Locally advanced but operable colon cancer Cancer Malignant neoplasm of colon
Conditions
Interventions
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 reg
Sponsors
University of Leeds
Eligibility
Sex/Gender
All
Inclusion criteria
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 50 ml/min as assessed by local standards 8. Adequate hepatobiliary function: bilirubin 3.0 x10^9/l; Neutrophils =1.5 x10^9/l; Plts >100 x10^9/l. Anaemia (Hb 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 confir
Exclusion criteria
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 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 syndrom
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 a | — |
Countries
Australia, England, France, India, Netherlands, Scotland, Sweden, United Kingdom, Wales
Contacts
Public ContactClaire Dimbleby
Outcome results
None listed