Oxaliplatin and Cetuximab in First-line Treatment of Metastatic Colorectal Cancer (mCRC) (OPUS)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Merck KGaA

ClinicalTrials.gov Identifier:

NCT00125034

First received: July 28, 2005

Last updated: August 23, 2011

Last verified: August 2011

History of Changes

Results First Received: August 23, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Conditions:	Neoplasm Metastasis Colorectal Cancer
Interventions:	Biological: Cetuximab Drug: Oxaliplatin

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
First & last subject randomized: 27 Jul 2005 & 8 Mar 2006, respectively. Primary outcome and disease control rate cut-off dates 4 Aug 2006, others: 1 Mar 2007; except overall survival, KRAS overall survival and KRAS progression-free survival outcomes, metastatic surgery outcome and adverse events: 30 Nov 2008.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
629 subjects were prescreened, of whom 344 subjects were randomised. 338 subjects (Safety Population) received treatment. One subject was erroneously randomized, and was excluded from the ITT population (337 subjects).

Reporting Groups

Description

Cetuximab Plus FOLFOX-4

Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

FOLFOX-4 Alone

5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.

Participant Flow: Overall Study

	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
STARTED	170 ^[1]	168 ^[2]
COMPLETED	170	168
NOT COMPLETED	0	0

[1]	Randomized & treated. 1 subject was not randomized correctly and was excluded in the ITT population.
[2]	Randomized & treated

Baseline Characteristics

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Reporting Groups

	Description
Cetuximab Plus FOLFOX-4	Cetuximab plus 5-Fluorouracil(5-FU)/Folinic acid (FA) and oxaliplatin. Cetuximab will always be administered first, followed by oxaliplatin at least 1 hour later. Following completion of the oxaliplatin infusion or simultaneously with oxaliplatin FA will be administered (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day intravenously (IV) over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
FOLFOX-4 Alone	5-FU/FA and oxaliplatin. Oxaliplatin will always be administered first or simultaneously with FA (at a dose of 200 mg/m^2, infused over 120 minutes, on day 1 and day 2, every two weeks) and then 5-FU (as a bolus of 400 mg/m^2/day IV over 2-4 minutes followed by 600 mg/m^2/day infused over 22-hour, on day 1 and day 2, every two weeks). Until progression or unacceptable toxicity develops. Safety population: includes all treated subjects.
Total	Total of all reporting groups

Baseline Measures

	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone	Total
Number of Participants [units: participants]	169	168	337
Age [units: participants]
<=18 years	0	0	0
Between 18 and 65 years	96	109	205
>=65 years	73	59	132
Age [units: years] Median ( Full Range )	62.0 ( 24 to 82 )	60.0 ( 30 to 82 )	61.0 ( 24 to 82 )
Gender [units: participants]
Female	80	76	156
Male	89	92	181
Region of Enrollment ^[1] [units: participants]
Portugal	0	3	3
Spain	19	16	35
Ukraine	24	25	49
Austria	16	9	25
Russian Federation	25	24	49
Israel	0	1	1
Italy	8	6	14
France	3	12	15
Belgium	12	6	18
Poland	30	31	61
Romania	18	13	31
Germany	14	22	36

[1]	Figures refer to randomized and treated participants

Outcome Measures

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1. Primary:

Best Overall Response Rate - Independent Review Committee (IRC) [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006 ]

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2. Secondary:

Best Overall Response Rate (Chinese V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Wild-Type Population) [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007 ]

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3. Secondary:

Best Overall Response Rate (KRAS Mutant Population) [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 1 Mar 2007 ]

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4. Secondary:

Progression-free Survival Time [ Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 01 Mar 2007 ]

Show Outcome Measure 4

5. Secondary:

Progression-free Survival Time (KRAS Wild-Type Population) [ Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008 ]

Show Outcome Measure 5

6. Secondary:

Progression-free Survival Time (KRAS Mutant Population) [ Time Frame: Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008 ]

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Measure Type	Secondary
Measure Title	Progression-free Survival Time (KRAS Mutant Population)
Measure Description	Duration from randomization until radiological progression as assessed by an IRC (based on modified WHO criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
Time Frame	Time from randomisation to disease progression, death or last tumour assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
KRAS Mutant population

Reporting Groups

Description

Cetuximab Plus FOLFOX-4

FOLFOX-4 Alone

Measured Values

	Cetuximab Plus FOLFOX-4	FOLFOX-4 Alone
Number of Participants Analyzed [units: participants]	77	59
Progression-free Survival Time (KRAS Mutant Population) [units: months] Median ( 95% Confidence Interval )	5.5 ( 4.0 to 7.3 )	8.6 ( 6.5 to 9.4 )

Statistical Analysis 1 for Progression-free Survival Time (KRAS Mutant Population)

Groups ^[1]	All groups
Method ^[2]	Stratified Log Rank
P Value ^[3]	0.0153
Hazard Ratio (HR) ^[4]	1.720
95% Confidence Interval	( 1.104 to 2.679 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Kaplan-Meier method used to estimate median OS time. HR was calculated using Cox proportional hazards model stratified by randomization strata.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[4]	Other relevant estimation information:
	No text entered.

7. Secondary:

Overall Survival Time [ Time Frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 Nov 2008 ]

Show Outcome Measure 7

8. Secondary:

Overall Survival Time (KRAS Wild-Type Population) [ Time Frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008 ]

Show Outcome Measure 8

9. Secondary:

Overall Survival Time (KRAS Mutant Population) [ Time Frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008 ]

Show Outcome Measure 9

10. Secondary:

Participants With No Residual Tumor After Metastatic Surgery [ Time Frame: Time from first dose up to 30 days after the last dose of study treatment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 30 November 2008 ]

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11. Secondary:

Disease Control Rate (Cut Off Date 4 August 2006) [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 4 August 2006 ]

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12. Secondary:

Duration of Response [ Time Frame: Time from first assessment of Complete Response or Partial Response to disease progression,death or last tumor assessment, reported between day of first patient randomised, 27 Jul 2005, until cut-off date 01 Mar 2007 ]

Show Outcome Measure 12

13. Secondary:

Safety - Number of Patients Experiencing Any Adverse Event [ Time Frame: time from first dose up to 30 after last dose of study treatment, reported between day of first patient dose of study treatment, 27 Jul 2005, until cut-off date 30 Nov 2008 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
A non-specific outcome measure 'Safety' was deleted from this entry in error. A replacement outcome has been created. The 'Safety' outcome refers to adverse events and these are shown in the 'Adverse Events' section.

Results Point of Contact:

Name/Title: Inmaculada Ollero/Clinical Trial Manager
Organization: Merck Serono
phone: +34935655433
e-mail: iollero@merck.es

Publications of Results:

Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29.

Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12.

Responsible Party:	Merck KGaA
ClinicalTrials.gov Identifier:	NCT00125034 History of Changes
Other Study ID Numbers:	EMR 62202-047
Study First Received:	July 28, 2005
Results First Received:	August 23, 2011
Last Updated:	August 23, 2011
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices

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