Study to Evaluate the Efficacy and Safety of FOLFOX-4 Plus Cetuximab Versus UFOX Plus Cetuximab.

Study Overview
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Brief Summary
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This is an exploratory study to compare activity and safety in 400 patients with previously untreated metastatic carcinoma of the colon treated with UFOX (a combination regimen of UFT® (Tegafur plus Uracil), Oxaliplatin, Folinic Acid) plus Cetuximab or FOLFOX-4 (a combination regimen of 5 Fluorouracil (5-FU), Oxaliplatin and Folinic Acid) plus Cetuximab)

Official Title
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A Randomized, Open-label Phase II Study Evaluating the Efficacy and Safety of FOLFOX-4 Plus Cetuximab Versus UFOX Plus Cetuximab as First-line Therapy in Subjects With Metastatic Colorectal Cancer.

Conditions
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Previously Untreated Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: UFOX + Cetuximab
* Drug: FOLFOX4 + Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Signed written informed consent Inpatient or outpatient ≥ 18 years of age Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum First occurrence of metastatic disease (not curatively resectable) Presence of at least one lesion measurable uni dimensionally by computerised tomography (CT) scan or magnetic resonance imaging (MRI). (Target lesion(s) must not lie within an irradiated area) Life expectancy of ≥ 3 months Karnofsky performance status of ≥ 60, at study entry White blood cell count (WBC) ≥ 3 x 10^9/L, with neutrophils ≥ 1.5 x 10^9/L, platelets ≥ 100 x 10^9/L, and hemoglobin ≥ 9 g/dL Aspartate transaminase and alanine transaminase ≤ 2.5 x Upper Limit of Normal (ULN) (≤ 5 x ULN if liver metastasis are present) Normal serum creatinine (in case of elevated creatinine, labelled ethylenediaminetetraacetic acid clearance ≥ 65 mL/min is acceptable) Effective contraception for both male and female subjects if the risk of conception exists Tumor biopsy or archived sample available Exclusion criteria: Brain metastasis and/or leptomeningeal disease (known or suspected) Previous chemotherapy for colorectal cancer except adjuvant treatment with progression of disease documented > 6 months after end of adjuvant treatment. Previous oxaliplatin-based chemotherapy Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to randomization Concurrent or previous chronic systemic immune therapy, targeted therapy, anti-vascular epithelial growth factor (VEGF) therapy, epidermal growth factor receptor (EGFR) pathway targeting therapy not indicated in the study protocol Concurrent hormonal therapy not indicated in the study protocol except for physiologic replacement or contraception Clinically relevant coronary artery disease, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia Peripheral neuropathy >grade 1 Known hypersensitivity reaction to any of the components of the treatment. Any concurrent malignancy other than basal cell cancer of the skin, or pre-invasive cancer of the cervix. (Subjects with a previous malignancy but without evidence of disease for ≥ 5 years will be allowed to enter the study) Pregnancy (absence to be confirmed by ß-human chorionic gonadotrophin test) or lactation period Known drug abuse/alcohol abuse Legal incapacity or limited legal capacity Medical or psychological condition which in the opinion of the investigator would not permit the subject to complete the study or sign meaningful informed consent Participation in another clinical study within the 30 days before randomization Significant disease which, in the investigator's opinion, would exclude the subject 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>UFOX + Cetuximab | Drug: UFOX + Cetuximab<br>* Cetuximab infusion (400 mg/m^2 on day 1 of cycle 1 and 250 mg/m^2 at each subsequent day 1, as well as on days 8, 15 and 22) Oxaliplatin infusion (85mg/m^2) on days 1 and 15 (every 2 weeks) Oral UFT® (250mg/m^2 tegafur + 560 mg/m^2 uracil in 3 daily doses rounded to the nearest number of whole capsules) on days 1-21 Oral Folinic Acid (90 mg in 3 daily divided doses) on days 1-21<br>|
| Active Comparator: 2<br>FOLFOX4 + Cetuximab | Drug: FOLFOX4 + Cetuximab<br>* Cetuximab infusion (400 mg/m^2 on day 1 of cycle 1 and 250 mg/m^2 at each subsequent day 1, as well as on days 8, 15 and 22) Oxaliplatin infusion (85 mg/m^2) on days 1 and 15 (every 2 weeks) 5-FU bolus + infusions (400 mg/m^2) on days 1, 2, 15 and 16 Folinic Acid infusions (200 mg/m^2) on days 1, 2, 15 and 16<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Duration from randomization until progression or death due to any cause. Only deaths within 12 weeks of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment. Response and progression were assessed by the Investigators using response evaluation criteria in solid tumors (RECIST) 1.0 criteria | Time from randomization to disease progression, death, or last tumor assessment reported between day of first patient randomised, Feb 2007, until cut off date, 30 Jun 2009 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) | BOR defined as percentage of subjects, whose BOR was either (confirmed) complete response (CR) or partial response (PR), relative to the number of subjects belonging to the study population of interest. CR defined as Disappearance of all target lesions plus disappearance of all non-target lesions & without appearance of any new lesions; confirmed minimum 4 weeks later. PR defined as At least 30% reduction in the SOLD of target lesions plus no significant change in non-target lesions to qualify for either CR or PD without appearance of new lesions; confirmed minimum 4 weeks later | Evaluations were performed every 8 weeks until disease progression, reported between day of first patient randomised, Feb 2007, until cut off date, 30 Jun 2009 | 
| Overall Survival (OS) | Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. | Time from randomization to death or last known to be alive, reported between day of first patient randomised, Feb 2007, until cut off date, 30 Jun 2009 | 
| Overall Survival (OS) | Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. | Time from randomization to death or last known to be alive, reported between day of first patient randomised, Feb 2007, until cut off date, 31 Aug 2011 | 
| Quality of Life (QOL) Functional Assessment of Cancer Therapy-Colorectal (FACT-C) | All of the single-item measures of the FACT-C are assessed on ordinal response categories ranging from 0=Not at all to 4=Very much. For scoring purposes the response scores are reversed on negatively phrased questions. The principle for scoring the sub-scales is the same in all cases: subscale score = (Sum of items × Number of items in the subscale) / numbers of items answered. The lowest possible total score is 0 and the highest is 136. A high scale score represents a high QOL. | At baseline, at every first day of every third cycle during active - treatment, and at final tumor assessment , reported between day of first patient randomised, Feb 2007, until cut-off date, 30 Jun 2009. Cycles were 4 weeks long unless dosing delays | 
| QOL EuroQuol-5D (EQ-5D) Health Outcome Questionnaire | The EQ-5D questionnaire is a measure of health status that provides a simple descriptive profile and a single index value. The optional part of the questionnaire was not applied. The EQ-5D defines health in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5 items are combined to generate health profiles. These profiles were converted to a continuous single index score using a one to one matching. The lowest possible score is -0.59 and the highest is 1.00, higher scores on the EQ-5D represent a better QOL. | at baseline, at every first day of every third cycle during active - treatment, and at final tumor assessment , reported between day of first patient randomised, Feb 2007, until cut-off date, 30 Jun 2009. All cycles were 4 weeks long unless dosing delays | 
| QOL Therapy Preference Questionnaire (TPQ) | TPQ was used to investigate which features of chemotherapy treatment are the most relevant in ensuring patient satisfaction. The most essential characteristics of a cancer medication are shown at baseline and at cycle 3, along with percentage of subjects selecting that characteristic. | at baseline, at every first day of every third cycle during active - treatment, and at final tumor assessment , reported between day of first patient randomised, Feb 2007, until cut-off date, 30 Jun 2009. All cycles were 4 weeks long unless dosing delays | 
| Treatment Impact on Social Daily Living and Health Care Resource Utilization | Non-protocol medical care visits and consultations | From randomisation until final visit, reported between day of first patient randomised, Feb 2007, until cut-off date, 30 Jun 2009 | 
| Safety - Number of Patients Experiencing Any Adverse Event | Please refer to Adverse Events section for details of individual serious adverse events and other adverse events | Time from first dose up to 30 days after last dose of study treatment, reported between day of first patient randomised, Feb 2007, until cut off date, 30 Jun 2009 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Colorectal, Metastatic, Untreated