Fluoropyrimidine, oxaliplatin and targeted receptor pre-operative therapy: a controlled trial in high-risk operable colon cancer

ISRCTN	ISRCTN87163246
DOI	https://doi.org/10.1186/ISRCTN87163246
ClinicalTrials.gov (NCT)	NCT00647530
Clinical Trials Information System (CTIS)	2007-001987-55
Protocol serial number	N/A
Sponsor	University of Birmingham (UK)
Funder	Cancer Research UK (CRUK) (UK)

Submission date: 28/11/2006
Registration date: 30/03/2007
Last edited: 20/01/2025

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

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-chemotherapy-and-panitumumab-before-and-after-surgery-for-bowel-cancer

Contact information

Dr Laura Magill
Scientific

Birmingham Clinical Trials Unit (BCTU)
Institute of Applied Health Research
College of Medical and Dental Sciences
Public Health Building
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom

Study information

Primary study design	Interventional
Study design	Open multicentre randomised controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Fluoropyrimidine, Oxaliplatin and Targeted Receptor pre-Operative Therapy: a controlled trial in high-risk operable colon cancer
Study acronym	FOxTROT
Study objectives	For patients with high risk, operable colon cancer: 1. Does giving potent Oxaliplatin/FluoroPyrimidine (OxFP) chemotherapy preoperatively facilitate surgical clearance and eradicate micrometastases more effectively than delayed post-operative chemotherapy? 2. Does the addition of the Epidermal Growth Factor Receptor (EGFR)-targeted therapy, panitumumab, enhance the efficacy of OxFP?
Ethics approval(s)	West Glasgow Research Ethics Committee, 05/06/2007, ref: 07/S0703/57
Health condition(s) or problem(s) studied	High risk, operable colon cancer
Intervention	Current interventions as of 05/01/2017: An open, multicentre, randomised controlled trial. First phase: randomised phase II assessing tolerability, feasibility and radiological/pathological downstaging. Second phase: randomised phase III trial with primary endpoint relapse-free survival. Arm A: Six weeks of pre-operative oxaliplatin/fluoropyrimidine chemotherapy followed by surgery then 18 weeks of post-operative oxaliplatin/fluoropyrimidine chemotherapy Arm B: The same chemotherapy with concomitant panitumumab for the first six weeks Arm C: Surgery then twenty four weeks of post-operative oxaliplatin/fluoropyrimidine chemotherapy The two allowable oxaliplatin/fluoropyrimidine chemotherapy regimens are twelve two-week courses of Oxaliplatin and Modified deGramont (OxMdG), or eight three-week courses of Oxaliplatin and Capecitabine (OxCap). Patients randomised to receive panitumumab receive this by intravenous (IV) infusion over 60 minutes at 6 mg/kg on day one of each of the first three two-week OxMdG cycles, immediately prior to the start of the chemotherapy regimen. Post-operative adjuvant therapy will be given, regardless of trial arm and operative histology. Previous interventions: An open, multicentre, randomised controlled trial. First phase: randomised phase II assessing tolerability, feasibility and radiological/pathological downstaging. Second phase: randomised phase III trial with primary endpoint relapse-free survival. Arm A: Six weeks of pre-operative oxaliplatin/fluoropyrimidine chemotherapy followed by surgery then 18 weeks of post-operative oxaliplatin/fluoropyrimidine chemotherapy Arm B: The same chemotherapy with concomitant panitumumab for the first six weeks Arm C: Surgery then twenty four weeks of post-operative oxaliplatin/fluoropyrimidine chemotherapy Arm D: Schedule C with concomitant panitumumab for the first six weeks of post operative therapy The two allowable oxaliplatin/fluoropyrimidine chemotherapy regimens are twelve two-week courses of Oxaliplatin and Modified deGramont (OxMdG), or eight three-week courses of Oxaliplatin and Capecitabine (OxCap). Patients randomised to receive panitumumab receive this by intravenous (IV) infusion over 60 minutes at 6 mg/kg on day one of each of the first three two-week OxMdG cycles; or at 9 mg/kg on day one of each of the first two three-week OxCap cycles, immediately prior to the start of the chemotherapy regimen. Post-operative adjuvant therapy will be given, regardless of trial arm and operative histology.
Intervention type	Drug
Phase	Phase II/III
Drug / device / biological / vaccine name(s)	Fluoropyrimidine, oxaliplatin, panitumumab
Primary outcome measure(s)	Current primary outcome measures as of 26/01/2018: 1. Freedom from recurrent of persistent disease (including failure of macroscopic disease clearance at primary surgery) within the first two years following randomisation 2. Pathological down-staging as measured by depth of extramural spread among patients allocated to preoperative chemotherapy with or without panitumumab Previous primary outcome measures: 1. Pre- plus post-operative versus post-operative chemotherapy: freedom from recurrence (or residual disease) at two years after randomisation (arms A and B versus C and D) 2. Panitumumab versus not: pathological down-staging (arm B versus A)
Key secondary outcome measure(s)	Current secondary outcome measures as of 26/01/2018: 1. Death from colon cancer 2. Overall survival 3. Freedom from recurrence or persistent disease at 2 years (panitumumab comparison) 4. Pathological assessment of downstaging (involvement of lymph nodes, serosa, and resection margin) and quality of resection specimen 5. Quality of resection specimen and distance to high-tie 6. Radiological assessment of response to neoadjuvant treatment 7. Quality of life by EORTC QLQ C-30 and EuroQol EQ-5D 8. Length of hospital stay 9. Surgical morbidity/mortality 10. Chemotherapy toxicity 11. Adverse events Previous secondary outcome measures: 1. Death from colon cancer 2. Overall survival 3. Health-related quality of life 4. Pathological assessment of down-staging (involvement of lymph nodes, serosa, resection margin), and quality of resection specimen 5. Radiological assessment of response in neoadjuvant treatment arms 6. CarcinoEmbryonic Antigen (CEA) level following neo-adjuvant therapy 7. Health Service resource usage 8. Adverse events 9. Surgical morbidity/mortality
Completion date	31/12/2019

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	1050
Key inclusion criteria	Current inclusion criteria as of 26/01/2018: 1. Histologically proven adenocarcinoma of the colon or high grade dysplasia on histology plus unequivocal radiological evidence of invasive cancer 2. A candidate for adjuvant oxaliplatin/ fluoropyrimidine chemotherapy based on: 2.1. Either radiological high risk (rT4 or rT3 tumour with extramural extension ≥ 5mm) 2.2. Or radiological intermediate risk (rT3 tumour with <5mm extramural extension) and younger age/good general health 3. Patients presenting with acute colonic obstruction may enter the trial only after obstruction is relieved by a successful defunctioning stoma, and when recovered to a fitness level consistent with the other eligibility criteria 4. Adequate full blood count: WBC >3.0 x109/l; Plts >100 x109/l. Anaemia (Hb < 10.0 g/dl) is not an exclusion, but should be corrected by transfusion prior to surgery and chemotherapy. If Hb remains low despite transfusions, surgery and chemotherapy can be given at the decision of the surgical and oncology teams. 5. Adequate renal biochemistry: GFR >50 ml/min calculated by the Wright or Cockroft formula or EDTA clearance >70 ml/min 6. Adequate hepatobiliary function: bilirubin < 25 μmol/l (Patients with Gilbert’s syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study.) 7. Aged 18 or over 8. WHO performance status of 0, 1 or 2 9. If female and of childbearing potential, must: 9.1. Have a negative pregnancy test ≤72hours prior to initiating study treatment 9.2. Agree to avoid pregnancy during and for 6 months after study treatment 10. If male with a partner of childbearing potential, must: - Agree to use adequate, medically approved, contraceptive precautions during and for 90 days after the last dose of study treatment 11. Patient able and willing to provide written informed consent for the study Previous inclusion criteria: 1. Histologically proven colon cancer with a radiological staging of T3, NX, M0 2. Computed Tomography (CT) scan criteria of poor prognosis (T4 or T3 and more than 5 mm extramural depth and/or probable nodal involvement and/or probable vascular invasion) 3. Fit for the neoadjuvant treatments 4. Patients who have presented with acute colonic obstruction if a successful defunctioning or stent procedure has been performed 5. Patients able and willing to provide written informed consent for the study
Key exclusion criteria	Current exclusion criteria as of 26/01/2018: 1. MorbidityAny patient for whom radiotherapy is advised by the MDT 2. Strong evidence of distant metastases or peritoneal nodules (M1) 3. Peritonitis (secondary to perforated tumour) 4. Colonic obstruction that has not been defunctioned 5. Serious medical comorbidity, eg uncontrolled inflammatory bowel disease, uncontrolled angina or recent (<6 months) MI 6. Another serious medical condition judged to compromise ability to tolerate neoadjuvant therapy and/or surgery 7. Any other malignant disease within the preceding 5 years with the exception of non-melanomatous skin cancer, carcinoma in situ and early stage disease with a recurrence risk <5% Additional exclusion criteria for panitumumab randomisation 1. RAS-mutant or unknown RAS status tumours 2. Allocated post-operative chemotherapy 3. History of interstitial pneumonitis or pulmonary fibrosis 4. History of severe or life-threatening hypersensitivity reactions 5. Serum magnesium levels within the normal range at trial entry (which can include intravenous correction) Previous exclusion criteria: 1. Tumour within 15 cm of the anal verge as judged by sigmoidoscopy, or below the level of the sacral promontory, as judged by sagittal CT 2. Indication for radiotherapy 3. Evidence of disseminated disease (M1) 4. Peritonitis (secondary to perforated tumour) 5. Under the age of 18 or pregnant 6. Serious medical co-morbidity
Date of first enrolment	01/04/2008
Date of final enrolment	23/12/2016

Locations

Countries of recruitment

United Kingdom
England
Denmark
Sweden

Study participating centre

University of Birmingham

Birmingham
B15 2TT
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		19/01/2023	20/01/2023	Yes	No
Interim results article	Pilot/feasibility results	01/11/2012		Yes	No
Other publications		11/01/2025	20/01/2025	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Plain English results				No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

20/01/2025: Publication reference added.
20/01/2023: Publication reference added.
02/08/2019: Cancer Research UK lay results summary link added to Results (plain English).
26/01/2018: The primary and secondary outcome measures have been updated. The recruitment end date has been updated from 31/12/2016 to 23/12/2016.
05/01/2017: the overall trial end date was changed from 01/03/2018 to 31/12/2019.
19/02/2016: the recruitment end date was changed from 31/12/2015 to 31/12/2016.
10/07/2015: the overall trial end date was changed from 31/12/2015 to 01/03/2018.
25/06/2015: Sweden and Denmark were added to the countries of recruitment.