Trial Outcomes & Findings for Phase II Randomized Trial of mFOLFIRINOX +/- Ramucirumab in Advanced Pancreatic Cancer (NCT NCT02581215)

Last Updated: 2025-01-01

Results Overview

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time of registration until disease progression met by RECIST 1.1 or death from any cause.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

84 participants

Primary outcome timeframe

9 months

Results posted on

2025-01-01

Participant Flow

Participant milestones

Participant milestones
Measure	Arm A: Experimental Arm mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm A will receive ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Ramucirumab: Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.	Arm B: Placebo Arm mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were ramucirumab mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Placebo: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.
Overall Study STARTED	42	42
Overall Study COMPLETED	42	40
Overall Study NOT COMPLETED	0	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A: Experimental Arm mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm A will receive ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Ramucirumab: Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.	Arm B: Placebo Arm mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were ramucirumab mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Placebo: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.
Overall Study Screen Failure Before Therapy Start	0	1
Overall Study Eligibility Criteria Not Met	0	1

Baseline Characteristics

Phase II Randomized Trial of mFOLFIRINOX +/- Ramucirumab in Advanced Pancreatic Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A: Experimental Arm n=42 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm A will receive ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Ramucirumab: Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.	Arm B: Placebo Arm n=40 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were ramucirumab mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Placebo: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.	Total n=82 Participants Total of all reporting groups
Age, Continuous	62 years n=5 Participants	65 years n=7 Participants	63 years n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	20 Participants n=7 Participants	39 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	20 Participants n=7 Participants	43 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	41 Participants n=5 Participants	35 Participants n=7 Participants	76 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) White	35 Participants n=5 Participants	34 Participants n=7 Participants	69 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Region of Enrollment United States	42 participants n=5 Participants	40 participants n=7 Participants	82 participants n=5 Participants

PRIMARY outcome

Timeframe: 9 months

Outcome measures

Outcome measures
Measure	Arm A: Experimental Arm n=42 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm A will receive ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Ramucirumab: Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.	Arm B: Placebo Arm n=40 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were ramucirumab mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Placebo: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.
Progression Free Survival (PFS) at 9 Month	25.1 Percentage of participants Interval 11.6 to 41.3	35 Percentage of participants Interval 19.8 to 50.6

SECONDARY outcome

Timeframe: Up to a maximum of 53 months

Overall survival is defined by the date of randomization to date of death from any cause.

Outcome measures

Outcome measures
Measure	Arm A: Experimental Arm n=42 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm A will receive ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Ramucirumab: Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.	Arm B: Placebo Arm n=40 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were ramucirumab mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Placebo: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.
Overall Survival (OS)	10.3 Months Interval 6.0 to 11.8	9.7 Months Interval 6.4 to 15.9

SECONDARY outcome

Timeframe: Up to 44 months

Population: The analysis population for the endpoint Response Rate (RR) was defined as all participants with at least one post-baseline disease assessment.

Outcome measures

Outcome measures
Measure	Arm A: Experimental Arm n=34 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm A will receive ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Ramucirumab: Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.	Arm B: Placebo Arm n=31 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were ramucirumab mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Placebo: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.
Response Rate (RR)	17.7 Percentage of participants	22.6 Percentage of participants

SECONDARY outcome

Timeframe: From date of first dose until 30 days after the last treatment, assessed up to 44 months

Adverse events will be assessed to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.

Outcome measures

Outcome measures
Measure	Arm A: Experimental Arm n=42 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm A will receive ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Ramucirumab: Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.	Arm B: Placebo Arm n=40 Participants mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were ramucirumab mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Placebo: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.
Number of Participants With Adverse Events	42 Participants	40 Participants

Adverse Events

Arm B: Placebo Arm

Serious events: 17 serious events

Other events: 39 other events

Deaths: 35 deaths

Arm A: Experimental Arm

Serious events: 19 serious events

Other events: 41 other events

Deaths: 33 deaths

Serious adverse events

Other adverse events

Additional Information

Fauzia Sharmin

Hoosier Cancer Research Network

Phone: 317-921-2050

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm B: Placebo Arm n=40 participants at risk mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm B will receive a placebo infusion every 2 weeks. Due to the double-blinded nature of this study, the volume of placebo will be calculated as if it were ramucirumab mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Placebo: Placebo infusion with volume calculated as if it were ramucirumab every 2 weeks.	Arm A: Experimental Arm n=42 participants at risk mFOLFIRINOX will be administered every 2 weeks, and consist of: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. * Arm A will receive ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks. mFOLFIRINOX: mFOLFIRINOX: * Oxaliplatin 85 mg/m2 over 2-4 hours * Irinotecan 165 mg/m2 over 90 minutes * 5-FU 2,400 mg/m2 as a 46-hour continuous infusion without the 5-FU bolus to decrease the risk of neutropenia. Ramucirumab: Ramucirumab administered as an intravenous infusion over 60 minutes (infusion rate should not exceed 25 mg/min), at a fixed dose of 8 mg/kg every 2 weeks.
Gastrointestinal disorders ABDOMINAL DISTENSION	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders ABDOMINAL PAIN	5.0% 2/40 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Metabolism and nutrition disorders ANOREXIA	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Investigations BLOOD BILIRUBIN INCREASED	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	4.8% 2/42 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Hepatobiliary disorders CHOLECYSTITIS	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders COLITIS	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Psychiatric disorders CONFUSION	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders CONSTIPATION	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Metabolism and nutrition disorders DEHYDRATION	5.0% 2/40 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	4.8% 2/42 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders DIARRHEA	2.5% 1/40 • Number of events 3 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	7.1% 3/42 • Number of events 3 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders DUODENAL OBSTRUCTION	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	7.1% 3/42 • Number of events 3 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Respiratory, thoracic and mediastinal disorders DYSPNEA	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Nervous system disorders ENCEPHALOPATHY	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders ESOPHAGITIS	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
General disorders FATIGUE	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders GASTRITIS	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders GASTROINTESTINAL DISORDERS - OTHER, SPECIFY	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
General disorders GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Musculoskeletal and connective tissue disorders GENERALIZED MUSCLE WEAKNESS	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Metabolism and nutrition disorders HYPOKALEMIA	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Vascular disorders HYPOTENSION	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Respiratory, thoracic and mediastinal disorders HYPOXIA	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Infections and infestations INFECTIONS AND INFESTATIONS - OTHER, SPECIFY	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders MUCOSITIS ORAL	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders NAUSEA	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
General disorders PAIN	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Respiratory, thoracic and mediastinal disorders PLEURAL EFFUSION	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Infections and infestations SEPSIS	7.5% 3/40 • Number of events 4 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	7.1% 3/42 • Number of events 6 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Nervous system disorders SYNCOPE	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Vascular disorders THROMBOEMBOLIC EVENT	0.00% 0/40 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	2.4% 1/42 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders VOMITING	5.0% 2/40 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	7.1% 3/42 • Number of events 3 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Infections and infestations BLADDER INFECTION	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders COLONIC OBSTRUCTION	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
General disorders DEATH NOS	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Blood and lymphatic system disorders FEBRILE NEUTROPENIA	5.0% 2/40 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Hepatobiliary disorders HEPATOBILIARY DISORDERS - OTHER, SPECIFY	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Metabolism and nutrition disorders HYPONATREMIA	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Renal and urinary disorders RENAL CALCULI	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Nervous system disorders TRANSIENT ISCHEMIC ATTACKS	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Gastrointestinal disorders UPPER GASTROINTESTINAL HEMORRHAGE	5.0% 2/40 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.
Vascular disorders VISCERAL ARTERIAL ISCHEMIA	2.5% 1/40 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.	0.00% 0/42 • All-Cause Mortality was monitored up to a maximum of 53 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 44 months.