Trial Outcomes & Findings for Genotype-Directed Study Of Irinotecan Dosing In FOLFIRI + BevacizumabTreated Metastatic Colorectal Cancer (NCT NCT02138617)

NCT ID: NCT02138617

Last Updated: 2025-05-18

Results Overview

Progression-free Free Survival is defined as the time from day 1 (D1) of treatment to progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST)1.1 or death from any cause. Radiographic response will be measured by RECIST, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 100 participants
• Primary outcome timeframe: From date of registration until date of first documented progression up to 8 years.
• Results posted on: 2025-05-18

Participant Flow

Participants were enrolled in the study between 5/6/2014 and 08/29/20192 at eight cancer centers in the United States.

Participant milestones

Measure	*1/*1 Genotype FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*1/*28 Genotype FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*28/*28 FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Overall Study STARTED	47	43	10
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	47	43	10

Reasons for withdrawal

Measure	*1/*1 Genotype FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*1/*28 Genotype FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*28/*28 FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Overall Study Death	1	2	2
Overall Study Adverse Event	8	5	2
Overall Study Disease Progression	20	13	4
Overall Study Withdrawal by Subject	7	10	2
Overall Study other complicating disease	0	2	0
Overall Study Protocol Violation	1	0	0
Overall Study Physician Decision	7	6	0
Overall Study financial reason	0	1	0
Overall Study other therapy	3	4	0

Baseline Characteristics

Genotype-Directed Study Of Irinotecan Dosing In FOLFIRI + BevacizumabTreated Metastatic Colorectal Cancer

Baseline characteristics by cohort

Measure	*1/*1 Genotype n=47 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*1/*28 Genotype n=43 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*28/*28 n=10 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	Total n=100 Participants Total of all reporting groups
Age, Continuous	59 years n=93 Participants	59 years n=4 Participants	62 years n=27 Participants	59 years n=483 Participants
Sex: Female, Male Female	22 Participants n=93 Participants	18 Participants n=4 Participants	8 Participants n=27 Participants	48 Participants n=483 Participants
Sex: Female, Male Male	25 Participants n=93 Participants	25 Participants n=4 Participants	2 Participants n=27 Participants	52 Participants n=483 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	3 Participants n=483 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	41 Participants n=93 Participants	43 Participants n=4 Participants	10 Participants n=27 Participants	94 Participants n=483 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	3 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	2 Participants n=483 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Black or African American	3 Participants n=93 Participants	7 Participants n=4 Participants	2 Participants n=27 Participants	12 Participants n=483 Participants
Race (NIH/OMB) White	40 Participants n=93 Participants	35 Participants n=4 Participants	8 Participants n=27 Participants	83 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	3 Participants n=483 Participants
Region of Enrollment United States	47 participants n=93 Participants	43 participants n=4 Participants	10 participants n=27 Participants	100 participants n=483 Participants

PRIMARY outcome

Timeframe: From date of registration until date of first documented progression up to 8 years.

Population: Participants started the study and response assessments were completed.

Progression-free Free Survival is defined as the time from day 1 (D1) of treatment to progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST)1.1 or death from any cause. Radiographic response will be measured by RECIST, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Outcome measures

Measure	*1/*1 Genotype n=41 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*1/*28 Genotype n=36 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*28/*28 n=6 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Progression Free Survival The response was achieved, or the disease remained stable	38 Participants	34 Participants	6 Participants
Progression Free Survival Disease Progression	3 Participants	2 Participants	0 Participants

SECONDARY outcome

Timeframe: From date of registration up to 8 years.

Population: Participants started the study and adverse event assessments were completed.

The toxicity profile when irinotecan is dosed according to isoenzyme uridine diphosphate glucuronosyl transferase (UGT1A1) Genotypes was evaluated and Grade 3 or higher adverse events were reported. Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.03).

Outcome measures

Measure	*1/*1 Genotype n=47 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*1/*28 Genotype n=39 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*28/*28 n=10 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Number of Participants With Grade 3 or Higher Adverse Events Leukopenia	2 Participants	3 Participants	3 Participants
Number of Participants With Grade 3 or Higher Adverse Events Lymphopenia	0 Participants	5 Participants	1 Participants
Number of Participants With Grade 3 or Higher Adverse Events Anemia	1 Participants	3 Participants	3 Participants
Number of Participants With Grade 3 or Higher Adverse Events Thrombocytopenia	2 Participants	2 Participants	3 Participants
Number of Participants With Grade 3 or Higher Adverse Events Nausea	1 Participants	2 Participants	1 Participants
Number of Participants With Grade 3 or Higher Adverse Events Vomiting	2 Participants	3 Participants	1 Participants
Number of Participants With Grade 3 or Higher Adverse Events Diarrhea	6 Participants	5 Participants	1 Participants
Number of Participants With Grade 3 or Higher Adverse Events Mucositis	4 Participants	3 Participants	2 Participants
Number of Participants With Grade 3 or Higher Adverse Events Hypertension	5 Participants	4 Participants	1 Participants
Number of Participants With Grade 3 or Higher Adverse Events General Fatigue	2 Participants	5 Participants	1 Participants
Number of Participants With Grade 3 or Higher Adverse Events Febrile neutropenia	1 Participants	0 Participants	1 Participants
Number of Participants With Grade 3 or Higher Adverse Events Neutropenia	24 Participants	20 Participants	5 Participants
Number of Participants With Grade 3 or Higher Adverse Events Sepsis	1 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: 5 years

Population: Participants started the study and response assessments were completed.

Overall Response (OR =Complete Response +Partial Response) will be defined per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Outcome measures

Measure	*1/*1 Genotype n=41 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*1/*28 Genotype n=36 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*28/*28 n=6 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Overall Response Complete Response or Partial Response was achieved	28 Participants	20 Participants	3 Participants
Overall Response Stable disease or progression	13 Participants	16 Participants	3 Participants

SECONDARY outcome

Timeframe: 8 years

Population: Participants started the study.

The Overall Survival rate (OS) is defined as the percentage of participants alive after time from D1 of treatment to death from any cause.

Outcome measures

Measure	*1/*1 Genotype n=43 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*1/*28 Genotype n=39 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*28/*28 n=9 Participants FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Overall Survival Rate	26.5 months Interval 19.1 to 32.9	25.9 months Interval 17.6 to 37.7	13.4 months Interval 2.3 to 20.5

Adverse Events

*1/*1 Genotype

Serious events: 14 serious events

Other events: 47 other events

Deaths: 38 deaths

*1/*28 Genotype

Serious events: 13 serious events

Other events: 43 other events

Deaths: 34 deaths

*28/*28

Serious events: 4 serious events

Other events: 9 other events

Deaths: 9 deaths

Serious adverse events

Measure	*1/*1 Genotype n=47 participants at risk FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*1/*28 Genotype n=43 participants at risk FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*28/*28 n=10 participants at risk FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Blood and lymphatic system disorders Anemia	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Blood and lymphatic system disorders Febrile Neutropenia	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Chest Pain - Cardiac	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Myocardial Infarction	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Pericarditis	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Sinus Tachycardia	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Ventricular Tachycardia	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Abdominal Pain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders colonic obstruction	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders colonic perforation	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders colonic ulcer	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders constipation	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Diarrhea	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Nausea	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Rectal ulcer	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Small intestinal perforation	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Vomiting	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Death NOS	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Fatigue	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Infections and infestations - Other, specify	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Sepsis	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Injury, poisoning and procedural complications Urostomy leak	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Injury, poisoning and procedural complications Vascular access complication	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Alkaline phosphatase increased	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Cardiac troponin I increased	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Neutrophil count decreased	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Platelet count decreased	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations White blood cell decreased	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Dehydration	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hypocalcemia	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Stroke	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Acute kidney injury	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Urinary retention	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Bronchospasm	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Dyspnea	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Sore throat	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Vascular disorders Hypotension	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Vascular disorders Thromboembolic event	6.4% 3/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.

Other adverse events

Measure	*1/*1 Genotype n=47 participants at risk FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 310 mg/m2,(IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*1/*28 Genotype n=43 participants at risk FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 260 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)	*28/*28 n=10 participants at risk FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) Irinotecan dose 180 mg/m2, FOLFIRI (IV, Day 1, 15); Bevacizumab (IV, Day 1, 15), repeat treatment cycle every 28 days. 5-Fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, Day 1 and Day 15 . Leucovorin: 200-400 mg/m2 IV over 2 hours, Day 1 and Day 15 Irinotecan: IV infusion over 90 minutes, dosed at 180, 260 or 310 mg/m2 based on genotype. Bevacizumab: Bevacizumab (5 mg/kg IV infused as per institutional policy, IV, Day 1, 15)
Blood and lymphatic system disorders Anemia	59.6% 28/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	58.1% 25/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	80.0% 8/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Blood and lymphatic system disorders Leukocytosis	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Blood and lymphatic system disorders Thrombotic thrombocytopenic purpura	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Acute coronary syndrome	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Atrial fibrillation	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Cardiac disorders - Other, specify	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Chest pain - cardiac	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Heart failure	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Palpitations	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Sinus bradycardia	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Cardiac disorders Sinus tachycardia	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Ear and labyrinth disorders Ear and labyrinth disorders - Other, specify	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Ear and labyrinth disorders Vertigo	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Endocrine disorders Hyperthyroidism	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Eye disorders Blurred vision	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Eye disorders Cataract	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Eye disorders Dry eye	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Eye disorders Flashing lights	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Eye disorders Floaters	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Eye disorders Watering eyes	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Abdominal pain	34.0% 16/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	34.9% 15/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Anal hemorrhage	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Anal mucositis	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Anal pain	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Ascites	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Bloating	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Colitis	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Colonic obstruction	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Colonic ulcer	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Constipation	25.5% 12/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	53.5% 23/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.0% 2/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Diarrhea	63.8% 30/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	72.1% 31/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	60.0% 6/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Dry mouth	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Dyspepsia	10.6% 5/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Dysphagia	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	9.3% 4/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Esophageal pain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Esophagitis	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Flatulence	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Gastroesophageal reflux disease	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	9.3% 4/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.0% 2/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Gastrointestinal disorders - Other, specify	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Gingival pain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Hemorrhoidal hemorrhage	6.4% 3/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Hemorrhoids	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	9.3% 4/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Lower gastrointestinal hemorrhage	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Mucositis oral	61.7% 29/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	53.5% 23/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	40.0% 4/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Nausea	68.1% 32/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	81.4% 35/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	70.0% 7/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Oral dysesthesia	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Oral hemorrhage	6.4% 3/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Oral pain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Proctitis	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Rectal hemorrhage	6.4% 3/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Rectal pain	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Rectal ulcer	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Gastrointestinal disorders Vomiting	36.2% 17/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	46.5% 20/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	60.0% 6/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Chills	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Edema limbs	17.0% 8/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	11.6% 5/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Fatigue	63.8% 30/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	67.4% 29/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	60.0% 6/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Fever	6.4% 3/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	11.6% 5/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Flu like symptoms	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders General disorders and administration site conditions - Other, specify	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Infusion related reaction	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Injection site reaction	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Localized edema	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Malaise	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
General disorders Non-cardiac chest pain	17.0% 8/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	16.3% 7/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.0% 2/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Hepatobiliary disorders Hepatobiliary disorders - Other, specify	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Bronchial infection	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Cecal infection	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Enterocolitis infectious	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Gum infection	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Infections and infestations - Other, specify	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Lip infection	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Lung infection	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Mucosal infection	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.0% 2/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Nail infection	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Otitis externa	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Penile infection	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Prostate infection	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Rhinitis infective	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Skin infection	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Upper respiratory infection	14.9% 7/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Infections and infestations Urinary tract infection	14.9% 7/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Injury, poisoning and procedural complications Bruising	10.6% 5/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	11.6% 5/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Injury, poisoning and procedural complications Fracture	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Injury, poisoning and procedural complications Postoperative hemorrhage	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Injury, poisoning and procedural complications Vascular access complication	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Activated partial thromboplastin time prolonged	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Alanine aminotransferase increased	27.7% 13/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	9.3% 4/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Alkaline phosphatase increased	31.9% 15/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	30.2% 13/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Aspartate aminotransferase increased	34.0% 16/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	23.3% 10/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Blood bilirubin increased	6.4% 3/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	40.0% 4/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Cholesterol high	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Creatine Phosphokinase increased	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Creatinine increased	17.0% 8/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	23.3% 10/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations INR (international normalized ratio)	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Investigations - Other, specify	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Lipase increased	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Lymphocyte count decreased	23.4% 11/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	32.6% 14/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	30.0% 3/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Neutrophil count decreased	78.7% 37/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	72.1% 31/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	70.0% 7/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Platelet count decreased	25.5% 12/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	27.9% 12/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	50.0% 5/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Weight gain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations Weight loss	17.0% 8/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	16.3% 7/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	40.0% 4/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Investigations White blood cell decreased	44.7% 21/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	41.9% 18/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	50.0% 5/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Anorexia	55.3% 26/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	51.2% 22/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	40.0% 4/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Dehydration	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	18.6% 8/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hypercalcemia	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hyperglycemia	21.3% 10/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	11.6% 5/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hyperkalemia	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hypermagnesemia	14.9% 7/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.9% 9/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.0% 2/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hypernatremia	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	9.3% 4/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.0% 2/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hypoalbuminemia	38.3% 18/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	39.5% 17/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	40.0% 4/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hypocalcemia	31.9% 15/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.9% 9/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	30.0% 3/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hypokalemia	42.6% 20/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	39.5% 17/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	60.0% 6/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hypomagnesemia	25.5% 12/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	32.6% 14/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.0% 2/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hyponatremia	25.5% 12/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	25.6% 11/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	40.0% 4/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Hypophosphatemia	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Metabolism and nutrition disorders Metabolism and nutrition disorders - Other, specify	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Arthralgia	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Back pain	10.6% 5/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	11.6% 5/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Bone pain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders buttock pain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Chest wall pain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Flank pain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, specify	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Myalgia	6.4% 3/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Neck pain	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Musculoskeletal and connective tissue disorders Pain in extremity	14.9% 7/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	9.3% 4/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Concentration impairment	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Dizziness	17.0% 8/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	14.0% 6/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Dysgeusia	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	11.6% 5/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Headache	34.0% 16/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.9% 9/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Nervous system disorders - Other, specify	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Paresthesia	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	9.3% 4/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Peripheral sensory neuropathy	14.9% 7/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	9.3% 4/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Sinus pain	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Nervous system disorders Syncope	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Psychiatric disorders Agitation	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Psychiatric disorders Anxiety	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Psychiatric disorders Confusion	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Psychiatric disorders Depression	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Psychiatric disorders Insomnia	31.9% 15/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	32.6% 14/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.0% 2/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Psychiatric disorders Psychiatric disorders - Other, specify	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Acute kidney injury	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Cystitis noninfective	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Hematuria	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	14.0% 6/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Hemoglobinuria	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Proteinuria	29.8% 14/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	32.6% 14/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Renal and urinary disorders - Other, specify	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Renal calculi	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Reproductive system and breast disorders Urinary frequency	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Urinary incontinence	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Urinary retention	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Urinary tract obstruction	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Urinary urgency	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Urine discoloration	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Erectile dysfunction	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Renal and urinary disorders Genital edema	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Reproductive system and breast disorders Pelvic pain	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Reproductive system and breast disorders Penile pain	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Reproductive system and breast disorders Reproductive system and breast disorders - Other, specify	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	11.6% 5/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Cough	10.6% 5/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.9% 9/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Dyspnea	29.8% 14/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	34.9% 15/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Epistaxis	19.1% 9/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	23.3% 10/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Hiccups	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Hoarseness	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Hypoxia	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Laryngeal edema	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Nasal congestion	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Postnasal drip	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other, specify	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Sinus disorder	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Sore throat	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Respiratory, thoracic and mediastinal disorders Voice alteration	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Alopecia	29.8% 14/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	30.2% 13/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	40.0% 4/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Dry skin	6.4% 3/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Pain of skin	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	2.3% 1/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	14.9% 7/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Pruritus	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Rash acneiform	6.4% 3/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Rash maculo-papular	10.6% 5/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, specify	4.3% 2/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Skin and subcutaneous tissue disorders Skin ulceration	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Surgical and medical procedures Surgical and medical procedures - Other, specify	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Vascular disorders Flushing	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Vascular disorders Hematoma	2.1% 1/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Vascular disorders Hot flashes	8.5% 4/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	7.0% 3/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	0.00% 0/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Vascular disorders Hypertension	38.3% 18/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	34.9% 15/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	40.0% 4/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Vascular disorders Hypotension	0.00% 0/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	4.7% 2/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	20.0% 2/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.
Vascular disorders Thromboembolic event	12.8% 6/47 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	16.3% 7/43 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.	10.0% 1/10 • Up to 8 years. Adverse events were collected from day one of the study treatment. Per protocol, all hospitalizations were graded as serious adverse events.

Additional Information

Melahat Canter

UNC Lineberger Comprehensive Cancer Center

Phone: (919) 962-0000

Email: Melahat_Canter@med.unc.edu

Results disclosure agreements

• Principal investigator is a sponsor employee Subcontractor agrees that the first publication of the Study results will be made by Institution as a multi-site publication. Subcontractor can publish its site-specific results after Institution's publication, 12 months post-study completion, or upon Institution's notice. Subcontractor must provide Institution 30 days for manuscript review and may delay publication for 45 days for patent filing. Institution will register the Study and post results as required by law.
• Publication restrictions are in place

Restriction type: OTHER