Fluorouracil and folinic acid (FOLFIRI) plus an endothelin receptor antagonist (ERAT) in advanced colorectal cancer patients who have failed on oxaliplatin-containing chemotherapy
| ISRCTN | ISRCTN73199181 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN73199181 |
| ClinicalTrials.gov number | NCT01205711 |
| Secondary identifying numbers | SPON671-09 |
- Submission date
- 03/06/2009
- Registration date
- 20/07/2009
- Last edited
- 24/07/2019
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English summary of protocol
Contact information
Dr Anne Thomas
Scientific
Scientific
University of Leicester
Osborne Building
Leicester Royal Infirmary
Leicester
LE15WW
United Kingdom
| Phone | +44 (0)116 258 7602 |
|---|---|
| at107@le.ac.uk |
Study information
| Study design | Multicentre phase II parallel group double-blind randomised controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to rquest a patient information sheet |
| Scientific title | A randomised phase II study of Irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) with or without the addition of an endothelin receptor antagonist in patients with metastatic colorectal cancer after failure of oxaliplatin-containing chemotherapy |
| Study acronym | FOLFERA |
| Study objectives | The availability of agents including irinotecan, oxaliplatin, cetuximab and bevacizumab, has improved the median survival of patients with metastatic colorectal cancer (mCRC), however the prognosis remains poor. There is a need to develop other agents to improve the outcome for these patients. Endothelin-1 (ET-1) is a potent vasoconstrictor and acts through its G-protein coupled receptors ETA (ETAR) and ETB (ETBR). ET-1 and ETAR are over-expressed in colorectal cancer and are prognostic for poor outcome. Inhibition of ETAR has been shown to enhance cytotoxicity when combined pre-clinically with chemotherapy agents such as 5-fluorouracil (5-FU), and platinums (e.g., cisplatin). ZD4054 is a specific inhibitor of ETAR. Irinotecan is licensed for the treatment of metastatic colorectal cancer. In this study, we hypothesise that it may be possible to increase the anti-tumour activity of irinotecan and 5-FU (FOLFIRI) regimen by combining it with ZD4054. Please note, as of 01/03/2011 the anticipated end date for this trial has been updated from 01/09/2011 to 07/04/2012 and the target number of participants has increased from 112 to 122. |
| Ethics approval(s) | Nottingham Research Ethics Committee 2 on 13/11/2009 (ref: 09/H0408/88) |
| Health condition(s) or problem(s) studied | Locally advanced and/or metastatic colorectal cancer (mCRC) |
| Intervention | Patients will be recruited over 18 months. Participants randomised to the control arm will receive 12 cycles (q14 days) of FOLFIRI chemotherapy: irinotecan (180 mg/m^2) administered as a two hour infusion on day 1, leucovorin (400 mg/m^2) administered as a two hour infusion on day 1, followed by a loading dose of 5-FU (400 mg/m^2) intravenous (IV) bolus administered on day 1, then 5-FU (2400 mg/m^2) administered by ambulatory pump for a period of 46 hours every two weeks. Patients will also receive the placebo tablet daily. Participants randomised to the experimental arm will receive 12 cycles (q14 days) of the FOLFIRI regimen as outlined above with an oral daily dose of 10 mg ZD4054. Participants, who have at least stabilisation of their disease at the end of the 24 week treatment period, may continue on their allocated ZD4054/placebo monotherapy until disease progression, unacceptable toxicity or they withdraw consent. The following assessments will be made after the patient has consented to enter the trial: Baseline (inclusive of eligibility screening collected after patient consent): 1. Medical history 2. Full clinical examination to evaluate measurable disease by RECIST v1.1 criteria 3. Computerised axial tomography (CT) scan of chest, abdomen and pelvis 4. Haematology, serum and urine biochemistry 5. WHO performance status 6. Pregnancy test (females of child bearing potential only) 7. Electrocardiogram (ECG) 8. Baseline toxicity 9. Collection of tumour tissue biopsy (optional for participant) Before, during and at end of treatment (each cycle unless stated otherwise): 1. Full clinical examination to evaluate disease response by RECIST v1.1 criteria (weeks 8, 16 and 24) 2. CT scan of chest, abdomen and pelvis (weeks 8, 16 and 24) 3. Haematology and serum biochemistry 4. WHO performance status 5. Evaluation of toxicities using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 and real-time serious adverse events (SAE) reporting 6. Documentation of dose delays and/or reduction At Follow up (weeks 36, 48 and 60) 1. WHO performances status 2. Full clinical examination to evaluate disease response by RESIST v1.1 criteria 3. CT scan (every 12 weeks for all patients until disease progression) 4. Haematology and serum biochemistry 5. Evaluation of toxicities using NCI CTCAE v 3.0 and real-time SAE reporting |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Irinotecan, leucovorin, 5-fluorouracil (5-FU), ZD4054 |
| Primary outcome measure | Progression free survival (PFS) at 16 weeks from the date of enrolment. This is the proportion of participants who are alive at 16 weeks without disease progression according to RECIST v1.1. |
| Secondary outcome measures | 1. PFS (time-to-event). This is the proportion of participants who are alive at 16 weeks without disease progression according to RECIST v1.1. 2. Safety, tolerability (side effects) and feasibility of use (number of participants requiring dose delays or reductions and/or treatment withdrawal) 3. Objective response rate as assessed by RECIST v1.1 4. Overall survival (OS). Time from enrolment to death. Those still alive will be censored at time last seen. 5. To assess tumours for ETAR expression, K-ras status and alterations in relevant pathways such as MAPK/ERK and to potentially look at circulating tumour and lymphocyte cells in the blood |
| Overall study start date | 01/09/2009 |
| Completion date | 27/06/2012 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | Added 01/03/2011: 122 (112 at time of registration) |
| Key inclusion criteria | 1. Histological or cytological diagnosis of metastatic colorectal cancer 2. If patients progress within 6 months of adjuvant oxaliplatin containing chemotherapy they will be included in this study providing that they have no significant ongoing toxicity (excluding grade 1 neurotoxicity) 3. Measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST v 1.1) 4. Adequate bone marrow, hepatic and renal function including the following: 4.1. Haemoglobin greater than or equal to 9.0 g/dl (no prior transfusion) or greater than or equal to 10.0 g/dl (transfusion within last 4 weeks), absolute neutrophil count greater than or equal to 1.5 x 10^9/L, platelets greater than or equal to 100 x 10^9/L 4.2. Total bilirubin less than 1.5 x upper normal limit 4.3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x upper normal limit (or less than or equal to 5 x UNL in the presence of liver metastases) 4.4. Creatinine less than or equal to 1.5 x upper normal limit 5. Aged greater than or equal to 16 years, either sex 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 7. Patients must have recovered from effects of major surgery 8. In view of concerns of possible teratogenicity, female patients must have no reproductive potential, i.e. must have a negative urine or serum pregnancy test within 7 days prior to start of trial, and must be post-menopausal 9. Males with reproductive potential should be prepared to use adequate contraception 10. Patient has provided written informed consent 11. Life expectancy of at least 12 weeks |
| Key exclusion criteria | 1. Any chemotherapy, radiotherapy (except for palliative reasons), endocrine therapy or immunotherapy within four weeks prior to trial entry. Patients may continue the use of corticosteroids provided the dose is stable for 4 weeks and not altered during the first 15 days of the study. 2. Have received more than one course of chemotherapy for metastatic disease, and any previous treatment with ZD4054 or irinotecan. Where oxaliplatin has been used in an intermittent schedule allowing patient holidays it will be considered equivalent to one prior line of therapy providing that patients have at least stable disease whilst on active treatment. 3. Extensive prior irradiation (likely to deplete bone marrow reserve) 4. Major surgery within 4 weeks of starting the study 5. Co-existing active infection or serious concurrent medical condition 6. Significant cardiovascular disease as defined by: 6.1. History of congestive heart failure requiring therapy 6.2. History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry 6.3. Presence of severe valvular heart disease 6.4. Presence of a ventricular arrhythmia requiring treatment 7. Any co-existing medical condition that in the investigators judgement will substantially increase the risk associated with the patients participation in the study or potentially hamper compliance with the study protocol and follow-up schedule 8. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or compliance with the study protocol 9. Bone metastases 10. Known brain or leptomeningeal metastases unless patients have stable disease following surgical resection or radiosurgery of oligometastases 11. Gastrointestinal disorders likely to interfere with absorption of the study drug (e.g., partial bowel obstruction or malabsorption) 12. Patients known to be serologically positive for hepatitis B or hepatitis C (mandatory testing not required) 13. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) (mandatory testing not required) 14. Other previous or current malignant disease likely to interfere with protocol treatment or comparisons |
| Date of first enrolment | 01/09/2009 |
| Date of final enrolment | 07/04/2012 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
University of Leicester
Leicester
LE15WW
United Kingdom
LE15WW
United Kingdom
Sponsor information
Cardiff University (UK)
University/education
University/education
Research and Commercial Division (RACD)
7th Floor
30-36 Newport Road
Cardiff
CF24 ODE
Wales
United Kingdom
| Website | http://www.cf.ac.uk/racdv/index.html |
|---|---|
"ROR" |
https://ror.org/03kk7td41 |
Funders
Funder type
Charity
Astra Zeneca (UK) - providing ZD4054 and its distribution costs free-of-charge as an educational grant (subject to contract)
No information available
Cancer Research UK (CRUK) (UK) - WCTU is core funded by CRUK and WCTU core resources will be used to support this trial
No information available
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/02/2013 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
24/07/2019: The overall trial end date has been changed from 07/04/2012 to 27/06/2012.
