Trial Outcomes & Findings for Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Celecoxib in Treating Patients With Stage III Colon Cancer Previously Treated With Surgery (NCT NCT01150045)

Last Updated: 2022-03-22

Results Overview

Disease-Free Survival (DFS) is defined as the time of randomization until documented progression or death from any cause. The endpoint of this trial is to compare disease-free survival of patients with stage III colon cancer randomized to standard chemotherapy only (FOLFOX; Arm A and Arm C) or standard chemotherapy (FOLFOX) with 3 years of celecoxib 400 mg daily (Arm B and Arm D). The percentage of patients who were alive and disease free after 3 years are reported here. A log-rank test stratified with the stratification factors was used to compare disease-free survival (celecoxib vs placebo)

Recruitment status

UNKNOWN

Study phase

PHASE3

Target enrollment

2527 participants

Primary outcome timeframe

At 3 years of follow-up

Results posted on

2022-03-22

Participant Flow

One patient withdrew from the trial before being randomized and was excluded from any analysis.

Participant milestones

Participant milestones
Measure	Arm A - 12 Cycles of FOLFOX Plus Placebo Daily The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. \> Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm B - 12 Cycles of FOLFOX Plus Celecoxib Daily The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. \> Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm C - 6 Cycles of FOLFOX Plus Placebo Daily The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. \> Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm D - 6 Cycles of FOLFOX Plus Celecoxib Daily The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. \> Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.
Overall Study STARTED	615	647	646	618
Overall Study COMPLETED	615	646	646	617
Overall Study NOT COMPLETED	0	1	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A - 12 Cycles of FOLFOX Plus Placebo Daily The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. \> Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm B - 12 Cycles of FOLFOX Plus Celecoxib Daily The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. \> Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm C - 6 Cycles of FOLFOX Plus Placebo Daily The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. \> Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm D - 6 Cycles of FOLFOX Plus Celecoxib Daily The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. \> Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.
Overall Study Protocol Violation	0	1	0	1

Baseline Characteristics

Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Celecoxib in Treating Patients With Stage III Colon Cancer Previously Treated With Surgery

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A - FOLFOX and Placebo (12 Treatments) n=615 Participants The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil.\> Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm B - 12 Cycles of FOLFOX Plus Celecoxib Daily n=646 Participants The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil.\> Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm C - 6 Cycles of FOLFOX Plus Placebo Daily n=646 Participants The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil.\> Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm D - 6 Cycles of FOLFOX Plus Celecoxib Daily n=617 Participants The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil.\> Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Total n=2524 Participants Total of all reporting groups
Age, Continuous	61.0 years n=5 Participants	61.9 years n=7 Participants	61.0 years n=5 Participants	61.5 years n=4 Participants	61.3 years n=21 Participants
Sex: Female, Male Female	265 Participants n=5 Participants	297 Participants n=7 Participants	296 Participants n=5 Participants	276 Participants n=4 Participants	1134 Participants n=21 Participants
Sex: Female, Male Male	350 Participants n=5 Participants	349 Participants n=7 Participants	350 Participants n=5 Participants	341 Participants n=4 Participants	1390 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	42 Participants n=5 Participants	45 Participants n=7 Participants	55 Participants n=5 Participants	49 Participants n=4 Participants	191 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	559 Participants n=5 Participants	586 Participants n=7 Participants	571 Participants n=5 Participants	552 Participants n=4 Participants	2268 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	14 Participants n=5 Participants	15 Participants n=7 Participants	20 Participants n=5 Participants	16 Participants n=4 Participants	65 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=5 Participants	5 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants	15 Participants n=21 Participants
Race (NIH/OMB) Asian	22 Participants n=5 Participants	32 Participants n=7 Participants	21 Participants n=5 Participants	32 Participants n=4 Participants	107 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	7 Participants n=21 Participants
Race (NIH/OMB) Black or African American	82 Participants n=5 Participants	88 Participants n=7 Participants	76 Participants n=5 Participants	73 Participants n=4 Participants	319 Participants n=21 Participants
Race (NIH/OMB) White	487 Participants n=5 Participants	500 Participants n=7 Participants	522 Participants n=5 Participants	488 Participants n=4 Participants	1997 Participants n=21 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=4 Participants	6 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	20 Participants n=5 Participants	15 Participants n=7 Participants	19 Participants n=5 Participants	19 Participants n=4 Participants	73 Participants n=21 Participants
Region of Enrollment Canada	57 participants n=5 Participants	44 participants n=7 Participants	70 participants n=5 Participants	61 participants n=4 Participants	232 participants n=21 Participants
Region of Enrollment United States	558 participants n=5 Participants	602 participants n=7 Participants	576 participants n=5 Participants	556 participants n=4 Participants	2292 participants n=21 Participants

PRIMARY outcome

Timeframe: At 3 years of follow-up

Population: All patients that were randomized and evaluable were included in this analysis.

Outcome measures

Outcome measures
Measure	FOLFOX and Placebo (Arms A +C) n=1261 Participants Arm A The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity. Arm C The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	FOLFOX Plus Celecoxib Daily (Arms B + D) n=1263 Participants Arm B The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity. Arm D The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.
Disease-free Survival	73.4 percentage of participants Interval 70.8 to 76.0	76.3 percentage of participants Interval 73.8 to 78.8

SECONDARY outcome

Timeframe: up to 3 years from registration

Population: All patients that were randomized and evaluable were included in this analysis.

Overall Survival (DFS) is defined as the time of randomization until documented death from any cause. The endpoint is to compare overall survival of patients with stage III colon cancer randomized to standard chemotherapy only (FOLFOX; Arm A and Arm C) or standard chemotherapy (FOLFOX) with 5 years of celecoxib 400 mg daily (Arm B and Arm D). The percentage of patients who were alive after 3 years are reported here.

Outcome measures

Outcome measures
Measure	FOLFOX and Placebo (Arms A +C) n=1261 Participants Arm A The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity. Arm C The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	FOLFOX Plus Celecoxib Daily (Arms B + D) n=1263 Participants Arm B The FOLFOX regimen consisted of every 2 weeks cycles for 12 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity. Arm D The FOLFOX regimen consisted of every 2 weeks cycles for 6 cycles of 2-hour infusions of oxaliplatin at 85 mg/m2 and leucovorin at 400 mg/m2, followed by a bolus infusion of 400-mg/m2 of fluorouracil following by 46-48-hour continuous infusion of 2400-mg/m2 of fluorouracil. Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.
Overall Survival	81.6 percentage of participants Interval 79.4 to 83.9	84.3 percentage of participants Interval 82.2 to 86.5

Adverse Events

Arm A - FOLFOX and Placebo (12 Treatments)

Serious events: 77 serious events

Other events: 574 other events

Deaths: 10 deaths

Arm B - 12 Cycles of FOLFOX Plus Celecoxib Daily

Serious events: 93 serious events

Other events: 615 other events

Deaths: 8 deaths

Arm C - 6 Cycles of FOLFOX Plus Placebo Daily

Serious events: 72 serious events

Other events: 618 other events

Deaths: 10 deaths

Arm D - 6 Cycles of FOLFOX Plus Celecoxib Daily

Serious events: 78 serious events

Other events: 589 other events

Deaths: 9 deaths

Serious adverse events

Other adverse events

Additional Information

Jeffrey A. Meyerhardt, MD, MPH

Alliance for Clinical Trials in Oncology

Phone: 617-632-6855

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Serious adverse events
Measure	Arm A - FOLFOX and Placebo (12 Treatments) n=615 participants at risk Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm B - 12 Cycles of FOLFOX Plus Celecoxib Daily n=647 participants at risk Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm C - 6 Cycles of FOLFOX Plus Placebo Daily n=646 participants at risk Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm D - 6 Cycles of FOLFOX Plus Celecoxib Daily n=618 participants at risk Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.
Gastrointestinal disorders Small intestinal perforation	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Upper gastrointestinal hemorrhage	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Gastric ulcer	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/646 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Gastritis	0.33% 2/615 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/647 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.62% 4/646 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Blood and lymphatic system disorders Blood disorder	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Blood and lymphatic system disorders Febrile neutropenia	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/646 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.49% 3/618 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Blood and lymphatic system disorders Hemoglobin decreased	0.49% 3/615 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.77% 5/647 • Number of events 5 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.93% 6/646 • Number of events 6 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.97% 6/618 • Number of events 6 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Blood and lymphatic system disorders Hemolysis	0.49% 3/615 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/647 • Number of events 5 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/646 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.1% 7/618 • Number of events 7 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Blood and lymphatic system disorders Spleen disorder	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Arrhythmia	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Arrhythmia supraventricular	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Asystole	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Atrial fibrillation	0.33% 2/615 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/647 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/646 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.32% 2/618 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Cardiac disorder	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/647 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/646 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.32% 2/618 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Cardiac pain	0.16% 1/615 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Cardiac valve disease	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Cardiopulmonary arrest	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/647 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Conduction disorder	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Left ventricular dysfunction	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Left ventricular failure	0.33% 2/615 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Myocardial ischemia	0.81% 5/615 • Number of events 5 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.7% 11/647 • Number of events 11 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.4% 9/646 • Number of events 9 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.1% 7/618 • Number of events 7 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Palpitations	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Restrictive cardiomyopathy	0.33% 2/615 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Sinus bradycardia	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Sinus tachycardia	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Cardiac disorders Supraventricular tachycardia	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Ear and labyrinth disorders Hearing impaired	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Eye disorders Eye disorder	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Eye disorders Optic nerve disorder	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Eye disorders Vision blurred	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Abdominal distension	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.32% 2/618 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Abdominal pain	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/647 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/646 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.3% 8/618 • Number of events 8 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Anal mucositis (clin exam)	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Colitis	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Colonic obstruction	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/647 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Colonic perforation	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Constipation	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/646 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Diarrhea	4.4% 27/615 • Number of events 33 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	5.1% 33/647 • Number of events 35 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	3.7% 24/646 • Number of events 25 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.9% 12/618 • Number of events 13 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Dry mouth	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Duodenal ulcer	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).

Other adverse events
Measure	Arm A - FOLFOX and Placebo (12 Treatments) n=615 participants at risk Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm B - 12 Cycles of FOLFOX Plus Celecoxib Daily n=647 participants at risk Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm C - 6 Cycles of FOLFOX Plus Placebo Daily n=646 participants at risk Placebo was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Placebo was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.	Arm D - 6 Cycles of FOLFOX Plus Celecoxib Daily n=618 participants at risk Celecoxib was dosed at 400 mg orally daily, starting by day 1 of the second treatment of FOLFOX. Celecoxib was administered daily for 3 years from the date of initiation of the first dose or until recurrence of disease or unacceptable toxicity.
Infections and infestations Conjunctivitis	0.33% 2/615 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Injury, poisoning and procedural complications Fracture	0.65% 4/615 • Number of events 5 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.93% 6/647 • Number of events 6 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/646 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Investigations Blood bilirubin increased	0.65% 4/615 • Number of events 9 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.62% 4/647 • Number of events 6 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/646 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.65% 4/618 • Number of events 15 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Musculoskeletal and connective tissue disorders Arthralgia	0.81% 5/615 • Number of events 17 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.93% 6/647 • Number of events 11 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.7% 11/646 • Number of events 22 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.81% 5/618 • Number of events 8 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Gastrointestinal disorders Esophagitis	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Skin and subcutaneous tissue disorders Skin disorder	0.98% 6/615 • Number of events 6 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.62% 4/647 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.77% 5/646 • Number of events 16 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.97% 6/618 • Number of events 8 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Nervous system disorders Speech disorder	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 5 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Nervous system disorders Syncope	1.5% 9/615 • Number of events 9 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.4% 9/647 • Number of events 10 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/646 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.5% 9/618 • Number of events 9 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Nervous system disorders Syncope vasovagal	0.33% 2/615 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Nervous system disorders Tremor	0.33% 2/615 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/647 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Psychiatric disorders Agitation	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Psychiatric disorders Anxiety	0.98% 6/615 • Number of events 14 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.5% 10/647 • Number of events 17 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.5% 10/646 • Number of events 18 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	2.1% 13/618 • Number of events 20 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Psychiatric disorders Confusion	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Psychiatric disorders Depression	0.81% 5/615 • Number of events 16 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.77% 5/647 • Number of events 8 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.1% 7/646 • Number of events 18 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.1% 7/618 • Number of events 10 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Psychiatric disorders Insomnia	1.3% 8/615 • Number of events 24 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.5% 10/647 • Number of events 19 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.1% 7/646 • Number of events 24 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.9% 12/618 • Number of events 29 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Psychiatric disorders Irritability	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Psychiatric disorders Personality change	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Psychiatric disorders Psychosis	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Bladder hemorrhage	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Bladder obstruction	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Cystitis	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Glomerular filtration rate decreased	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/647 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Hemoglobin urine positive	0.33% 2/615 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Hemorrhage urinary tract	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Kidney pain	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Proteinuria	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.32% 2/618 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Renal failure	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.32% 2/618 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Ureteric obstruction	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.46% 3/646 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Urinary frequency	0.33% 2/615 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.32% 2/618 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Urinary incontinence	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.49% 3/618 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Urinary retention	0.16% 1/615 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Renal and urinary disorders Urogenital disorder	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.77% 5/647 • Number of events 5 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	1.2% 8/646 • Number of events 9 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.32% 2/618 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Reproductive system and breast disorders Breast pain	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 2 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Reproductive system and breast disorders Erectile dysfunction	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.31% 2/646 • Number of events 3 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Reproductive system and breast disorders Irregular menstruation	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 4 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Reproductive system and breast disorders Nipple deformity	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Reproductive system and breast disorders Scrotal pain	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Reproductive system and breast disorders Vaginal discharge	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/646 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.16% 1/618 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Reproductive system and breast disorders Vaginal hemorrhage	0.00% 0/615 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.15% 1/647 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).
Reproductive system and breast disorders Vaginal inflammation	0.16% 1/615 • Number of events 1 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/647 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/646 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).	0.00% 0/618 • Adverse events were collected after every 2-week cycle during treatment (up to 12 cycles or 24 weeks of treatment).