Trial Information
Status:
Open
Specialty:
Colorectal
Date Opened:
20-03-2023
Planned Close date:
31-07-2026
Sponsors:
The Royal Marsden NHS Foundation Trust
Site Recruitment:
7 /
0
Principal Investigator:
Dr Kellati Prasad
Study Title:
TRACC C
Contacts
Research Nurse / Study Coordinator:
Sarah Keith
Administrator:
Philippa Springle
Tracking mutations in cell free tumour DNA to predict Relapse in Early Colorectal Cancer
TRACC C is a prospective, randomised, multi-centre, study enrolling a total of 1681 patients Patients with high risk stage II or stage III colorectal cancer (CRC) whose pre-surgery blood test confirms presence of circulating tumour DNA (ctDNA) will be randomised to 1:1 with 810 patients treated in standard of care arm where patients are offered adjuvant chemotherapy according to national guidelines and 810 patients in the experimental arm, in which patients are treated based on ctDNA results . Patients will be stratified according to:
1. High risk stage II versus stage III
2. Site of primary tumour: right colon versus left colon versus rectum
Hypothesis: ctDNA directed adjuvant chemotherapy administration will enable biomarker driven selection of patients who would benefit from adjuvant chemotherapy, thereby reducing the proportion of patients receiving adjuvant chemotherapy without compromising disease free survival.
Background: There are 42,000 new cases of CRC, a top four cancer, diagnosed in the UK each year (CRUK Bowel Cancer Statistics, 2017). Approximately half of these cases are curable and include stage II (n=9600/year) and III
(n=10,500/year). In patients with high risk stage II and stage III colorectal patients, adjuvant chemotherapy is currently determined by pathological features of the tumour resected at surgery. This is not a precise method of risk stratification of relapse and we are undoubtedly over-treating a proportion of patients already cured. Around 15-25% of patients offered standard oxaliplatin containing chemotherapy have permanent peripheral sensory neuropathy which can be quite debilitating and distressing (Grothey, Sem in Onc, 2003).
Progress has been made in minimising unnecessary chemotherapy with the landmark UK-led publication (Iverson T et al, Lancet Onc, April 2018), confirmed by international meta-analyses (Grothey A et al, NEJM, March 2018) indicating that 3 months of post-operative chemotherapy was non-inferior to 6 months, without loss of benefit. The 3 year disease-free survival (DFS) in the 3-month group was 76.7% (95% CI 75.1–78.2) and in the 6-month group was 77.1% (75.6–78.6) [HR: 1.006 (0.909–1.114)]. The incidence of peripheral sensory neuropathy was of significantly less magnitude, with the rate being 58% in the 6 month group versus 25% in the 3 month group. The SCOT trial has changed clinical practice and our current standard of care is either 3 months of doublet capecitabine and oxaliplatin
Eligibility criteria to be used prior to registration (for all
patients, Part A and B):
Inclusion Criteria:
• New diagnosis of histologically confirmed CRC scheduled to
undergo surgery with curative intent, with no radiological
evidence of metastatic disease.
• Patients with lesions with high degree of suspicion on histology
but not confirmed to be an adenocarcainoma and whose
imaging is strongly suggestive of colorectal carcinoma (CRC)
will be included. This patients will be excluded post-surgery if
carcinoma diagnosis is not confirmed
• Age≥18
• Ability to give informed consent
• Able to adhere to follow up schedule
Additional eligibility criteria for rectal cancer patients following
completion of pre-operative radiotherapy or
chemoradiotherapy
All patients proceeding to surgery
Eligibility criteria at the first post-operative visit:
Inclusion Criteria:
• Stage I, II or III CRC based on the post-operative histopathology
report
• Availability of FFPE tumour tissue from surgery, for processing
and analysis at the CMP
For patients in the ctDNA guided interventional arm of the
study only (Part C)
Inclusion Criteria:
1. Subject ≥ 18 years of age
2. Subjects with histologically proven high risk stage II or stage
III colon or rectal cancer treated with curative intent with
surgery alone (any T, N1 or N2) with no evidence of
metastatic disease. Subjects must be due to receive
adjuvant chemotherapy following surgery.
Subjects with histologically proven stage III rectal cancer are
eligible, including patients treated with neoadjuvant
chemoradiotherapy (any T, N1 or N2, M0) with no evidence
of metastatic disease. Subjects must be due to receive
adjuvant chemotherapy following surgery.
3. Fully surgically resected tumour with clear resection margins (i.e., >1 mm)
4. Patients must have detectable levels of ctDNA (i.e.,
ctDNA positive) in blood samples at baseline; this is
collected pre-operatively if being treated with surgery
alone, or before chemoradiotherapy in patients with
locally advanced rectal cancer being treated with
neoadjuvant chemoradiotherapy before surgery
5. Adequate organ function
- Absolute neutrophil function ≥1.0 x 109
/ L
- Platelet Count ≥ 75 x 109 / L
- Haemoglobin ≥80g/L (blood transfusion before
randomisation is allowed)
- Adequate renal function as calculated by Cockcroft and
Gault equation (GFR ≥ 30ml/min if FOLFOX chemotherapy
chosen and GFR ≥ 50ml/min if single agent capecitabine or
CAPOX chosen)
- Aspartate aminotransferase/ Alanine aminotransferase
levels ≤ 2.5 upper limit of normal
6. Absence of major post-operative complications or other
clinical conditions that, in the opinion of the investigator,
would not contraindicate adjuvant chemotherapy
7. Patients should be assessed by Oncology team for
suitability and assessment for adjuvant chemotherapy, be
able to have post-operative ctDNA sample collected and be
randomised by week 4-8 after surgery.
8. ECOG performance status 0- 2
9. Able to give informed consent
patients, Part A and B):
Inclusion Criteria:
• New diagnosis of histologically confirmed CRC scheduled to
undergo surgery with curative intent, with no radiological
evidence of metastatic disease.
• Patients with lesions with high degree of suspicion on histology
but not confirmed to be an adenocarcainoma and whose
imaging is strongly suggestive of colorectal carcinoma (CRC)
will be included. This patients will be excluded post-surgery if
carcinoma diagnosis is not confirmed
• Age≥18
• Ability to give informed consent
• Able to adhere to follow up schedule
Additional eligibility criteria for rectal cancer patients following
completion of pre-operative radiotherapy or
chemoradiotherapy
All patients proceeding to surgery
Eligibility criteria at the first post-operative visit:
Inclusion Criteria:
• Stage I, II or III CRC based on the post-operative histopathology
report
• Availability of FFPE tumour tissue from surgery, for processing
and analysis at the CMP
For patients in the ctDNA guided interventional arm of the
study only (Part C)
Inclusion Criteria:
1. Subject ≥ 18 years of age
2. Subjects with histologically proven high risk stage II or stage
III colon or rectal cancer treated with curative intent with
surgery alone (any T, N1 or N2) with no evidence of
metastatic disease. Subjects must be due to receive
adjuvant chemotherapy following surgery.
Subjects with histologically proven stage III rectal cancer are
eligible, including patients treated with neoadjuvant
chemoradiotherapy (any T, N1 or N2, M0) with no evidence
of metastatic disease. Subjects must be due to receive
adjuvant chemotherapy following surgery.
3. Fully surgically resected tumour with clear resection margins (i.e., >1 mm)
4. Patients must have detectable levels of ctDNA (i.e.,
ctDNA positive) in blood samples at baseline; this is
collected pre-operatively if being treated with surgery
alone, or before chemoradiotherapy in patients with
locally advanced rectal cancer being treated with
neoadjuvant chemoradiotherapy before surgery
5. Adequate organ function
- Absolute neutrophil function ≥1.0 x 109
/ L
- Platelet Count ≥ 75 x 109 / L
- Haemoglobin ≥80g/L (blood transfusion before
randomisation is allowed)
- Adequate renal function as calculated by Cockcroft and
Gault equation (GFR ≥ 30ml/min if FOLFOX chemotherapy
chosen and GFR ≥ 50ml/min if single agent capecitabine or
CAPOX chosen)
- Aspartate aminotransferase/ Alanine aminotransferase
levels ≤ 2.5 upper limit of normal
6. Absence of major post-operative complications or other
clinical conditions that, in the opinion of the investigator,
would not contraindicate adjuvant chemotherapy
7. Patients should be assessed by Oncology team for
suitability and assessment for adjuvant chemotherapy, be
able to have post-operative ctDNA sample collected and be
randomised by week 4-8 after surgery.
8. ECOG performance status 0- 2
9. Able to give informed consent
Eligibility criteria to be used prior to registration (for all
patients, Part A and B):
Exclusion Criteria:
• Scheduled to have neoadjuvant chemotherapy, (neoadjuvant
chemoradiotherapy for patients with rectal cancer is permitted)
• Current or previous other malignancy within 5 years of study
entry, except cured basal or squamous cell skin cancer,
superficial bladder cancer, prostate intraepithelial neoplasm,
carcinoma in situ of the cervix or other non-invasive malignancy.
Additional eligibility criteria for rectal cancer patients following
completion of pre-operative radiotherapy or
chemoradiotherapy
Patients scheduled to have further pre-operative treatment with chemotherapy
• Patients that are no longer proceeding with surgery i.e. those in
whom surgery is considered too high risk
• Patients that are no longer proceeding with surgery as they are
proceeding with a deferral of surgery approach
Eligibility criteria at the first post-operative visit:
Patients with no confirmed tissue diagnosis or high grade
dysplasia included in the study based on imaging diagnosis but
subsequent histopathology of surgical specimen confirms no
carcinoma will be excluded
• Scheduled to receive post-operative radiotherapy
For patients in the ctDNA guided interventional arm of the
study only (Part C)
Exclusion Criteria:
1. History of concurrent and previous malignancy within the
last 3 years, with the exception of non- melanomatous skin
cancer and carcinoma in situ
2. Any major post-operative complications or other clinical conditions that in the opinion of the investigator would
contra-indicate adjuvant chemotherapy
3. Any subject not due to receive adjuvant chemotherapy will
not be eligible for Part C of the study
4. Hypersensitivity or contraindication to the drug(s) associated
with the planned choice of systemic chemotherapy (CAPOX,
FOLFOX or single agent 5-FU or capecitabine) as stated in
the SPC for each of the drugs
patients, Part A and B):
Exclusion Criteria:
• Scheduled to have neoadjuvant chemotherapy, (neoadjuvant
chemoradiotherapy for patients with rectal cancer is permitted)
• Current or previous other malignancy within 5 years of study
entry, except cured basal or squamous cell skin cancer,
superficial bladder cancer, prostate intraepithelial neoplasm,
carcinoma in situ of the cervix or other non-invasive malignancy.
Additional eligibility criteria for rectal cancer patients following
completion of pre-operative radiotherapy or
chemoradiotherapy
Patients scheduled to have further pre-operative treatment with chemotherapy
• Patients that are no longer proceeding with surgery i.e. those in
whom surgery is considered too high risk
• Patients that are no longer proceeding with surgery as they are
proceeding with a deferral of surgery approach
Eligibility criteria at the first post-operative visit:
Patients with no confirmed tissue diagnosis or high grade
dysplasia included in the study based on imaging diagnosis but
subsequent histopathology of surgical specimen confirms no
carcinoma will be excluded
• Scheduled to receive post-operative radiotherapy
For patients in the ctDNA guided interventional arm of the
study only (Part C)
Exclusion Criteria:
1. History of concurrent and previous malignancy within the
last 3 years, with the exception of non- melanomatous skin
cancer and carcinoma in situ
2. Any major post-operative complications or other clinical conditions that in the opinion of the investigator would
contra-indicate adjuvant chemotherapy
3. Any subject not due to receive adjuvant chemotherapy will
not be eligible for Part C of the study
4. Hypersensitivity or contraindication to the drug(s) associated
with the planned choice of systemic chemotherapy (CAPOX,
FOLFOX or single agent 5-FU or capecitabine) as stated in
the SPC for each of the drugs