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

Primary Purpose

Previously Untreated Metastatic Colorectal Cancer

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
UFOX + Cetuximab
FOLFOX4 + Cetuximab
Sponsored by
Merck KGaA, Darmstadt, Germany
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Previously Untreated Metastatic Colorectal Cancer focused on measuring Cancer, Colorectal, Metastatic, Untreated

Eligibility Criteria

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

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

Sites / Locations

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Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

1

2

Arm Description

UFOX + Cetuximab

FOLFOX4 + Cetuximab

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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.
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.
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.
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.
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.
Treatment Impact on Social Daily Living and Health Care Resource Utilization
Non-protocol medical care visits and consultations
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

Full Information

First Posted
February 22, 2007
Last Updated
June 18, 2014
Sponsor
Merck KGaA, Darmstadt, Germany
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1. Study Identification

Unique Protocol Identification Number
NCT00439517
Brief Title
Study to Evaluate the Efficacy and Safety of FOLFOX-4 Plus Cetuximab Versus UFOX Plus Cetuximab.
Acronym
FUTURE
Official Title
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.
Study Type
Interventional

2. Study Status

Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
February 2007 (undefined)
Primary Completion Date
June 2009 (Actual)
Study Completion Date
May 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck KGaA, Darmstadt, Germany

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Previously Untreated Metastatic Colorectal Cancer
Keywords
Cancer, Colorectal, Metastatic, Untreated

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
302 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
UFOX + Cetuximab
Arm Title
2
Arm Type
Active Comparator
Arm Description
FOLFOX4 + Cetuximab
Intervention Type
Drug
Intervention Name(s)
UFOX + Cetuximab
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
FOLFOX4 + Cetuximab
Intervention Description
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
Primary Outcome Measure Information:
Title
Progression-free Survival (PFS)
Description
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 Frame
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 Measure Information:
Title
Best Overall Response (BOR)
Description
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
Time Frame
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
Title
Overall Survival (OS)
Description
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 Frame
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
Title
Overall Survival (OS)
Description
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 Frame
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
Title
Quality of Life (QOL) Functional Assessment of Cancer Therapy-Colorectal (FACT-C)
Description
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.
Time Frame
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
Title
QOL EuroQuol-5D (EQ-5D) Health Outcome Questionnaire
Description
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.
Time Frame
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
Title
QOL Therapy Preference Questionnaire (TPQ)
Description
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.
Time Frame
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
Title
Treatment Impact on Social Daily Living and Health Care Resource Utilization
Description
Non-protocol medical care visits and consultations
Time Frame
From randomisation until final visit, reported between day of first patient randomised, Feb 2007, until cut-off date, 30 Jun 2009
Title
Safety - Number of Patients Experiencing Any Adverse Event
Description
Please refer to Adverse Events section for details of individual serious adverse events and other adverse events
Time Frame
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jean-Yves Douillard, MD PhD
Organizational Affiliation
Centre R Gauducheau
Official's Role
Principal Investigator
Facility Information:
Facility Name
Research Site
City
Buenos Aires
Country
Argentina
Facility Name
Research Site
City
Ciudad Autónoma Buenos Aires
Country
Argentina
Facility Name
Research Site
City
Perth
Country
Australia
Facility Name
Research Site
City
Wollongong
Country
Australia
Facility Name
Research Site
City
Graz
Country
Austria
Facility Name
Research Site
City
Wien
Country
Austria
Facility Name
Research Site
City
Leuven
Country
Belgium
Facility Name
Research Site
City
Liège
Country
Belgium
Facility Name
Research Site
City
Belo Horizonte
Country
Brazil
Facility Name
Research site
City
Cep Sao Paulo-SP
Country
Brazil
Facility Name
Research Site
City
Fortaleza
Country
Brazil
Facility Name
Research Site
City
Besancon Cedex
Country
France
Facility Name
Research Site
City
Caen-Cedex 5
Country
France
Facility Name
Research Site
City
La Roche sur Yon
Country
France
Facility Name
Research Site
City
Lille
Country
France
Facility Name
Research Site
City
Marseille
Country
France
Facility Name
Research Site
City
Nice
Country
France
Facility Name
Research Site
City
Saint-Herblain
Country
France
Facility Name
Research Site
City
Strasbourg
Country
France
Facility Name
Research Site
City
Berlin
Country
Germany
Facility Name
Research Site
City
Dortmund
Country
Germany
Facility Name
Research Site
City
Dresden
Country
Germany
Facility Name
Research Site
City
Frankfurt / Main
Country
Germany
Facility Name
Research Site
City
Hamburg
Country
Germany
Facility Name
Research Site
City
Hannover
Country
Germany
Facility Name
Research Site
City
Heidelberg
Country
Germany
Facility Name
Research Site
City
Kassel
Country
Germany
Facility Name
Research Site
City
Krefeld
Country
Germany
Facility Name
Research Site
City
Magdeburg
Country
Germany
Facility Name
Research Site
City
München
Country
Germany
Facility Name
Research Site
City
Oldenburg
Country
Germany
Facility Name
Research Site
City
Wiesbaden
Country
Germany
Facility Name
Research Site
City
Dragana
Country
Greece
Facility Name
Research Site
City
Thessaloniki
Country
Greece
Facility Name
Research Site
City
Voutes
Country
Greece
Facility Name
Research Site
City
Hong Kong
Country
Hong Kong
Facility Name
Research Site
City
Sha Tin
Country
Hong Kong
Facility Name
Research Site
City
Haifa
Country
Israel
Facility Name
Research Site
City
Jerusalem
Country
Israel
Facility Name
Research Site
City
Benevento
Country
Italy
Facility Name
Research Site
City
Brescia
Country
Italy
Facility Name
Research Site
City
Cremona
Country
Italy
Facility Name
Research Site
City
Forli
Country
Italy
Facility Name
Research Site
City
Padova
Country
Italy
Facility Name
Research Site
City
Pavia
Country
Italy
Facility Name
Research Site
City
Potenza
Country
Italy
Facility Name
Research Site
City
Reggio Emilia
Country
Italy
Facility Name
Research Site
City
Rimini
Country
Italy
Facility Name
Research Site
City
Roma
Country
Italy
Facility Name
Research Site
City
Sassari
Country
Italy
Facility Name
Research Site
City
Mexico-City
Country
Mexico
Facility Name
Research Site
City
Krakow
Country
Poland
Facility Name
Research Site
City
Lublin
Country
Poland
Facility Name
Research Site
City
Opole
Country
Poland
Facility Name
Research Site
City
Warsaw
Country
Poland
Facility Name
Research Site
City
Bangkok
Country
Thailand
Facility Name
Research Site
City
Pathumwan
Country
Thailand

12. IPD Sharing Statement

Citations:
PubMed Identifier
24370353
Citation
Douillard JY, Zemelka T, Fountzilas G, Barone C, Schlichting M, Heighway J, Eggleton SP, Srimuninnimit V. FOLFOX4 with cetuximab vs. UFOX with cetuximab as first-line therapy in metastatic colorectal cancer: The randomized phase II FUTURE study. Clin Colorectal Cancer. 2014 Mar;13(1):14-26.e1. doi: 10.1016/j.clcc.2013.11.009. Epub 2013 Nov 16.
Results Reference
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Study to Evaluate the Efficacy and Safety of FOLFOX-4 Plus Cetuximab Versus UFOX Plus Cetuximab.

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