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Trial of Neoadjuvant Chemotherapy in Locally Advanced Colon Cancer (ECKINOXE)

Primary Purpose

Colon Cancer, Locally Advanced Malignant Neoplasm

Status
Unknown status
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Perioperative simplified FOLFOX-4 chemotherapy
Perioperative FOLFOX4+Cetuximab chemotherapy
Surgery followed by FOLFOX4 chemotherapy
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colon Cancer focused on measuring Neoadjuvant chemotherapy, Locally advanced malignant neoplasm, colon cancer

Eligibility Criteria

18 Years - 76 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Hopital Henri MondorRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Other

Arm Label

1

2

3

Arm Description

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).

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).

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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

Full Information

First Posted
February 2, 2012
Last Updated
January 14, 2016
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Federation Francophone de Cancerologie Digestive, UNICANCER, Association de Recherche Experimentale et Clinique en Chirurgie Digestive, Association Européenne de Recherche en Oncologie, Merck Serono S.A., Geneva
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1. Study Identification

Unique Protocol Identification Number
NCT01675999
Brief Title
Trial of Neoadjuvant Chemotherapy in Locally Advanced Colon Cancer
Acronym
ECKINOXE
Official Title
PRODIGE 22-ECKINOXE : Randomized Phase II Trial of Neoadjuvant FOLFOX 4 Versus FOLFOX 4 With Cetuximab Versus Immediate Surgery in Locally Advanced Colon Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
January 2012
Overall Recruitment Status
Unknown status
Study Start Date
May 2012 (undefined)
Primary Completion Date
May 2012 (Actual)
Study Completion Date
February 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Federation Francophone de Cancerologie Digestive, UNICANCER, Association de Recherche Experimentale et Clinique en Chirurgie Digestive, Association Européenne de Recherche en Oncologie, Merck Serono S.A., Geneva

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
See Synopsis below

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colon Cancer, Locally Advanced Malignant Neoplasm
Keywords
Neoadjuvant chemotherapy, Locally advanced malignant neoplasm, colon cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
186 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
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).
Arm Title
2
Arm Type
Experimental
Arm Description
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).
Arm Title
3
Arm Type
Other
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
Perioperative simplified FOLFOX-4 chemotherapy
Intervention Description
Preoperative chemotherapy
Intervention Type
Other
Intervention Name(s)
Perioperative FOLFOX4+Cetuximab chemotherapy
Intervention Description
Preoperative chemotherapy
Intervention Type
Other
Intervention Name(s)
Surgery followed by FOLFOX4 chemotherapy
Intervention Description
Preoperative chemotherapy
Primary Outcome Measure Information:
Title
Histological tumor response in the primary tumor according to the simplified Tumor Regression Grade (TRG) of Ryan
Description
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)
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Safety and tolerability and efficacy of the neoadjuvant chemotherapy
Description
Tolerability of the neoadjuvant therapies. SAFETY ISSUE Postoperative morbidity at 60 days. SAFETY ISSUE
Time Frame
9 years
Title
•Disease free survival and regression free survival at 3 years
Time Frame
3 years
Title
•Overall survival at 6 and 7 years
Time Frame
6 and 7 years
Title
•Quality of life (EORTC QLQ-C30, QLQ-CR29)
Time Frame
5 years
Title
•Quality and radicality of the surgical excision
Time Frame
2 years
Title
•Accuracy of pre-treatment CT scan staging and evaluation of radiological response to chemotherapy
Time Frame
2 years
Title
•Correlation between radiological and histological response
Time Frame
2 years
Title
•Evaluation of another histopathological grade
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
76 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mehdi karoui, PH
Phone
+33 (0) 1 42 17 56 11
Email
mehdi.karoui@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
mehdi karoui, PH
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hopital Henri Mondor
City
Paris
ZIP/Postal Code
94010
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mehdi KAROUI, PH
Phone
+33 (0) 1 42 17 56 11
Email
mehdi.karoui@gmail.com

12. IPD Sharing Statement

Citations:
PubMed Identifier
33580623
Citation
Karoui M, Gallois C, Piessen G, Legoux JL, Barbier E, De Chaisemartin C, Lecaille C, Bouche O, Ammarguellat H, Brunetti F, Prudhomme M, Regimbeau JM, Glehen O, Lievre A, Portier G, Hartwig J, Goujon G, Romain B, Lepage C, Taieb J; for PRODIGE 22 investigators/Collaborators. Does neoadjuvant FOLFOX chemotherapy improve the prognosis of high-risk Stage II and III colon cancers? Three years' follow-up results of the PRODIGE 22 phase II randomized multicentre trial. Colorectal Dis. 2021 Jun;23(6):1357-1369. doi: 10.1111/codi.15585. Epub 2021 Mar 10.
Results Reference
derived
PubMed Identifier
31356278
Citation
Karoui M, Rullier A, Piessen G, Legoux JL, Barbier E, De Chaisemartin C, Lecaille C, Bouche O, Ammarguellat H, Brunetti F, Prudhomme M, Regimbeau JM, Glehen O, Lievre A, Portier G, Hartwig J, Goujon G, Romain B, Lepage C, Taieb J; for PRODIGE 22 investigators/collaborators. Perioperative FOLFOX 4 Versus FOLFOX 4 Plus Cetuximab Versus Immediate Surgery for High-Risk Stage II and III Colon Cancers: A Phase II Multicenter Randomized Controlled Trial (PRODIGE 22). Ann Surg. 2020 Apr;271(4):637-645. doi: 10.1097/SLA.0000000000003454.
Results Reference
derived
PubMed Identifier
26156156
Citation
Karoui M, Rullier A, Luciani A, Bonnetain F, Auriault ML, Sarran A, Monges G, Trillaud H, Le Malicot K, Leroy K, Sobhani I, Bardier A, Moreau M, Brindel I, Seitz JF, Taieb J. Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial--the PRODIGE 22--ECKINOXE trial. BMC Cancer. 2015 Jul 10;15:511. doi: 10.1186/s12885-015-1507-3.
Results Reference
derived

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Trial of Neoadjuvant Chemotherapy in Locally Advanced Colon Cancer

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