Comparison of Combination Chemotherapy Regimens With or Without Cetuximab in Treating Patients Who Have Undergone Surgery For Stage III Colon Cancer

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions:	Adenocarcinoma of the Colon; Stage III Colon Cancer
Interventions:	Drug: irinotecan hydrochloride; Drug: oxaliplatin; Drug: leucovorin calcium; Drug: fluorouracil; Biological: cetuximab; Drug: Locally Directed Therapy

  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
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Arm A (Combination Chemotherapy)	Patients received oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease. oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV
Arm B (Combination Chemotherapy)	Patients received irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease. irinotecan hydrochloride: Given IV leucovorin calcium: Given IV fluorouracil: Given IV
Arm C (Combination Chemotherapy)	Patients received the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease. irinotecan hydrochloride: Given IV oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV
Arm D (Combination Chemotherapy, Monoclonal Antibody)	Patients received cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease. oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV cetuximab: Given IV
Arm E (Combination Chemotherapy, Monoclonal Antibody)	Patients received cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease. irinotecan hydrochloride: Given IV leucovorin calcium: Given IV fluorouracil: Given I cetuximab: Given IV
Arm F (Combination Chemotherapy, Monoclonal Antibody)	Patients received cetuximab as in arm D and chemotherapy as in arm C. irinotecan hydrochloride: Given IV oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV cetuximab: Given IV
Arm G (Locally Directed Therapy)	Patients determined to have mutated Kirsten rat sarcoma (KRAS) (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists. Locally Directed Therapy: Patients determined to have mutated KRAS (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists.

Participant Flow:   Overall Study

	Arm A (Combination Chemotherapy)	Arm B (Combination Chemotherapy)	Arm C (Combination Chemotherapy)	Arm D (Combination Chemotherapy, Monoclonal Antibody)	Arm E (Combination Chemotherapy, Monoclonal Antibody)	Arm F (Combination Chemotherapy, Monoclonal Antibody)	Arm G (Locally Directed Therapy)
STARTED	1402	111	111	1350	45	46	332
COMPLETED	1081	84	84	906	30	26	332
NOT COMPLETED	321	27	27	444	15	20	0
Withdrawal by Subject	111	10	12	163	7	8	0
Adverse Event	130	8	8	184	7	8	0
Recurrence	21	0	1	15	0	2	0
Alternate Treatment	6	1	0	3	0	0	0
Other Medical Problems	6	1	0	7	0	0	0
Death	4	0	1	15	0	0	0
Cytogenetic resistance	0	0	0	2	0	0	0
Not Specified	43	7	5	55	1	2	0

  Baseline Characteristics

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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.
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Reporting Groups

	Description
Arm A (Combination Chemotherapy)	Patients received oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease. oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV
Arm B (Combination Chemotherapy)	Patients received irinotecan IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease. irinotecan hydrochloride: Given IV leucovorin calcium: Given IV fluorouracil: Given IV
Arm C (Combination Chemotherapy)	Patients received the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease. irinotecan hydrochloride: Given IV oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV
Arm D (Combination Chemotherapy, Monoclonal Antibody)	Patients received cetuximab IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease. oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV cetuximab: Given IV
Arm E (Combination Chemotherapy, Monoclonal Antibody)	Patients received cetuximab as in arm D and irinotecan, leucovorin calcium, and fluorouracil as in arm B. Treatment repeated every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease. irinotecan hydrochloride: Given IV leucovorin calcium: Given IV fluorouracil: Given IV cetuximab: Given IV
Arm F (Combination Chemotherapy, Monoclonal Antibody)	Patients received cetuximab as in arm D and chemotherapy as in arm C. irinotecan hydrochloride: Given IV oxaliplatin: Given IV leucovorin calcium: Given IV fluorouracil: Given IV cetuximab: Given IV
Arm G (Locally Directed Therapy)	Patients determined to have mutated KRAS (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists. Locally Directed Therapy: Patients determined to have mutated KRAS (or KRAS not evaluable) were assigned to an event monitoring arm in which adjuvant therapy was determined and assigned by the treating oncologist. The determination of the type of therapy, duration of treatment, and dose modification was the responsibility of the treating oncologists.
Total	Total of all reporting groups

Baseline Measures

	Arm A (Combination Chemotherapy)	Arm B (Combination Chemotherapy)	Arm C (Combination Chemotherapy)	Arm D (Combination Chemotherapy, Monoclonal Antibody)	Arm E (Combination Chemotherapy, Monoclonal Antibody)	Arm F (Combination Chemotherapy, Monoclonal Antibody)	Arm G (Locally Directed Therapy)	Total
Overall Participants Analyzed; [Units: Participants]	1402	111	111	1350	45	46	332	3397
Age; [Units: Years]; Median (Full Range)	58; (19 to 85)	57; (25 to 82)	60; (24 to 82)	58; (22 to 86)	59; (30 to 82)	60.5; (30 to 81)	56; (22 to 84)	58; (19 to 86)
Gender; [Units: Participants]
Female	662	53	50	647	20	21	160	1613
Male	740	58	61	703	25	25	172	1784
Ethnicity (NIH/OMB); [Units: Participants]
Hispanic or Latino	64	5	3	62	4	2	18	158
Not Hispanic or Latino	1107	103	103	1060	38	41	225	2677
Unknown or Not Reported	231	3	5	228	3	3	89	562
Race (NIH/OMB); [Units: Participants]
American Indian or Alaska Native	6	1	1	7	0	0	1	16
Asian	66	4	2	62	3	0	12	149
Native Hawaiian or Other Pacific Islander	8	0	1	7	0	0	0	16
Black or African American	94	6	7	96	5	2	29	239
White	1202	98	100	1154	37	43	275	2909
More than one race	3	2	0	3	0	0	1	9
Unknown or Not Reported	23	0	0	21	0	1	14	59
Region of Enrollment; [Units: Participants]
United States	1258	109	109	1224	44	46	303	3093
Canada	138	2	2	124	1	0	28	295
Jamaica	1	0	0	0	0	0	0	1
Puerto Rico	5	0	0	2	0	0	1	8
Positive Nodes [1]; [Units: Participants]
1-3	816	71	70	790	29	28	203	2007
4+	586	40	41	560	16	18	129	1390
[1] Number of positive nodes
Tumor Stage [1]; [Units: Participants]
T1 or T2	198	18	14	213	5	5	56	509
T3	1046	78	93	983	35	39	214	2488
T4	158	15	4	153	4	2	62	398
Not Availabe	0	0	0	1	1	0	0	2
[1] T1: Tumor invades submucosa T2: Tumor invades muscularis propria T3: Tumor invades through the muscularis propria into the subserosa or into non-peritonealized pericolic or perirectal tissues T4: (T4a+) Tumor perforates the visceral peritoneum without adherence to or invasion of other organs or structures or (T4b) Tumor is adherent to or directly invades other organs or structures
Histologic Grade [1]; [Units: Participants]
High	357	25	28	345	10	12	60	837
Low	1045	86	83	1005	35	34	272	2560
[1] High=poorly differentiated or undifferentiated > Low=well or moderately differentiated
KRAS Status; [Units: Participants]
Unknown	56	6	6	51	3	4	6	132
Mutant	391	33	43	345	15	13	326	1166
Wildtype	955	72	62	954	27	29	0	2099

  Outcome Measures

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1. Primary:

Disease-free Survival (Arms A and D: Wild-type KRAS Patients) [ Time Frame: At 3 years ]

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2. Secondary:

Disease-free Survival (Arms A and D: Mutant KRAS Patients) [ Time Frame: At 3 years ]

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3. Secondary:

Disease-free Survival [ Time Frame: Up to 5 years ]

Results not yet reported.   Anticipated Reporting Date:   No text entered.  

4. Secondary:

Overall Survival [ Time Frame: Up to 8 years ]

Results not yet reported.   Anticipated Reporting Date:   01/2018  

5. Secondary:

Toxicity [ Time Frame: Assessed up to 8 years ]

Results not yet reported.   Anticipated Reporting Date:   No text entered.  

  Serious Adverse Events

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  Other Adverse Events

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  Limitations and Caveats

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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
Accrual to arms A and D terminated early based on the results of the planned 2nd interim analysis. Sample sizes limit statistical conclusions for data from the irinotecan treated patients as those treatment arms were discontinued early in the study.

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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.

Results Point of Contact:  

Name/Title: Dr. Steven Alberts
Organization: North Central Cancer Treatment Group
phone: 507-284-8432
e-mail: alberts.steven@mayo.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zaanan A, Shi Q, Taieb J, Alberts SR, Meyers JP, Smyrk TC, Julie C, Zawadi A, Tabernero J, Mini E, Goldberg RM, Folprecht G, Van Laethem JL, Le Malicot K, Sargent DJ, Laurent-Puig P, Sinicrope FA. Role of Deficient DNA Mismatch Repair Status in Patients With Stage III Colon Cancer Treated With FOLFOX Adjuvant Chemotherapy: A Pooled Analysis From 2 Randomized Clinical Trials. JAMA Oncol. 2018 Mar 1;4(3):379-383. doi: 10.1001/jamaoncol.2017.2899.

Sinicrope FA, Shi Q, Allegra CJ, Smyrk TC, Thibodeau SN, Goldberg RM, Meyers JP, Pogue-Geile KL, Yothers G, Sargent DJ, Alberts SR. Association of DNA Mismatch Repair and Mutations in BRAF and KRAS With Survival After Recurrence in Stage III Colon Cancers : A Secondary Analysis of 2 Randomized Clinical Trials. JAMA Oncol. 2017 Apr 1;3(4):472-480. doi: 10.1001/jamaoncol.2016.5469.

Sticca RP, Alberts SR, Mahoney MR, Sargent DJ, Finstuen LM, Nelson GD, Husted TM, Franko J, Goldman CD, Pockaj BA. Current use and surgical efficacy of laparoscopic colectomy in colon cancer. J Am Coll Surg. 2013 Jul;217(1):56-62; discussion 62-3. doi: 10.1016/j.jamcollsurg.2013.02.023. Epub 2013 Apr 24.

Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, Smyrk TC, Sinicrope FA, Chan E, Gill S, Kahlenberg MS, Shields AF, Quesenberry JT, Webb TA, Farr GH Jr, Pockaj BA, Grothey A, Goldberg RM. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012 Apr 4;307(13):1383-93. doi: 10.1001/jama.2012.385.

Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00079274 History of Changes
Obsolete Identifiers:	NCT00170092
Other Study ID Numbers:	NCI-2009-00639; N0147; U10CA025224 ( U.S. NIH Grant/Contract ); CDR0000355132 ( Registry Identifier: PDQ (Physician Data Query) )
First Submitted:	March 8, 2004
First Posted:	March 10, 2004
Results First Submitted:	December 5, 2013
Results First Posted:	February 9, 2015
Last Update Posted:	February 9, 2015