Clinical trial NCT01675999: Trial of Neoadjuvant Chemotherapy in Locally Advanced Colon Cancer
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
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Colon Cancer
Locally Advanced Malignant Neoplasm
Keywords: Neoadjuvant chemotherapy
Locally advanced malignant neoplasm
colon cancer
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Federation Francophone de Cancerologie Digestive
name: UNICANCER
name: Association de Recherche Experimentale et Clinique en Chirurgie Digestive
name: Association Européenne de Recherche en Oncologie
name: Merck Serono S.A., Geneva
First posted: 2012-08-30
Enrollment: 186
Sex: ALL
Minimum age (years): 18
Maximum age (years): 76
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Primary outcomes:
measure: Histological tumor response in the primary tumor according to the simplified Tumor Regression Grade (TRG) of Ryan
timeFrame: 2 years
Secondary outcomes:
measure: Safety and tolerability and efficacy of the neoadjuvant chemotherapy
timeFrame: 9 years
measure: •Disease free survival and regression free survival at 3 years
timeFrame: 3 years
measure: •Overall survival at 6 and 7 years
timeFrame: 6 and 7 years
measure: •Quality of life (EORTC QLQ-C30, QLQ-CR29)
timeFrame: 5 years
measure: •Quality and radicality of the surgical excision
timeFrame: 2 years
measure: •Accuracy of pre-treatment CT scan staging and evaluation of radiological response to chemotherapy
timeFrame: 2 years
measure: •Correlation between radiological and histological response
timeFrame: 2 years
measure: •Evaluation of another histopathological grade
timeFrame: 2 years
Other outcomes:
Locations:
city: Paris
country: France
facility: Hopital Henri Mondor
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: mehdi karoui, PH
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.