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.
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.
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.
