Preoperative Chemosensitivity Testing to Predict Treatment Benefit in Adjuvant Stage III Colon Cancer

Study Overview
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Brief Summary
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The primary working hypothesis is that preoperative chemo-sensitivity testing using fluorodeoxyglucose positron emission tomography (FDG-PET) performed before and after one course of FOLFOX (folinic acid, fluorouracil, oxaliplatin) can identify the patients that will least likely have a significant benefit from adjuvant FOLFOX for stage III colon cancer. The benefit will be analyzed by correlating the preoperative FDG-PET uptake changes to the disease free and overall survival.

Detailed Description
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Patients with histological confirmed colon adenocarcinoma compatible with clinical stage II or III are eligible for study screening. Receipt of a signed informed consent and study inclusion should be done within 15 days after histological diagnosis. A usual workup for preoperative staging of colon cancer must be done not more than 1 month before study inclusion and include CEA assessment, positive histological sample for colon adenocarcinoma and chest and abdominal CT scan. After receipt of the written consent, the patient undergoes baseline PET/CT scan and donates blood samples for CTC and SNP analyses. Delay between baseline examinations and histological diagnosis must not exceed 21 days. The baseline examinations should be done within 1 week before beginning of the first course of FOLFOX chemotherapy. Thirteen to 15 days after chemotherapy, the PET/CT and blood sampling for CTC analysis are repeated. Standard surgery follows after 15 days but no more than 30 days from Day 1 of preoperative chemotherapy. Two frozen tissue cores are obtained during surgery and sent immediately in dry ice shipping to the central Tumour Bank (Jules Bordet Institute) or stored locally at -80°C to be sent in batches to the central tumour bank. Thereafter, the patient receives standard care, according to tumour pathological stage. In fully eligible patients, FOLFOX chemotherapy should be started not more than 45 days after surgery. In stage III patients otherwise ineligible, recommendation is to start FOLFOX chemotherapy within 45 days after surgery although such patients will not be included in the primary analysis. Treatment in case of stage II or stage IV colon cancer is left at investigator's discretion. Eleven courses of adjuvant FOLFOX are foreseen, in order to match the usual recommendation coming from the Mosaic Trial. Follow-up procedures after completion of adjuvant treatment will follow standard European clinical recommendations for stage II and III patients. Clinical follow-up data will be obtained for all patients, including those with stage II disease, with a minimum follow-up time of three years.

Official Title
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Preoperative Chemosensitivity Testing as Predictor of Treatment Benefit in Adjuvant Stage III Colon Cancer: PePiTA Trial

Conditions
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Colon Cancer

Intervention / Treatment
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* Drug: FOLFOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Clinical/radiological evaluation compatible with stage III colon adenocarcinoma No prior chemotherapy No prior abdominal or pelvic irradiation WHO performance status 0 or 1 Effective contraception during the study and the following six months Signed informed consent obtained prior to any study-specific screening procedures Tumour considered as curatively resectable (R0) based on standard preoperative evaluations White blood cell count ≥ 3×109/L with neutrophils ≥ 1.5×109/L, platelet count ≥ 100×109/L, haemoglobin ≥ 9 g/dL (5.6 mmol/L) Direct bilirubin ≤ 1.5×ULN; ASAT and ALAT ≤ 2.5×ULN; Alkaline phosphatase ≤ 2.5×ULN; Serum creatinine ≤ 1.5×ULN Delay between assessment of screening criteria and first PET/CT < 21 days Blood glucose < 150 mg/dl at the time of FDG administration. Insulin or oral anti-diabetic medication is not allowed on the days of PET/CT imaging. Compliance to the first chemotherapy course to be administered before surgery Delay between the first PET/CT imaging and the start of neoadjuvant FOLOFX < 7 days Second PET/CT imaging performed on D14 (range: D13-D15, with D1 as the first day of chemo administration) Delay between the second PET/CT and surgery < 7 days Stage III (ypTNM) as assessed after surgery CEA < 1.5 x ULN 1 month after surgery - Exclusion Criteria: Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to screening. Incompletely healed wounds or anticipation of the need for major surgical procedure during the course of the study Any suspicion of metastatic disease Rectal cancer located within 15 cm from the anal verge by endoscopy or under the peritoneal reflection at surgery Inflammatory bowel disease Pregnancy (absence to be confirmed by ß-hCG blood test) or breast-feeding History or current central nervous system disease or peripheral neuropathy Hypersensitivity to any of the components of study treatments Previous malignancy in the last five years except basal-cell carcinoma of the skin or in situ cervical carcinoma Clinically relevant coronary artery disease or history of myocardial infarction in the last 6 weeks or high risk of uncontrolled arrhythmia Medical, geographical, sociological, psychological or legal conditions that would not permit the patient to complete the study or sign informed consent Any significant disease which, in the investigator's opinion, would exclude the patient from the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: adjuvant FOLFOX (1 pre-operative cycle)<br>One cycle of preoperative standard FOLFOX chemotherapy followed by eleven cycles post-operatively. PET/CT before and after the pre-operative chemotherapy cycle. | Drug: FOLFOX<br>* One cycle of standard FOLFOX pre-operatively followed by 11 cycles of standard adjuvant FOLFOX chemotherapy.<br>* Other names: FOLFOX-4 or equivalent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Examine the predictive value of PET-assessed tumour FDG uptake response after one course of preoperative chemotherapy on the outcome of adjuvant therapy, measured by 3-year DFS. |  | Within 3 years after completion of adjuvant chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Examine the predictive value of PET-assessed tumour FDG uptake changes after one course of preoperative chemotherapy on OS |  | Within 3 years after completion of adjuvant chemotherapy | 
| Evaluate the best cut-off value for relative delta SUV in assessment of preoperative chemotherapy response by FDG-PET/CT imaging. |  | Within 3 years after completion of adjuvant chemotherapy | 
| Analyze the cost-effectiveness of preoperative chemo-sensitivity testing |  | Within 3 years after completion of adjuvant chemotherapy | 
| Assess the predictive value of circulating tumour cells on disease-free survival |  | Within 3 years after completion of adjuvant chemotherapy | 
| Assess the predictive value of SNPs on toxicity- and drug target-related genes on DFS |  | Within 3 years after completion of adjuvant chemotherapy | 
| Create a frozen tumour bank for future studies |  | Within 2 years from the beginning of study |