Trial of Neoadjuvant Chemotherapy in Locally Advanced Colon Cancer

Study Overview
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Brief Summary
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In patients with locally advanced colon cancer (high risk stage II and stage III), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 30-40% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for locally advanced colon cancer and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery. ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy (response rate) and feasibility (safety, tolerance) of these two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4+Cetuximab) in a neoadjuvant strategy in patients with locally advanced colon cancer. Control arm includes patients for whom standard treatment comprises surgery followed by adjuvant FOLFOX-4 chemotherapy. This phase II study will assess the feasibility of a neoadjuvant strategy in these patients and determine which neoadjuvant regimen is the most effective in terms of response rate.

Detailed Description
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See Synopsis below

Official Title
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PRODIGE 22-ECKINOXE : Randomized Phase II Trial of Neoadjuvant FOLFOX 4 Versus FOLFOX 4 With Cetuximab Versus Immediate Surgery in Locally Advanced Colon Cancer

Conditions
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Colon Cancer, Locally Advanced Malignant Neoplasm

Intervention / Treatment
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* Other: Perioperative simplified FOLFOX-4 chemotherapy
* Other: Perioperative FOLFOX4+Cetuximab chemotherapy
* Other: Surgery followed by FOLFOX4 chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed colon adenocarcinoma (≥ 15 cm from the anal verge) Assessment of RAS status of the primary colon cancer on biopsies (WT or mutated) Colon cancer classified: poor prognosis T3 (T3 bad) - T4 and/ or N2 by abdominal CT scan. Non metastatic colon cancer (lung, liver, peritoneal) Non complicated primary tumor (obstruction, perforation, bleeding), patients with cancer treated by stomie de derivation may be included in the study. DPD deficency Absence of synchronous colorectal cancer Age ≥ 18 years and < 76 years ECOG performance status 0-1 No prior chemotherapy within the last 5 years No prior abdominal or pelvic irradiation within the last 5 years Life expectancy of 5 years or more No history of colorectal cancer within the last 5 years Patients with childbearing potential should use effective contraception during the study and the following 6 months White blood cell count of 3 x 109/L or more with neutrophils of1.5 x 109/L or more, platelet count of 100 x 109/L or more, hemoglobin of 9 g/dL (5,6 mmol/l) or more Total bilirubin of 1.5 x ULN (upper limit of normal) or less ASAT and ALAT of 2.5 x ULN or less Alkaline phosphatase of 1.5 x ULN or less Serum creatinine of 1.5 x ULN or less Signed written informed consent obtained prior to any study specific screening procedures Exclusion Criteria: contra-indication to iodinated contrast medium injection including allergy to iodinated contrast medium and renal insufficiency proscribing iodinated injection Age > 70 years Rectal cancer located within 15 cm from the anal verge by endoscopy or under the peritoneal reflection at surgery or having received radiation therapy prior to surgery Complicated primary colon cancer (obstruction, bleeding, perforation) Synchronous colorectal cancer Metastatic spread at baseline assessment (lung, liver, peritoneal) History or current evidence on physical examination of central nervous system disease or peripheral neuropathy ≥ grade 1 Common Toxicity Criteria for Adverse Events (CTCAE) v.3.0 Known hypersensitivity reaction to any of the components of study treatments Presence of inflammatory bowel disease HNPCC syndrome or polyposis Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to study treatment start. Incompletely healed wounds or anticipation of the need for major surgical procedure during the course of the study Clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia Pregnancy (absence to be confirmed by ß-hCG test) or breast-feeding period Previous malignancy in the last 5 years 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
Maximum Age: 76 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
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Perioperative simplified FOLFOX-4 chemotherapy - Simplified FOLFOX-4 (IV oxaliplatin given over 120 min at a dose of 85 mg/m2 on day 1 followed by IV leucovorin 400 mg/m2 over 2h, IV bolus 5-FU 400 mg/m2 and IV infusional 5-FU 2400 mg/m2 over 46h) for 4 cycles followed by colectomy (3 to 5 weeks after) followed by simplified FOLFOX-4 (8 cycles). | Other: Perioperative simplified FOLFOX-4 chemotherapy<br>* Preoperative chemotherapy<br>|
| Experimental: 2<br>Perioperative FOLFOX4+Cetuximab chemotherapy Simplified FOLFOX-4 (IV oxaliplatin given over 120 min at a dose of 85 mg/m2 on day 1 followed by IV leucovorin 400 mg/m2 over 2h, IV bolus 5-FU 400 mg/m2 and IV infusional 5-FU 2400 mg/m2 over 46h)+ Cetuximab (IV 500 mg/m2 every 2 weeks) for 4 cycles followed by colectomy (3 to 5 weeks after), followed by simplified FOLFOX-4 + Cetuximab (8 cycles). | Other: Perioperative FOLFOX4+Cetuximab chemotherapy<br>* Preoperative chemotherapy<br>|
| Other: 3<br>Surgery followed by FOLFOX4 chemotherapy No preoperative chemotherapy Colectomy (maximum 4 weeks after randomization) followed by simplified FOLFOX-4 (IV oxaliplatin given over 120 min at a dose of 85 mg/m2 on day 1 followed by IV leucovorin 400 mg/m2 over 2h, IV bolus 5-FU 400 mg/m2 and IV infusional 5-FU 2400 mg/m2 over 46h) for 12 cycles. | Other: Surgery followed by FOLFOX4 chemotherapy<br>* Preoperative chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological tumor response in the primary tumor according to the simplified Tumor Regression Grade (TRG) of Ryan | This primary outcome will be evaluated on the surgical specimens: Immediately after surgery (arm C) or after neoadjuvant chemotherapy (4 cycles) and surgery (arms A and B) | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability and efficacy of the neoadjuvant chemotherapy | Tolerability of the neoadjuvant therapies. SAFETY ISSUE Postoperative morbidity at 60 days. SAFETY ISSUE | 9 years | 
| •Disease free survival and regression free survival at 3 years |  | 3 years | 
| •Overall survival at 6 and 7 years |  | 6 and 7 years | 
| •Quality of life (EORTC QLQ-C30, QLQ-CR29) |  | 5 years | 
| •Quality and radicality of the surgical excision |  | 2 years | 
| •Accuracy of pre-treatment CT scan staging and evaluation of radiological response to chemotherapy |  | 2 years | 
| •Correlation between radiological and histological response |  | 2 years | 
| •Evaluation of another histopathological grade |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant chemotherapy, Locally advanced malignant neoplasm, colon cancer