A trial assessing preoperative chemotherapy in patients with locally advanced but operable colon cancer

ISRCTN	ISRCTN83842641
DOI	https://doi.org/10.1186/ISRCTN83842641
EudraCT/CTIS number	2021-002216-31
IRAS number	1003812
ClinicalTrials.gov number	NCT06293625 - France only
Secondary identifying numbers	MO21/126572, CPMS 49772, IRAS 1003812

Submission date: 24/05/2021
Registration date: 28/09/2021
Last edited: 14/08/2024

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English Summary

Background and study aims
After lung cancer, bowel (colorectal) cancer is the next most common cause of cancer death in the UK. Doctors usually treat bowel cancer with surgery often followed by chemotherapy to help stop the cancer from coming back. Despite all of the medical advances in recent years, until recently there have been no significant improvements to this treatment approach. However, an international research trial (FOxTROT 1) carried out in the UK, Denmark and Sweden, showed that having some chemotherapy (using the normal chemotherapy drugs for bowel cancer) before surgery (known as neoadjuvant chemotherapy), was safe and reduced the chances of the cancer coming back. However, patients in this study were mainly young and fit. Thanks to funding from Yorkshire Cancer Research, this important study will now be extended to see whether the same procedure is effective with gentler neoadjuvant chemotherapy before surgery in older patients or those with other medical problems (FOxTROT 2). This will be compared to the standard treatment of surgery first. FOxTROT 3 is a trial for younger, fitter patients. FOxTROT 4 (supported by Merck and Pierre Fabre) is a trial for people with a genetic mutation called BRAF. FOxTROT 5 (supported by GSK) is a trial for older patients or those with other medical problems whose tumour has an abnormality called deficient mismatch repair (dMMR).

Who can participate?
Patients who are at least 18 years old and have locally advanced but operable colon (bowel) cancer. Patients who are older and less fit will be considered for FOxTROT 2 and FOxTROT 5. Patients who are younger and fitter will be considered for FOxTROT 3. Patients with a genetic mutation called BRAF may be considered for FOxTROT 4. The patient's oncologist will decide which trial the patient is suitable for.

What does the study involve?
Patients will receive either the new approach (neoadjuvant treatment) or standard treatment. Patients allocated to the new approach will have neoadjuvant treatment (duration varies depending on the trial in which the patient is taking part) then a 3-to-4-week rest period. Then they will have an operation to remove the tumour. Patients allocated to standard treatment will have their operation first. For all patients there will then be a 4-to-8-week recuperation period after surgery to allow for recovery. Depending on the trial the patient is recruited to, they will then be offered further trial treatment or transfer to standard care.

What are the possible benefits and risks of participating?
There is no guarantee that participants will benefit from the treatment given in this study. The chemotherapy given before surgery in FOxTROT 2 and FOxTROT 3 is the same as that given in standard care (just given before surgery, rather than after surgery). Patients may be more likely to have chemotherapy as part of their cancer treatment if given before surgery, rather than after surgery (current usual treatment). This was the case for patients in the FOxTROT 1 trial. FOxTROT 1 also showed that patients tended to have fewer complications after the operation if they had chemotherapy first.
There is a small risk that the tumour may continue to grow whilst receiving the treatment and the patient may need to have an emergency operation or stent. There is a risk of severe side effects from the treatment that may mean that the surgery is delayed, or that the patient may not be fit enough for an operation. However, the side effects of the chemotherapy given are well known and will be closely monitored by the medical team.

Where is the study run from?
Clinical Trials Research Unit (CTRU) at the University of Leeds (UK)

When is the study starting and how long is it expected to run for?
December 2020 to August 2029

Who is funding the study?
1. Yorkshire Cancer Research (UK)
2. Merck (Germany)
3. Pierre Fabre (France)
4. GSK (UK)

Who is the main contact?
Dr Lucy Bailey, FOxTROT@leeds.ac.uk
Mrs Claire Dimbleby, FOxTROT@leeds.ac.uk (FOxTROT 4)

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-chemotherapy-before-surgery-for-bowel-cancer-in-older-people-foxtrot-2
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-comparing-2-combinations-of-chemotherapy-for-bowel-cancer-foxtrot-3

Study website

Contact information

Mrs Claire Dimbleby
Public

Level 10, Worsley Building
University of Leeds
Clarendon Way
Leeds
LS2 9JT
United Kingdom

Email	FOxTROT@leeds.ac.uk

Study information

Study design	Stratified multi-arm multi-site randomized trial platform
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 to request a patient information sheet
Scientific title	FOxTROT: personalising neo-adjuvant chemotherapy in locally advanced but operable colon cancer
Study acronym	FOxTROT
Study hypothesis	The overall aim of the FOxTROT trial platform is to refine and personalise the use of the neoadjuvant chemotherapy pathway in locally advanced operable colon cancer. As well as testing new clinical hypotheses within the platform, molecular stratification from diagnostic tissue will create future opportunities to test targeted novel agents with proven efficacy and safety in colon cancer. FOxTROT 2: The alternative hypothesis is that the proportion of patients alive and disease-free at 3 years after randomisation treated with neoadjuvant chemotherapy (OxFp) is superior compared to those going straight to surgery. The null hypothesis in that there is no difference is the proportion of patients alive and disease-free at 3 years after randomisation. FOxTROT 3: The alternative hypothesis is that the distribution of the tumour regression grade at the time of surgery allocated to mFOLFOXIRI is superior compared to those allocated to OxFp. The null hypothesis in that there is no difference in tumour regression grade (TRG). (added 17/10/2023): FOxTROT 4: The alternative hypothesis is that 6 weeks of neoadjuvant treatment with the EC doublet will be safe and result in significant tumour regression compared with 6 weeks of neoadjuvant oxaliplatin and fluoropyrimidine (OxFp) chemotherapy. (added 14/08/2024) FOxTROT 5: The alternative hypothesis is that in older and/or frail patients with untreated locally advanced dMMR/MSI-H CC, 12 weeks of neoadjuvant dostarlimab (an anti-PD1 monoclonal antibody) prior to surgery with curative intent, followed by 36 weeks of post-operative dostarlimab, will demonstrate similar efficacy to that seen in younger and fitter populations.
Ethics approval(s)	Approved 22/11/2021, Oxford-A Research Ethics Committee (Level 3, Block B, Whitefriars, Bristol, BS1 2NT, United Kingdom; +44 (0)207 1048206; oxforda.rec@hra.nhs.uk), ref: 21/SC/0277
Condition	Locally advanced but operable colon cancer
Intervention	Current interventions as of 14/08/2024: FOxTROT is a stratified, multi-arm, multi-site randomised trial platform for patients with locally advanced but operable colon cancer. Prior to the initial registration period, all patients will have been assessed at a colon cancer MDT for review of pathology and radiology and potential participants will be identified. Patients meeting the registration eligibility criteria will be registered and a decision will be made about which FOxTROT comparison is most suitable. Participants will then be randomised in the appropriate comparison. FOxTROT 2 randomises participants between two trial arms: 1. Straight to surgery: patients will proceed straight to surgery as soon as possible and will be assessed for adjuvant chemotherapy as standard care. 2. Neoadjuvant chemotherapy followed by surgery. Participants in this arm will receive 6 weeks of OxFP chemotherapy with a choice (non-randomised) between two regimens: OxMdG (2-weekly oxaliplatin/calcium folinate/infusional fluorouracil) or OxCap (3-weekly oxaliplatin with capecitabine). These should be delivered as per local practice. The clinician has two options of initial dosing as described above: full dose OxFp, or 80% dose OxFp. Treatment should start as soon as possible following randomisation. Patients should be reviewed prior to each cycle of treatment to assess for toxicity and any evidence of disease progression. Following the completion of neoadjuvant chemotherapy, all participants will be reviewed in the oncology clinic to be assessed for adjuvant chemotherapy. FOxTROT 3 randomises participants between two trial arms: 1. In the control arm, Neoadjuvant chemotherapy (NAC) consists of 6 weeks of standard OxFp with a choice (non-randomised) of either OxMdG (2-weekly oxaliplatin/calcium folinate/infusional fluorouracil) or OxCap (3-weekly oxaliplatin with capecitabine). 2. In the experimental arm, NAC comprises three 2-weekly cycles of mFOLFOXIRI (oxaliplatin, irinotecan, calcium folinate, then a 46-hour infusion of fluorouracil). For both arms, treatment should start as soon as possible following randomisation. Patients will receive postoperative adjuvant chemotherapy (AC) of either 6 or 18 weeks, bringing the total NAC/AC duration to 3 or 6 months respectively. In the control arm, AC is with OxFp; in the experimental arm AC may be either mFOLFOXIRI or OxFp. FOxTROT 4 randomises participants between two trial arms: 1. In the control arm, NAC consists of 6 weeks of standard OxFp with a choice (non-randomised) of either OxMdG (2-weekly oxaliplatin/calcium folinate/infusional fluorouracil) or OxCap (oxaliplatin and capecitabine). 2. In the experimental arm, Neoadjuvant systemic anti-cancer therapy (NA SACT) comprises three 2-week cycles of cetuximab and encorafenib once daily (EC). Treatment should start as soon as possible following randomisation. Postoperative adjuvant treatment will be as per local practice. FOxTROT 5 is a single-arm study and all participants will receive 12 weeks (a maximum of four, 3-weekly cycles; 500 mg IV on day 1 of each cycle) of preoperative dostarlimab and 36 weeks (a maximum of six, 6-weekly cycles; 1000 mg IV on day 1 of each cycle) of postoperative dostarlimab. Treatment should start as soon as possible following enrolment. Participants will be randomised or enrolled using a central automated 24-hour internet service based at the Leeds Clinical and Translational Research Unit (CTRU). _____ Previous interventions as of 17/10/2023: FOxTROT is a stratified, multi-arm, multi-site randomised trial platform for patients with locally advanced but operable colon cancer. Prior to the initial registration period, all patients will have been assessed at a colon cancer MDT for review of pathology and radiology and potential participants will be identified. Patients meeting the registration eligibility criteria will be registered and a decision will be made about which FOxTROT comparison is most suitable. Participants will then be randomised in the appropriate comparison. FOxTROT 2 randomises participants between two trial arms: 1. Straight to surgery: patients will proceed straight to surgery as soon as possible and will be assessed for adjuvant chemotherapy as standard care. 2. Neoadjuvant chemotherapy followed by surgery. Participants in this arm will receive 6 weeks of OxFP chemotherapy with a choice (non-randomised) between two regimens: OxMdG (2-weekly oxaliplatin/calcium folinate/infusional fluorouracil) or OxCap (3-weekly oxaliplatin with capecitabine). These should be delivered as per local practice. The clinician has two options of initial dosing as described above: full dose OxFp, or 80% dose OxFp. Treatment should start as soon as possible following randomisation. Patients should be reviewed prior to each cycle of treatment to assess for toxicity and any evidence of disease progression. Following the completion of neoadjuvant chemotherapy, all participants will be reviewed in the oncology clinic to be assessed for adjuvant chemotherapy. FOxTROT 3 randomises participants between two trial arms: 1. In the control arm, Neoadjuvant chemotherapy (NAC) consists of 6 weeks of standard OxFp with a choice (non-randomised) of either OxMdG (2-weekly oxaliplatin/calcium folinate/infusional fluorouracil) or OxCap (3-weekly oxaliplatin with capecitabine). 2. In the experimental arm, NAC comprises three 2-weekly cycles of mFOLFOXIRI (oxaliplatin, irinotecan, calcium folinate, then a 46-hour infusion of fluorouracil). For both arms, treatment should start as soon as possible following randomisation. Patients will receive postoperative adjuvant chemotherapy (AC) of either 6 or 18 weeks, so bringing the total NAC/AC duration to 3 or 6 months respectively. In the control arm, AC is with OxFp; in the experimental arm AC may be either mFOLFOXIRI or OxFp. FOxTROT 4 randomises participants between two trial arms: 1. In the control arm, NAC consists of 6 weeks of standard OxFp with a choice (non-randomised) of either OxMdG (2-weekly oxaliplatin/calcium folinate/infusional fluorouracil) or OxCap (oxaliplatin and capecitabine). 2. In the experimental arm, Neoadjuvant systemic anti-cancer therapy (NA SACT) comprises three 2-week cycles of cetuximab and encorafenib once daily (EC). Treatment should start as soon as possible following randomisation. Postoperative adjuvant treatment will be as per local practice. Participants will be randomised using a central automated 24-hour internet service based at the Leeds Clinical and Translational Research Unit (CTRU). _____ Previous interventions: FOxTROT is a stratified, multi-arm, multi-site randomised trial platform for patients with locally advanced but operable colon cancer. All patients will have been assessed at a colon cancer MDT for review of pathology and radiology and potential participants will be identified. Patients meeting the registration eligibility criteria will be registered and a decision will be made about which FOxTROT comparison is most suitable. Participants will then be randomised in the appropriate comparison. FOxTROT 2 randomises participants between two trial arms: 1. Straight to surgery: patients will proceed straight to surgery as soon as possible and will be assessed for adjuvant chemotherapy as standard care. 2. Neoadjuvant chemotherapy followed by surgery. Participants in this arm will receive 6 weeks of OxFP chemotherapy with a choice (non-randomised) between two regimens: OxMdG (2-weekly oxaliplatin/calcium folinate/infusional fluorouracil) or OxCap (3-weekly oxaliplatin with capecitabine). These should be delivered as per local practice. The clinician has two options of initial dosing as described above: full dose OxFp, or 80% dose OxFp. Treatment should start as soon as possible following randomisation. Patients should be reviewed prior to each cycle of treatment to assess for toxicity and any evidence of disease progression. Following the completion of neoadjuvant chemotherapy, all participants will be reviewed in the oncology clinic to be assessed for adjuvant chemotherapy. Participants will be randomised using a central automated 24-hour internet service based at the Leeds Clinical and Translational Research Unit (CTRU).
Intervention type	Drug
Pharmaceutical study type(s)	Not Applicable
Phase	Phase II/III
Drug / device / biological / vaccine name(s)	FOxTROT 2: Oxaliplatin, calcium folinate, infusional fluorouracil, capecitabine; FOxTROT 3: Irinotecan, Oxaliplatin, calcium folinate, Fluorouracil, Capecitabine; FOxTROT 4: Oxaliplatin, calcium folinate, infusional fluorouracil, capecitabine, Cetuximab, Encorafenib; FOxTROT 5: Dostarlimab.
Primary outcome measure	FOxTROT 2: Disease-free survival (DFS), defined as the time from randomisation to disease recurrence, treatment failure, or death from any cause. The date of recurrence will be taken as the date of the CT scan which concluded disease recurrence. If a CT scan is not carried out, the date of recurrence will be taken as the date of the sample which indicated disease recurrence. Individuals who are lost to follow-up or are alive and disease-free at the time of analysis will be censored at their last date known to be alive and disease-free. FOxTROT 3: Tumour regression grade (TRG) (categorised as no response, mild, moderate, marked and complete response), measured at the time of surgery according to the modified Dworak grading system. DFS will be defined as per the FOxTROT 2 primary endpoint. (added 17/10/2023) FOxTROT 4: Tumour regression grade (TRG) categorised as response or no response, measured at the time of surgery according to the modified Dworak grading system, where response includes the subcategories mild, moderate, marked and complete response. (added 14/08/2024) FOxTROT 5: Proportion of participants with a pathological complete response in the resected tumour following neoadjuvant dostarlimab.
Secondary outcome measures	Current secondary outcome measures as of 14/08/2024: Applicable to FOxTROT 2, FOxTROT 3, FOxTROT 4 and FOxTROT 5, where not part of the primary outcome measures: 1. Tumour regression grade (TRG) measured according to the modified Dworak grading system at the time of surgery 2. Tumour regression score (TRS) (categorised as poor/no response, partial, near complete and complete response), measured at the time of surgery 3. Histopathological endpoints, measured from pathological samples at the time of surgery: 3.1. Tumour cell density 3.2. Maximum tumour size 3.3. Depth of invasion 3.4. Apical node involvement 3.5. Peritoneal involvement 3.6. Nodal involvement 3.7. R1/R2 resection rates 4 Short-term efficacy (and association with longer-term outcomes): 4.1. Downstaging by T-stage, measured at pre-registration, post- neoadjuvant treatment (NAT) and 3-years post randomisation 4.2. Minimal residual disease by ctDNA and ctDNA alterations during NAT measured from blood samples collected at baseline, prior to each cycle of NAT, post-NAT and prior to adjuvant therapy 5. Safety and toxicity (treatment related) defined as the adverse reactions (ARs or irARs) and serious adverse events (SAEs) (including serious adverse reactions (SARs) and serious unexpected serious adverse reactions (SUSARs)) reported on the trial according to CTCAE v5.0 and Clavien-Dindo. 6. Cancer-related survival, defined as the time from randomisation to death caused by the same cancer, whether due to the original tumour or to a second primary same cancer. Individuals who are lost to follow-up or are still alive at the time of analysis will be censored at their last date known to be alive. Death not related to cancer will be specified as a competing risk. 7. Overall survival, defined as the time from randomisation to death from any cause. Individuals who are lost to follow-up or are still alive at the time of analysis will be censored at their last date known to be alive. 8. Surgical morbidity, defined as any surgery-related complication within 30 days post-surgery and surgical mortality, defined as death from any cause within 30 days post-surgery. 9. Patient-reported outcomes (PROs) assessed according to outcomes measured on the EQ-5D5L and QLQ-C30 and CR29. PROs will be collected at timepoints defined according to the protocol. 10. Geriatric assessment scoring, will be determined by the collection of domains used to assess frailty, full details of which are provided in the FOxTROT 2 protocol. Geriatric assessment data will be collected at baseline, and prior to adjuvant treatment – FOxTROT 2 and FOxTROT 5 only 11. Disease-free survival (DFS) _______ Previous secondary outcome measures as of 17/10/2023 to 14/08/2024: 1. Tumour regression grade (TRG) measured according to the modified Dworak grading system at the time of surgery – FOxTROT 2 only 2. Tumour regression score (TRS) (categorised as poor/no response, partial, near complete and complete response), measured at the time of surgery – FOxTROT 2, FOxTROT 3 & FOxTROT 4 3. Histopathological endpoints, measured from pathological samples at the time of surgery – FOxTROT 2, FOxTROT 3 & FOxTROT 4: 3.1. Tumour cell density 3.2. Maximum tumour size 3.3. Depth of invasion 3.4. Apical node involvement 3.5. Peritoneal involvement 3.6. Nodal involvement 3.7. R1/R2 resection rates 4. Short-term efficacy (and association with longer-term outcomes) – FOxTROT 2, FOxTROT 3 and FOxTROT 4: 4.1. Downstaging by T-stage, measured at pre-registration, post-NAC and 3-years postrandomisation 4.2. Minimal residual disease by ctDNA and ctDNA alterations during neoadjuvant chemotherapy (NAC), measured from blood samples collected at baseline, prior to each cycle of NAC, post-NAC and prior to adjuvant chemotherapy 5. Safety and toxicity (both surgical and chemotherapy-related) defined as the adverse reactions (ARs) and serious adverse events (SAEs) (including serious adverse reactions (SARs) and serious unexpected serious adverse reactions (SUSARs)) reported on the trial according to CTCAE v5.0 and Clavien-Dindo – FOxTROT 2, 3 and 4 6. Cancer-related survival, defined as the time from randomisation to death caused by the same cancer, whether due to the original tumour or to a second primary same cancer. Individuals who are lost to follow-up or are still alive at the time of analysis will be censored at their last date known to be alive. Death not related to cancer will be specified as a competing risk – FOxTROT 2, FOxTROT 3 and FOxTROT 4 7. Overall survival, defined as the time from randomisation to death from any cause. Individuals who are lost to follow-up or are still alive at the time of analysis will be censored at their last date known to be alive – FOxTROT 2, FOxTROT 3 and FOxTROT 4 8. Surgical morbidity, defined as any surgery-related complication within 30 days post-surgery and surgical mortality, defined as death from any cause within 30 days post-surgery – FOxTROT 2, FOxTROT 3 and FOxTROT 4 9. Patient-reported outcomes (PROs) assessed according to outcomes measured on the EQ-5D5L and QLQ-C30 and CR29. PROs will be collected at baseline, post-NAC, prior to adjuvant chemotherapy, 12 months post-randomisation and 3 years post-randomisation – FOxTROT 2, 10. Geriatric assessment scoring, will be determined by the collection of domains used to assess frailty, full details of which are provided in the FOxTROT 2 protocol. Geriatric assessment data will be collected at baseline, and prior to adjuvant chemotherapy – FOxTROT 2 only 11. Disease-free survival (DFS) – FOxTROT 4 _____ Previous secondary outcome measures: 1. Tumour regression grade (TRG) measured according to the modified Dworak grading system at the time of surgery – FOxTROT 2 only 2. Tumour regression score (TRS) (categorised as poor/no response, partial, near complete and complete response), measured at the time of surgery – FOxTROT 2&3 3. Histopathological endpoints, measured from pathological samples at the time of surgery – FOxTROT 2&3: 3.1. Tumour cell density 3.2. Maximum tumour size 3.3. Depth of invasion 3.4. Apical node involvement 3.5. Peritoneal involvement 3.6. Nodal involvement 3.7. R1/R2 resection rates 4. Short-term efficacy (and association with longer-term outcomes) – FOxTROT 2 & 3: 4.1. Downstaging by T-stage, measured at pre-registration, post-NAC and 3-years post-randomisation 4.2. Minimal residual disease by ctDNA and ctDNA alterations during neoadjuvant chemotherapy (NAC), measured from blood samples collected at baseline, prior to each cycle of NAC, post-NAC and prior to adjuvant chemotherapy 5. Safety and toxicity (both surgical and chemotherapy-related) defined as the adverse reactions (ARs) and serious adverse events (SAEs) (including serious adverse reactions (SARs) and serious unexpected serious adverse reactions (SUSARs)) reported on the trial according to CTCAE v5.0 and Clavien-Dindo – FOxTROT 2 & 3 6. Cancer-related survival, defined as the time from randomisation to death caused by the same cancer, whether due to the original tumour or to a second primary same cancer. Individuals who are lost to follow-up or are still alive at the time of analysis will be censored at their last date known to be alive. Death not related to cancer will be specified as a competing risk – FOxTROT 2 & 3 7. Overall survival, defined as the time from randomisation to death from any cause. Individuals who are lost to follow-up or are still alive at the time of analysis will be censored at their last date known to be alive – FOxTROT 2 & 3 8. Surgical morbidity, defined as any surgery-related complication within 30 days post-surgery and surgical mortality, defined as death from any cause within 30 days post-surgery – FOxTROT 2 & 3 9. Patient-reported outcomes (PROs) assessed according to outcomes measured on the EQ-5D-5L and QLQ-C30 and CR29. PROs will be collected at baseline, post-NAC, prior to adjuvant chemotherapy, 12 months post-randomisation and 3 years post-randomisation – FOxTROT 2 & 3 10. Geriatric assessment scoring, will be determined by the collection of domains used to assess frailty, full details of which are provided in the FOxTROT 2 protocol. Geriatric assessment data will be collected at baseline, and prior to adjuvant chemotherapy – FOxTROT 2 only
Overall study start date	01/12/2020
Overall study end date	01/08/2029

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	N=759 patients will be randomised into FOxTROT 2 , N=873 patients will be randomised into FOXTROT 3 , N=45 patients will be randomised into FOxTROT 4, N=62 patients will be enrolled into FOxTROT 5.
Participant inclusion criteria	Current inclusion criteria as of 14/08/2024: FOxTROT Registration Inclusion Criteria: 1. Biopsy-confirmed adenocarcinoma of the colon (or upper rectum if too high for radiotherapy); high-grade dysplasia is acceptable with unequivocal radiological evidence of invasive cancer* 2. Radiological stage T3-4, N0-2, M0 3. Patient being treated with curative intent 4. Tumour tissue is available for molecular testing (local or central) 5. Age ≥18 years at the time of registration 6. Patient able and willing to provide written informed consent for the study * Patients with synchronous colonic tumours are eligible if the most advanced tumour meets the criteria above (please note MMR/MSI testing requirements for randomisation depending upon the location of the most advanced tumour) FOxTROT 2 Inclusion Criteria: 1. Patients will be unsuitable for mFOLFOXIRI due to oncologist assessed frailty or comorbidity 2. Proficient mismatch repair (pMMR)/MSS tumour status for right sided tumours 3. Colorectal cancer (CRC) specialist-assessed fit to receive 6 weeks of NAC with OxFp (either full or modified dose) and surgery 4. Adequate full blood count: white blood cell (WBC) >3.0 x 10e9/l; platelets (PLTs) >100 x 10^9/l. 5. Anaemia (Hb <10.0 g/dl) is not an exclusion, but should be corrected by transfusion prior to 6. surgery and chemotherapy. If Hb remains low despite transfusions, surgery and chemotherapy can be given at the decision of the surgical and oncology teams. 7. Adequate renal biochemistry: glomerular filtration rate (GFR) >50 ml/min as assessed by local standards 8. Adequate hepatobiliary function: bilirubin <1.5 upper limit of normal (ULN) (patients with Gilbert’s syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study) 9. If female and of childbearing potential must agree to avoid pregnancy during and for 6 months after last dose of 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. Signed the Informed Consent Document for randomisation FOxTROT 3 Inclusion Criteria: 1. Patients need to be fit and suitable for mFOLFOXIRI. There is no fixed age cut-off, but most patients will be under 70 years. 2. pMMR/MSS tumour status for right sided tumours 3. Adequate full blood count: WBC >3.0 x10^9/l; Neutrophils ≥1.5 x10^9/l; Plts >100 x10^9/l. Anaemia (Hb < 100 g/l) 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. 4. Adequate renal biochemistry: glomerular filtration rate (GFR) >50 ml/min as assessed by local standards 5. Adequate hepatobiliary function: bilirubin <1.5 upper limit of normal (ULN) (patients with Gilbert’s syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study) 6. If female and of childbearing potential must agree to avoid pregnancy during and for 6 months after last dose of study treatment 7. 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 8. Signed the Informed Consent Document for randomisation FOxTROT 4 inclusion criteria: 1. pMMR/MSS colon adenocarcinoma (histologically confirmed). 2. Suitable for surgical resection and peri-operative SACT 3. No metastatic disease on routine staging investigations. 4. No prior treatment for bowel cancer 5. BRAFV600E mutation present in tumour biopsy (tested locally or centrally) 6. Adequate full blood count: WBC >3.0 x10^9/l; Neutrophils ≥1.5 x10^9/l; Plts ≥100 x10^9/l. Anaemia (Hb < 100 g/l) is not an exclusion but should be corrected by transfusion prior to surgery and SACT. If Hb remains low despite transfusions, surgery and SACT can be given at the decision of the surgical and oncology teams. 7. Adequate renal biochemistry: GFR >50 ml/min as assessed by local standards 8. Adequate hepatobiliary function: bilirubin < 1.5 x ULN (Patients with Gilbert’s syndrome who have raised bilirubin, but otherwise normal liver function tests are eligible for the study.) AST /ALT <2.5 x ULN. 9. If female and of childbearing potential, must agree to avoid pregnancy during and for 6 months after the last dose of study treatment* 10. If male with a partner of childbearing potential, must agree to use adequate, medically approved, contraceptive precautions during and for 6 months after the last dose of study treatment* 11. Signed the Informed Consent Document for randomisation FOxTROT 5 inclusion criteria: 1. Patients aged 70 years or more and/or with investigator-assessed frailty 2. dMMR and/or MSI-H tumour status by local or central assessment 3. Colon cancer specialist assessed fit to receive neoadjuvant dostarlimab and undergo surgery (refer to section 8.1 and Table 1 for guidance on assessing patient suitability for inclusion in FOxTROT 5) 4. Adequate full blood count: WBC >3.0 x109/l; Platelets >100 x109/l; neutrophils ≥1.5x109/l. Anaemia (Hb <9.0 g/dl) is not an exclusion but should be corrected by transfusion prior to commencement of study treatment. If Hb remains low despite transfusions, surgery and immunotherapy can be given at the discretion of the surgical and oncology teams 5. Adequate renal biochemistry: GFR ≥30 ml/min/1.73m2 for participants with serum creatinine (Cr) ≥1.5 x ULN OR Cr <1.5 x ULN 6. Adequate hepatobiliary function: Bilirubin ≤1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) AST/ALT ≤2.5 x ULN 7. For participants not taking warfarin: INR <1.5 or PT <1.5 x ULN and either PTT or aPTT <1.5 x ULN. Participants taking warfarin may be included on a stable dose with a therapeutic INR <3.5 8. If female and of childbearing potential, must agree to avoid pregnancy during and for 4 months after last dose of study treatment* 9. If male with a partner of childbearing potential, must agree to use adequate, medically approved, contraceptive precautions during and for 4 months after the last dose of study treatment* 10. Signed the Informed Consent Document for participation _____ Previous inclusion criteria as of 17/10/2023 to 14/08/2024: FOxTROT Registration Inclusion Criteria: 1. Biopsy-confirmed adenocarcinoma of the colon (or upper rectum if too high for radiotherapy); high-grade dysplasia is acceptable with unequivocal radiological evidence of invasive cancer* 2. Radiological stage T3-4, N0-2, M0 3. Patient being treated with curative intent 4. Tumour tissue is available for molecular testing (local or central) 5. Age ≥18 years at the time of registration 6. Patient able and willing to provide written informed consent for the study * Patients with synchronous tumours are eligible if the most advanced tumour meets the criteria above (please note MMR/MSI testing requirements for randomisation depending upon the location of the most advanced tumour) FOxTROT 2 Inclusion Criteria: 1. Patients will be unsuitable for mFOLFOXIRI due to oncologist assessed frailty or comorbidity 2. Proficient mismatch repair (pMMR)/MSS tumour status for right sided tumours 3. Colorectal cancer (CRC) specialist-assessed fit to receive 6 weeks of NAC with OxFp (either full or modified dose) and surgery 4. Adequate full blood count: white blood cell (WBC) >3.0 x 10e9/l; platelets (PLTs) >100 x 10^9/l. 5. Anaemia (Hb <10.0 g/dl) is not an exclusion, but should be corrected by transfusion prior to 6. surgery and chemotherapy. If Hb remains low despite transfusions, surgery and chemotherapy can be given at the decision of the surgical and oncology teams. 7. Adequate renal biochemistry: glomerular filtration rate (GFR) >50 ml/min as assessed by local standards 8. Adequate hepatobiliary function: bilirubin <1.5 upper limit of normal (ULN) (patients with Gilbert’s syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study) 9. If female and of childbearing potential must agree to avoid pregnancy during and for 6 months after last dose of 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. Signed the Informed Consent Document for randomisation FOxTROT 3 Inclusion Criteria 1. Patients need to be fit and suitable for mFOLFOXIRI. There is no fixed age cut-off, but most patients will be under 70 years. 2. pMMR/MSS tumour status for right sided tumours 3. Adequate full blood count: WBC >3.0 x10^9/l; Neutrophils ≥1.5 x10^9/l; Plts >100 x10^9/l. Anaemia (Hb < 100 g/l) 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. 4. Adequate renal biochemistry: glomerular filtration rate (GFR) >50 ml/min as assessed by local standards 5. Adequate hepatobiliary function: bilirubin <1.5 upper limit of normal (ULN) (patients with Gilbert’s syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study) 6. If female and of childbearing potential must agree to avoid pregnancy during and for 6 months after last dose of study treatment 7. 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 8. Signed the Informed Consent Document for randomisation FOxTROT 4 inclusion criteria 1. pMMR/MSS colon adenocarcinoma (histologically confirmed). 2. Suitable for surgical resection and peri-operative SACT 3. No metastatic disease on routine staging investigations. 4. No prior treatment for bowel cancer 5. BRAFV600E mutation present in tumour biopsy (tested locally or centrally) 6. Adequate full blood count: WBC >3.0 x10^9/l; Neutrophils ≥1.5 x10^9/l; Plts ≥100 x10^9/l. Anaemia (Hb < 100 g/l) is not an exclusion but should be corrected by transfusion prior to surgery and SACT. If Hb remains low despite transfusions, surgery and SACT can be given at the decision of the surgical and oncology teams. 7. Adequate renal biochemistry: GFR >50 ml/min as assessed by local standards 8. Adequate hepatobiliary function: bilirubin < 1.5 x ULN (Patients with Gilbert’s syndrome who have raised bilirubin, but otherwise normal liver function tests are eligible for the study.) AST /ALT <2.5 x ULN. 9. If female and of childbearing potential, must agree to avoid pregnancy during and for 6 months after the last dose of study treatment* 10. If male with a partner of childbearing potential, must agree to use adequate, medically approved, contraceptive precautions during and for 6 months after the last dose of study treatment* 11. Signed the Informed Consent Document for randomisation _____ Previous inclusion criteria: FOxTROT registration inclusion criteria: 1. Biopsy-confirmed adenocarcinoma of the colon (or upper rectum if too high for radiotherapy); high-grade dysplasia is acceptable with unequivocal radiological evidence of invasive cancer* 2. Radiological stage T3-4, N0-2, M0 3. Patient being treated with curative intent 4. Tumour tissue is available for mismatch repair (MMR)/microsatellite instability (MSI) testing (local or central) 5. No clinical or radiological evidence of bowel obstruction 6. Age ≥18 years at the time of registration 7. Patient able and willing to provide written informed consent for the study * Patients with synchronous tumours are eligible if the most advanced tumour meets the criteria above (please note MMR/MSI testing requirements for randomisation depending upon the location of the most advanced tumour) FOxTROT 2 inclusion criteria: 8. Patients will be unsuitable for mFOLFOXIRI due to oncologist assessed frailty or comorbidity 9. Proficient mismatch repair (pMMR)/MSS tumour status (for rt sided tumours) 10. Colorectal cancer (CRC) specialist-assessed fit to receive 6 weeks of NAC with OxFp (either full or modified dose) and surgery 11. Adequate full blood count: white blood cell (WBC) >3.0 x 10e9/l; platelets (PLTs) >100 x 10e9/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. 12. Adequate renal biochemistry: glomerular filtration rate (GFR) >50 ml/min as assessed by local standards 13. Adequate hepatobiliary function: bilirubin <1.5 upper limit of normal (ULN) (patients with Gilbert’s syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study) 14. If female and of childbearing potential must agree to avoid pregnancy during and for 6 months after study treatment 15. 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 16. Signed the Informed Consent Document for randomisation
Participant exclusion criteria	Current exclusion criteria as of 14/08/2024: FOxTROT registration exclusion criteria: 1. Any patient for whom radiotherapy is advised by the multidisciplinary team (MDT) 2. Cases with a high index of suspicion of distant metastases or peritoneal nodules (cM1). However, cases with indeterminate abnormalities should be managed and investigated as per standard local MDT procedures and can be considered for trial entry if the MDT opinion is that these are considered most likely to be benign. 3. Colonic obstruction that has not been defunctioned* 4. Women who are pregnant or breastfeeding * Obstructed patients cannot be included in the FOxTROT trials, unless the obstruction has been relieved. This would usually be by defunctioning. Patients may also be stented, but there is more limited safety data on this and these cases should be individually discussed with the Trial Management Group (TMG). FOxTROT 2, FOxTROT 3 and FOxTROT 4 Exclusion Criteria: 1. Serious medical comorbidity, as assessed by the leading clinician (such as uncontrolled angina) 2. 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 <10% 3. Known deficient mismatch repair (dMMR)/microsatellite Instability High (MSI-H) tumour status FOxTROT 3 Additional Exclusion Criteria: 1. Known hypersensitivity to oxaliplatin, irinotecan or fluoropyrimidine therapy 2. Have a peripheral sensitive neuropathy with functional impairment 3. Have a severe chronic inflammatory bowel condition. 4. Known complete DPYD deficiency (homozygosity) 5. Recent or concomitant treatment with brivudine, sorivudine (or their chemically related analogues), St John’s Wort. FOxTROT 4 Additional Exclusion Criteria: 1. Impending bowel obstruction 2. Known hypersensitivity to oxaliplatin, or fluoropyrimidine therapy 3. Prior treatment with any RAF or EGFR inhibitors 4. Have a peripheral sensitive neuropathy with functional impairment 5. Have a severe chronic inflammatory bowel condition. 6. Known complete DPYD deficiency (homozygosity) 7. Recent or concomitant treatment with brivudine, sorivudine (or their chemically related analogues), St John’s Wort. FOxTROT 5 Exclusion Criteria: 1. Known pMMR or MSS/MSI-L colonic tumour status 2. Has a known additional malignancy that progressed or required active treatment within the past 2 years. Exceptions include adequately treated superficial skin cancers, superficial bladder cancers, and other in situ cancers 3. Is immunocompromised in the opinion of the investigator, is receiving any immunosuppressive medication, or has received systemic corticosteroids (>10mg prednisolone daily, or equivalent) within 7 days of first dose of study intervention. Use of inhaled steroids, local injection of steroids, topical steroids, and steroidal eye drops are allowed 4. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g. levothyroxine) is not considered a form of systemic treatment 5. Experienced any of the following with prior immunotherapy: any Grade 3 or higher immune-related adverse reaction (irAR), anygrade immune-related severe neurologic events (e.g. myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré syndrome, or transverse myelitis), any grade exfoliative dermatitis (Steven-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome), any grade myocarditis. Non-clinically significant laboratory abnormalities are not exclusionary 6. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrolment 7. Has any history of interstitial lung disease or pneumonitis 8. Cirrhosis or unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal/gastric varices, or persistent jaundice 9. Has a history or current evidence of any medical condition, therapy, or laboratory abnormality that might confound the study results, interfere with their participation for the full duration of the study intervention, or indicate it is not in the best interests of the participant to participate, in the opinion of the investigator 10. Has a history of allogenic stem cell transplantation or organ transplantation 11. Has a history of congenital long QT syndrome 12. Has a history or evidence of cardiac abnormalities such as serious, uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities within the 6 months prior to enrolment 13. Is receiving any other anticancer or experimental therapy 14. Received a live vaccine within 30 days of planned start of study therapy 15. Has documented presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to enrolment 16. Has a positive hepatitis C virus (HCV) antibody test result at screening or within 3 months prior to enrolment. Note: Participants with a positive HCV antibody test result due to prior resolved disease can be enrolled, only if a confirmatory HCV RNA test is obtained 17. Has a positive HCV RNA test result at screening or within 3 months prior to enrolment. Note: The HCV RNA test is optional and participants with negative HCV antibody test are not required to undergo HCV RNA testing as well 18. Is considered, in the investigator’s opinion, a poor medical risk due to severe, uncontrolled medical disorder, non-malignant systemic disease, or active infection requiring systemic therapy. 19. Has known history of human immunodeficiency virus (HIV) infection (unless the specific criteria in the FOxTROT 5 protocol are met) 20. A known history of severe allergic and/or anaphylactic reactions to chimeric, human or humanized antibodies, fusion proteins, or to dostarlimab or its excipients ______ Previous exclusion criteria as of 17/10/2023 to 14/08/2024: FOxTROT registration exclusion criteria: 1. Any patient for whom radiotherapy is advised by the multidisciplinary team (MDT) 2. Cases with a high index of suspicion of distant metastases or peritoneal nodules (cM1). However, cases with indeterminate abnormalities should be managed and investigated as per standard local MDT procedures and can be considered for trial entry if the MDT opinion is that these are considered most likely to be benign. 3. Colonic obstruction that has not been defunctioned* 4. Women who are pregnant or breastfeeding * Obstructed patients cannot be included in the FOxTROT trials, unless the obstruction has been relieved. This would usually be by defunctioning. Patients may also be stented, but there is more limited safety data on this and these cases should be individually discussed with the Trial Management Group (TMG). FOxTROT 2, FOxTROT 3 and FOxTROT 4 Exclusion Criteria: 1. Serious medical comorbidity, as assessed by the leading clinician (such as uncontrolled angina) 2. 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 <10% 3. Known deficient mismatch repair (dMMR)/microsatellite Instability High (MSI-H) tumour status FOxTROT 3 Additional Exclusion Criteria: 1. Known hypersensitivity to oxaliplatin, irinotecan or fluoropyrimidine therapy 2. Have a peripheral sensitive neuropathy with functional impairment 3. Have a severe chronic inflammatory bowel condition. 4. Known complete DPYD deficiency (homozygosity) 5. Recent or concomitant treatment with brivudine, sorivudine (or their chemically related analogues), St John’s Wort. FOxTROT 4 Additional Exclusion Criteria: 1. Impending bowel obstruction 2. Known hypersensitivity to oxaliplatin, or fluoropyrimidine therapy 3. Prior treatment with any RAF or EGFR inhibitors 4. Have a peripheral sensitive neuropathy with functional impairment 5. Have a severe chronic inflammatory bowel condition. 6. Known complete DPYD deficiency (homozygosity) 7. Recent or concomitant treatment with brivudine, sorivudine (or their chemically related analogues), St John’s Wort. _____ Previous exclusion criteria: FOxTROT randomisation exclusion criteria: 1. Any patient for whom radiotherapy is advised by the multidisciplinary team (MDT) 2. Strong evidence of distant metastases or peritoneal nodules (cM1), however patients with lung lesions of uncertain significance (<5 mm) are eligible 3. Peritonitis (secondary to perforated tumour) 4. Colonic obstruction that has not been defunctioned* * Obstructed patients cannot be included in the FOxTROT trials, unless the obstruction has been relieved. This would usually be by defunctioning. Patients may also be stented, but there is more limited safety data on this and these cases should be individually discussed with the Trial Management Group (TMG). FOxTROT 2 exclusion criteria: 5. Serious medical comorbidity, as assessed by the leading clinician (such as uncontrolled angina) 6. 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 <10% 7. Known deficient mismatch repair (dMMR)/microsatellite Instability High (MSI-H) tumour status
Recruitment start date	07/02/2022
Recruitment end date	01/04/2027

Locations

Countries of recruitment

Australia
England
France
India
Netherlands
Scotland
Sweden
United Kingdom
Wales

Study participating centres

Airedale General Hospital

Skipton Rd
Steeton
Keighley
BD20 6TD
United Kingdom

St Bartholomew's Hospital

W Smithfield
London
EC1A 7BE
United Kingdom

Ysbyty Gwynedd

Penrhosgarnedd
Bangor
LL57 2PW
United Kingdom

Bradford Royal Infirmary

Duckworth Ln
Bradford
BD9 6RJ
United Kingdom

Calderdale Rotal Hospital and Huddersfield Royal Infirmary

Acre St
Lindley
Huddersfield
HD3 3EA
United Kingdom

Addenbrooke's Hospital

Hills Rd
Cambridge
CB2 0QQ
United Kingdom

West Middlesex University Hospital

Twickenham Rd
Isleworth
TW7 6AF
United Kingdom

Chesterfield Royal Hospital

Chesterfield Rd
Calow
Chesterfield
S44 5BL
United Kingdom

Countess of Chester Hospital

Liverpool Rd
Chester
CH2 1UL
United Kingdom

Darlington Memorial Hospital

Hollyhurst Rd
Darlington
DL3 6HX
United Kingdom

Macclesfield District General Hospital

Victoria Rd
Macclesfield
SK10 3BL
United Kingdom

Ipswich Hospital

Heath Rd
Ipswich
IP4 5PD
United Kingdom

Conquest Hospital

The Ridge
Saint Leonards-on-Sea
TN37 7RD
United Kingdom

Bensham Hospital

Fontwell Dr
Gateshead
NE8 4YL
United Kingdom

Great Western Hospital

Marlborough Rd
Swindon
SN3 6BB
United Kingdom

Basingstoke and North Hampshire Hospital

Aldermaston Rd
Basingstoke
RG24 9NA
United Kingdom

Charing Cross Hospital and St Mary's

Fulham Palace Rd
London
W6 8RF
United Kingdom

Kettering General Hospital

Rothwell Rd
Kettering
NN16 8UZ
United Kingdom

St James's University Hospital

Beckett St
Harehills
Leeds
LS9 7TF
United Kingdom

Queen Elizabeth Hospital & Lewisham Hospital

Stadium Rd
London
SE18 4QH
United Kingdom

Royal Liverpool University Hospital

Prescot St
Liverpool
L7 8XP
United Kingdom

Manchester Royal Infirmary

Oxford Rd
Manchester
M13 9WL
United Kingdom

Crosshouse Hospital

Kilmarnock Rd
Crosshouse
Kilmarnock
KA2 0BE
United Kingdom

Queen Margaret Hospital and Victoria Hospital

Whitefield Rd
Dunfermline
KY12 0SU
United Kingdom

Forth Valley Royal Hospital

Stirling Rd
Larbert
FK5 4WR
United Kingdom

Beatson West of Scotland Cancer Centre

1053 Great Western Rd
Glasgow
G12 0YN
United Kingdom

Royal Edinburgh Hospital

Morningside Pl
Edinburgh
EH10 5HF
United Kingdom

Norfolk & Norwich University Hospital

Colney Ln
Colney
Norwich
NR4 7UY
United Kingdom

Northampton General Hospital

Cliftonville
Northampton
NN1 5BD
United Kingdom

Hexham General Hospital

Corbridge Rd
Hexham
NE46 1QJ
United Kingdom

Queen Alexandra Hospital

Cosham
Portsmouth
PO6 3LY
United Kingdom

Royal Cornwall Hospital

Treliske
Truro
TR1 3LJ
United Kingdom

Royal Devon and Exeter Hospital

Barrack Rd
Exeter
EX2 5DW
United Kingdom

Royal Free Hospital

Pond St
London
NW3 2QG
United Kingdom

Royal United Hospital

Combe Park
Bath
BA1 3NG
United Kingdom

Weston Park Cancer Centre

Whitham Rd
Broomhall
Sheffield
S10 2SJ
United Kingdom

St George's Hospital

Blackshaw Rd
London
SW17 0QT
United Kingdom

Musgrove Park Hospital

Parkfield Dr
Taunton
TA1 5DA
United Kingdom

The Christie

Wilmslow Rd
Manchester
M20 4BX
United Kingdom

Clatterbridge Cancer Centre Liverpool and Clatterbridge Cancer Centre Wirral

Clatterbridge Rd
Birkenhead
Wirral
CH63 4JY
United Kingdom

The Royal Marsden Hospital (Chelsea and Sutton)

203 Fulham Rd
London
SW3 6JJ
United Kingdom

Royal Surrey County Hospital

Egerton Rd
Guildford
GU2 7XX
United Kingdom

Harrogate District Hospital

Lancaster Park Rd
Harrogate
HG2 7SX
United Kingdom

Lincoln County Hospital

Greetwell Rd
Lincoln
LN2 5QY
United Kingdom

UCL Cancer Institute

72 Huntley St
London
WC1E 6DD
United Kingdom

Bristol Cancer Centre

22 Horfield Rd
Bristol
BS2 8ED
United Kingdom

University Hospital Coventry

Clifford Bridge Rd
Coventry
CV2 2DX
United Kingdom

Poole Hospital and Royal Bournemouth Hospital

Longfleet Rd
Poole
BH15 2JB
United Kingdom

Royal Derby Hospital

Uttoxeter Rd
Derby
DE22 3NE
United Kingdom

Royal Stoke University Hospital

Newcastle Rd
Stoke-on-Trent
ST4 6QG
United Kingdom

Derriford Hospital

Derriford Rd
Plymouth
PL6 8DH
United Kingdom

Leicester General Hospital

Gwendolen Rd
Leicester
LE5 4PW
United Kingdom

Velindre Cancer Centre

Velindre Rd
Cardiff
CF14 2TL
United Kingdom

Walsall Manor Hospital

Moat Rd
Walsall
WS2 9PS
United Kingdom

Worcestershire Royal Hospital

Charles Hastings Way
Worcester
WR5 1DD
United Kingdom

Royal Albert Edward Infirmary

Wigan Ln
Wigan
WN1 2NN
United Kingdom

York Teaching Hospital

Wigginton Rd
Clifton
York
YO31 8HE
United Kingdom

Dorset County Hospital

Williams Ave
Dorchester
DT1 2JY
United Kingdom

Colchester Hospital

Turner Rd
Colchester
CO4 5JL
United Kingdom

George Eliot Hospital

College St
Nuneaton
CV10 7DJ
United Kingdom

University Hospital Monklands

Monkscourt Ave
Airdrie
ML6 0JS
United Kingdom

University Hospital of North Tees

Hardwick Rd
Hardwick
Stockton-on-Tees
TS19 8PE
United Kingdom

The James Cook University Hospital

Middlesbrough
TS4 3BS
United Kingdom

Warwick Hospital

Lakin Rd
Warwick
CV34 5BW
United Kingdom

East Yorkshire Hospitals NHS Trust (head Office)

Castle Hill Hospital
Castle Road
Cottingham
HU16 5JQ
United Kingdom

Mid Cheshire Hospitals NHS Foundation Trust

Leighton Hospital
Leighton
Crewe
CW1 4QJ
United Kingdom

Milton Keynes University Hospital

Standing Way
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom

University Hospital Crosshouse

Kilmarnock Road
Kilmarnock
KA2 0BE
United Kingdom

Queen Margaret Hospital

Whitefield Road
Dunfermline
KY12 0SU
United Kingdom

Victoria Hospital

Hayfield Road
Kirkcaldy
KY2 5AH
United Kingdom

Ninewells Hospital

Ninewells Avenue
Dundee
DD1 9SY
United Kingdom

Churchill Hospital

Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
United Kingdom

Singleton Hospital

Sketty Lane
Sketty
Swansea
SA2 8QA
United Kingdom

Queen Elizabeth Hospital

Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom

Yeovil Hospital Bcsc

Yeovil District Hospital
Higher Kingston
Yeovil
BA21 4AT
United Kingdom

Christian Medical College and Hospital (Local Sponsor for FOxTROT 2 only)

Brown Rd, CMC Campus
Ludhiana
141008
India

CHU DIJON (Local Sponsor for FOxTROT 2 only)

1 Rue du Professeur Marion
Dijon
21000
France

Sponsor information

University of Leeds
University/education

Research & Innovation Centre
Leeds Teaching Hospitals NHS Trust
St James’s University Hospital
Beckett Street
Leeds
LS9 7TF
England
United Kingdom

Phone	+44 (0)113 2060454
Email	C.E.Skinner@leeds.ac.uk
Website	http://www.leeds.ac.uk/
"ROR"	https://ror.org/024mrxd33

Funders

Funder type

Charity

Yorkshire Cancer Research
Government organisation / Trusts, charities, foundations (both public and private)

Alternative name(s): YCR
Location: United Kingdom

Merck

No information available

Pierre Fabre

No information available

GSK

No information available

Results and Publications

Intention to publish date	01/08/2030
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in non-publicly available repository, Available on request
Publication and dissemination plan	Planned publications in a high-impact peer-reviewed journal. The protocol is currently not available online.
IPD sharing plan	De-identified individual participant data datasets generated and/or analysed during the current study will be available upon request from the Clinical Trials Research Unit, University of Leeds (contact CTRU-DataAccess@leeds.ac.uk in the first instance). Data will be made available at the end of the trial, i.e. usually when all primary and secondary endpoints have been met and all key analyses are complete. Data will remain available from then on for as long as CTRU retains the data. CTRU makes data available by a 'controlled access' approach. Data will only be released for legitimate secondary research purposes, where the Chief Investigator, Sponsor and CTRU agree that the proposed use has scientific value and will be carried out to a high standard (in terms of scientific rigour and information governance and security), and that there are resources available to satisfy the request. Data will only be released in line with participants' consent, all applicable laws relating to data protection and confidentiality, and any contractual obligations to which the CTRU is subject. No individual participant data will be released before an appropriate agreement is in place setting out the conditions of release. The agreement will govern data retention, usually stipulating that data recipients must delete their copy of the released data at the end of the planned project. The CTRU encourages a collaborative approach to data sharing, and believe it is best practice for researchers who generated datasets to be involved in subsequent uses of those datasets. Recipients of trial data for secondary research will also receive data dictionaries, copies of key trial documents and any other information required to understand and reuse the released datasets. The conditions of release for aggregate data may differ from those applying to individual participant data. Requests for aggregate data should also be sent to the above email address to discuss and agree suitable requirements for release.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No

Editorial Notes

14/08/2024: The following changes were made:
1. The hypothesis was updated.
2. Drug name(s) were updated from "FOxTROT 2: Oxaliplatin, calcium folinate, infusional fluorouracil, capecitabine; FOxTROT 3: Irinotecan, Oxaliplatin, calcium folinate, Fluorouracil, Capecitabine; FOxTROT 4: Oxaliplatin, calcium folinate, infusional fluorouracil, capecitabine, Cetuximab, Encorafenib".
3. The primary and secondary outcome measures were updated.
4. The participant inclusion and exclusion criteria were updated.
5. The target number of participants was changed from "N=759 patients will be randomised into FOxTROT 2 , N=873 patients will be randomised into FOXTROT 3 , N=45 patients will be randomised into FOxTROT 4".
6. The interventions were updated.
7. Merck, Pierre Fabre and GSK were added to the funders.
8. The plain English summary was updated to reflect these changes.
08/05/2024: ClinicalTrials.gov number added.
07/05/2024: Contact details updated.
22/03/2024: The following changes were made to the trial record:
1. The country of recruitment 'India' was added.
2. The study participating centres Christian Medical College and Hospital, CHU DIJON were added.
04/01/2024: The participant-level data-sharing statement was added.
17/10/2023: The following changes were made to the trial record:
1. The study hypothesis was changed.
2. The ethics approval was added.
3. The interventions were changed.
4. The phase was changed from Phase III to Phase II/III.
5. The drug names were changed from "FOxTROT 2: oxaliplatin, calcium folinate, infusional fluorouracil, capecitabine" to "FOxTROT 2: Oxaliplatin, calcium folinate, infusional fluorouracil, capecitabine; FOxTROT 3: Irinotecan, Oxaliplatin, calcium folinate, Fluorouracil, Capecitabine; FOxTROT 4: Oxaliplatin, calcium folinate, infusional fluorouracil, capecitabine, Cetuximab, Encorafenib"
6. The primary outcome measures were changed.
7. The secondary outcome measures were changed.
8. The study website was added.
9. The inclusion criteria were changed.
10. The exclusion criteria were changed.
11. The target number of participants was changed from "759 patients will be randomised into FOxTROT 2" to "N=759 patients will be randomised into FOxTROT 2 , N=873 patients will be randomised into FOXTROT 3 , N=45 patients will be randomised into FOxTROT 4".
12. The recruitment start date was changed from 31/10/2021 to 07/02/2022.
13. The recruitment end date was changed from 01/08/2026 to 01/04/2027.
14. The study participating centres East Yorkshire Hospitals NHS Trust (head Office), Mid Cheshire Hospitals NHS Foundation Trust, Milton Keynes University Hospital, University Hospital Crosshouse, Queen Margaret Hospital, Victoria Hospital, Ninewells Hospital, Churchill Hospital, Singleton Hospital, Queen Elizabeth Hospital, Yeovil Hospital Bcsc were added.
15. The plain English summary was updated to reflect these changes.
10/05/2023: Cancer Research UK plain English summary link added to plain English summary field.
30/09/2021: The ethics approval was added.
08/06/2021: Trial's existence confirmed by Yorkshire Cancer Research.