasant side effects.
Participants of the trial will also be asked for permission to use the tumour sample they have already given in future scientific studies. Specifically, we will look at other possible tests of proteins or of genes that may predict which treatment would work best for individual patients. In addition, we will ask participants for a blood sample for further research purposes.

Technical Summary

There are five active treatments for metastatic colorectal cancer (MCRC): fluorouracil (FU), irinotecan (Ir), oxaliplatin (ox), bevacizumab and EGFR targeted antibodies. Recent evidence indicates a more rational approach to selection of treatment may be possible based on molecular biomarkers in the patient?s tumour. Patients with low levels of topoisomerase-1, the target of irinotecan, in the tumour gained no added benefit from either Ir or Ox over FU alone in the previous FOCUS trial. Patients with tumour ras mutations gained no benefit from EGFR antibody in a recent trial of panitumumab versus best supportive care. The primary endpoint of this trial will be to ascertain in what proportion of consenting patients can a Formalin-fixed paraffin-embedded (FFPE) block containing tumour be retrieved from the local pathology department, sent to a central laboratory, be analysed for topo-1 IHC and k-ras mutational status and a reliable result returned to the MRC CTU for treatment allocation within two weeks of the patient?s initial consent.
Patients will be allocated into 4 strata based on topo-1 level (low v elevated) and ras mutational status (mutated v wildtype). Within each stratum patients will be randomly allocated to the control treatment (IrFU) or two alternative treatments testing the following hypotheses: 1. In patients with low topo-1 tumours, to confirm that FU alone is non inferior to IrFU. 2. In patients with high topo-1 tumours, the addition of oxaliplatin to IrFU is superior to IrFU alone. 3. In patients with k-raswt tumours the addition of cetuximab to chemotherapy is superior to chemotherapy alone. 4. In patients with k-ras mutant tumours the addition of Bevacizumab to chemotherapy is superior to chemotherapy alone.
The trial will also answer the following questions: How reproducible are the topo-1 and k-ras results when replicated in different laboratories? What are the real costs of molecular testing? What are the opinions of patients regarding a trial of this complexity requiring a delay in treatment for further diagnostic work? We will also asses other potential biomarkers which may further refine the EGFR therapy selection.
240 patients will be treated in the feasibility trial and if successful they will be included in the analysis of the future definitive trial to address the above hypotheses with a primary endpoint of progression free survival in a total patient number of 3000.

Publications

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Kaplan R (2013) Evaluating many treatments and biomarkers in oncology: a new design. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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Kaplan R (2015) The FOCUS4 design for biomarker stratified trials. in Chinese clinical oncology

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Lieu CH (2014) Association of age with survival in patients with metastatic colorectal cancer: analysis from the ARCAD Clinical Trials Program. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

 
Description Impact of new stratified medicine trial design for cancer
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description EME
Amount £3,525,623 (GBP)
Funding ID 11/100/50 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2013 
End 03/2018
 
Description FOCUS4 trial programme
Amount £3,525,623 (GBP)
Funding ID 11/100/50 
Organisation NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) 
Sector Public
Country United Kingdom
Start 04/2013 
End 03/2020
 
Description MRC Methodology Research Panel
Amount £225,000 (GBP)
Funding ID MR/N028171/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2017 
End 01/2020
 
Description S-CORT MRC-CRUK consortium: Stratification in COloRectal cancer: from biology to Treatment prediction
Amount £6,137,601 (GBP)
Funding ID MR/M016587/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2020
 
Title Combined FOCUS, FOCUS2, COIN, FOCUS3, and FOCUS4 specimen collection 
Description A pooled set of specimens plus complete corresponding clinical data, including outcome data from a series of colorectal cancer trials 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact Multiple use in piloting and quality assuring assays for biomarker and other translational studies, as well as serving as a resource for more definitive translational research 
 
Title FOCUS 3 tissue bank/database 
Description Molecularly characterised tissue suitable for investigations of predictive and prognostic biomarkers 
Type Of Material Biological samples 
Year Produced 2013 
Provided To Others? Yes  
Impact Some of the specimens are being used for PTEN and DNA repair assay validation in support of the successor FOCUS4 trial, for which MRC and CRUK funding applications have both been successful at the initial stage. sample sets have been provided to Oxford for validation of the ion Torrent platform in a technology strategy Board funded project 
 
Title New trial design for stratified medicine clinical trials 
Description A new clinical trials design intended to be much more efficient than most trials in stratified medicine have been thus far 
Type Of Material Improvements to research infrastructure 
Year Produced 2013 
Provided To Others? Yes  
Impact Other trials actively being developed, using this design 
URL http://jco.ascopubs.org/content/31/36/4562.full?sid=64cfcd5a-26c6-4690-bf24-e36aaf012852
 
Title Colorectal trial specimen collection and outcomes database 
Description A stored collection of specimens (tumour and blood) from patients on a series of colorectal cancer therapeutic trials including FOCUS, FOCUS2, COIN, FOCUS3 and FOCUS4, along with anonymised demographic and outcome data 
Type Of Material Database/Collection of data 
Year Produced 2009 
Provided To Others? Yes  
Impact At least 20 translational projects underway and many exploratory or pilot projects. Publications listed as specific outputs. 
 
Title FOCUS4 - Molecular selection of therapy in colorectal cancer: a molecularly-stratified randomised controlled trials programme 
Description FOCUS4 is an umbrella, or platform, for testing novel agents in biomarker-defined subpopulations of first-line advanced disease colorectal cancer patients who are not considered candidates for potentially curative surgery. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type. 
Type Support Tool - For Medical Intervention
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact THis design has made major impact internationally and informed trial design in other types of cancer both in academic and commercial sectors. 
URL http://www.focus4trial.org
 
Description NCRI conference industry seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact 100 researchers and patients attended this GSK sponsored session at the NCRI conference

researchers and public present responded with interest for stratified medicine trials
Year(s) Of Engagement Activity 2013