Trial Outcomes & Findings for Aldesleukin With or Without Ziv-Aflibercept in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery (NCT NCT01258855)

Last Updated: 2019-05-10

Results Overview

Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), 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

84 participants

Primary outcome timeframe

The time from the date of randomization until date of progression, death, or recurrence, assessed up to 5 years

Results posted on

2019-05-10

Participant Flow

Participant milestones

Participant milestones
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) Patients received HD IL2 for a maximum of 3 courses (6 cycles)
Overall Study STARTED	55	29
Overall Study COMPLETED	55	29
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Aldesleukin With or Without Ziv-Aflibercept in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=55 Participants Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=29 Participants Patients received HD IL2 for a maximum of 3 courses (6 cycles)	Total n=84 Participants Total of all reporting groups
Age, Continuous	55 years n=5 Participants	55 years n=7 Participants	55 years n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants	11 Participants n=7 Participants	33 Participants n=5 Participants
Sex: Female, Male Male	33 Participants n=5 Participants	18 Participants n=7 Participants	51 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	54 Participants n=5 Participants	28 Participants n=7 Participants	82 Participants n=5 Participants
Race/Ethnicity, Customized African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	55 Participants n=5 Participants	29 Participants n=7 Participants	84 Participants n=5 Participants

PRIMARY outcome

Timeframe: The time from the date of randomization until date of progression, death, or recurrence, assessed up to 5 years

Outcome measures

Outcome measures
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=55 Participants Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=29 Participants Patients received HD IL2 for a maximum of 3 courses (6 cycles)
Progression-free Survival	6.9 months Interval 4.1 to 8.7	2.3 months Interval 1.6 to 3.5

SECONDARY outcome

Timeframe: Until Death from any cause, up to 5 years

Estimated using the product-limit method of Kaplan and Meier.

Outcome measures

Outcome measures
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=55 Participants Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=29 Participants Patients received HD IL2 for a maximum of 3 courses (6 cycles)
Overall Survival	26.9 months Interval 14.4 to 63.6	24.2 months Interval 11.3 to 36.4

SECONDARY outcome

Timeframe: Up to 5 years

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; Overall Response (RR) = CR + PR.

Outcome measures

Outcome measures
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=55 Participants Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=29 Participants Patients received HD IL2 for a maximum of 3 courses (6 cycles)
Response Rate	22 percentage of participants	17 percentage of participants

SECONDARY outcome

Timeframe: Up to 5 years

Count of the number of participants with grade 3 \& 4 adverse events attributed to treatment agents. Events are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Outcome measures

Outcome measures
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=55 Participants Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=29 Participants Patients received HD IL2 for a maximum of 3 courses (6 cycles)
Count of Participants With Adverse Events Anemia	2 participants	0 participants
Count of Participants With Adverse Events Leukocytosis	1 participants	0 participants
Count of Participants With Adverse Events Lymphocyte count decreased	41 participants	20 participants
Count of Participants With Adverse Events Neutrophil count decreased	2 participants	0 participants
Count of Participants With Adverse Events Platelet count decreased	11 participants	9 participants
Count of Participants With Adverse Events Left ventricular systolic	1 participants	0 participants
Count of Participants With Adverse Events Sinus tachycardia	0 participants	1 participants
Count of Participants With Adverse Events Supraventricular tachycardia	1 participants	1 participants
Count of Participants With Adverse Events Hypertension	14 participants	0 participants
Count of Participants With Adverse Events Hypotension	1 participants	4 participants
Count of Participants With Adverse Events Thromboembolic event	2 participants	1 participants
Count of Participants With Adverse Events Fatigue	5 participants	3 participants
Count of Participants With Adverse Events Fever and chills	1 participants	1 participants
Count of Participants With Adverse Events Diarrhea	0 participants	1 participants
Count of Participants With Adverse Events Oral mucositis	0 participants	1 participants
Count of Participants With Adverse Events Nausea and vomiting	2 participants	2 participants
Count of Participants With Adverse Events LFTs increased	13 participants	9 participants
Count of Participants With Adverse Events Lipase increased	0 participants	2 participants
Count of Participants With Adverse Events Confusion	3 participants	0 participants
Count of Participants With Adverse Events Creatinine increased	2 participants	0 participants
Count of Participants With Adverse Events Proteinuria	6 participants	0 participants
Count of Participants With Adverse Events Urine output decreased	8 participants	7 participants
Count of Participants With Adverse Events Dyspnea	1 participants	4 participants
Count of Participants With Adverse Events Maculopapular rash	1 participants	0 participants

SECONDARY outcome

Timeframe: Up to 5 years

Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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. Median baseline measure for VEGF were used as the cut point for "low" vs "high" VEGF groups.

Outcome measures

Outcome measures
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=21 Participants Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=7 Participants Patients received HD IL2 for a maximum of 3 courses (6 cycles)
Progression-free Survival for Patients With High Vascular Endothelial Growth Factor (VEGF) Levels	8.7 months Interval 6.1 to 16.2	3.1 months Interval 1.5 to 7.4

SECONDARY outcome

Timeframe: Up to 5 years

Outcome measures

Outcome measures
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=23 Participants Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=6 Participants Patients received HD IL2 for a maximum of 3 courses (6 cycles)
Progression-free Survival for Patients With Low VEGF Levels	6.9 months Interval 4.4 to 11.6	4.0 months Interval 1.2 to 6.9

OTHER_PRE_SPECIFIED outcome

Timeframe: Until Death from any cause, up to 1 year

Estimated using the product-limit method of Kaplan and Meier.

Outcome measures

Outcome measures
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=55 Participants Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=29 Participants Patients received HD IL2 for a maximum of 3 courses (6 cycles)
1-year Overall Survival Rate	75.6 percentage of participants Interval 64.5 to 88.6	66.8 percentage of participants Interval 51.5 to 86.5

Adverse Events

Combination Arm (Ziv-Afilbercept+HD IL2)

Serious events: 28 serious events

Other events: 55 other events

Deaths: 37 deaths

Mono-therapy Arm (HD IL2 Alone)

Serious events: 7 serious events

Other events: 29 other events

Deaths: 20 deaths

Serious adverse events

Other adverse events

Additional Information

Paul Frankel, Ph.D.

City of Hope

Phone: 626-218-5265

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=55 participants at risk Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=29 participants at risk Patients received HD IL2 for a maximum of 3 courses (6 cycles)
Cardiac disorders Sinus bradycardia	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Abdominal distension	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Abdominal pain	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Colitis	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Colonic hemorrhage	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Nausea	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	6.9% 2/29 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Oral pain	3.6% 2/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Vomiting	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
General disorders Fatigue	0.00% 0/55 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
General disorders Fever	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
General disorders Infusion related reaction	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Hepatobiliary disorders Choledocholithiasis	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Hepatobiliary disorders Portal vein thrombosis	0.00% 0/55 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Infections and infestations Skin infection	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Infections and infestations Soft tissue infection	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Investigations Alanine aminotransferase increased	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Investigations Aspartate aminotransferase increased	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Investigations Blood bilirubin increased	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Investigations Lipase increased	3.6% 2/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Investigations Lymphocyte count decreased	27.3% 15/55 • Number of events 17 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	10.3% 3/29 • Number of events 3 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Investigations Lymphocyte count increased	1.8% 1/55 • Number of events 12 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Investigations Neutrophil count decreased	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Investigations Platelet count decreased	5.5% 3/55 • Number of events 4 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Investigations Serum amylase increased	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Metabolism and nutrition disorders Hyperkalemia	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Metabolism and nutrition disorders Hypermagnesemia	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Metabolism and nutrition disorders Hypoalbuminemia	5.5% 3/55 • Number of events 3 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Metabolism and nutrition disorders Hypoglycemia	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Metabolism and nutrition disorders Hypophosphatemia	12.7% 7/55 • Number of events 9 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Nervous system disorders Encephalopathy	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Nervous system disorders Seizure	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Psychiatric disorders Confusion	0.00% 0/55 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Psychiatric disorders Delirium	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Renal and urinary disorders Urinary retention	1.8% 1/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary edema	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/55 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Skin and subcutaneous tissue disorders Dry skin	3.6% 2/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Skin and subcutaneous tissue disorders Skin ulceration	3.6% 2/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Vascular disorders Hypertension	3.6% 2/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Vascular disorders Thromboembolic event	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.

Other adverse events
Measure	Combination Arm (Ziv-Afilbercept+HD IL2) n=55 participants at risk Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2	Mono-therapy Arm (HD IL2 Alone) n=29 participants at risk Patients received HD IL2 for a maximum of 3 courses (6 cycles)
Gastrointestinal disorders mouth sores	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders mouth ulcer	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders mouth ulceration	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Oral pain	12.7% 7/55 • Number of events 8 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	6.9% 2/29 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Pancreatitis	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Rectal hemorrhage	1.8% 1/55 • Number of events 3 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Rectal mucositis	1.8% 1/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Rectal pain	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Toothache	7.3% 4/55 • Number of events 4 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders Vomiting	54.5% 30/55 • Number of events 56 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	62.1% 18/29 • Number of events 40 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders early satiety	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Gastrointestinal disorders gum sensitivity	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Blood and lymphatic system disorders Anemia	72.7% 40/55 • Number of events 77 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	69.0% 20/29 • Number of events 39 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Blood and lymphatic system disorders Leukocytosis	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Blood and lymphatic system disorders hemoptysis	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Blood and lymphatic system disorders low carbon dioxide	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Blood and lymphatic system disorders red blood cells decreased	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Blood and lymphatic system disorders white blood cells increased	12.7% 7/55 • Number of events 10 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	6.9% 2/29 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Atrial fibrillation	3.6% 2/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	10.3% 3/29 • Number of events 5 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Chest pain - cardiac	3.6% 2/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Left ventricular systolic dysfunction	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Mobitz (type) II atrioventricular block	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Mobitz type I	3.6% 2/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Palpitations	3.6% 2/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Sinus bradycardia	5.5% 3/55 • Number of events 4 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Sinus tachycardia	70.9% 39/55 • Number of events 71 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	65.5% 19/29 • Number of events 61 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Supraventricular tachycardia	1.8% 1/55 • Number of events 3 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	6.9% 2/29 • Number of events 3 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Ventricular arrhythmia	0.00% 0/55 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders Ventricular tachycardia	5.5% 3/55 • Number of events 3 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	6.9% 2/29 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Cardiac disorders bigeminy ventricular arrhythemia	0.00% 0/55 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Ear and labyrinth disorders Ear pain	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Ear and labyrinth disorders Tinnitus	1.8% 1/55 • Number of events 2 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Endocrine disorders Hyperthyroidism	0.00% 0/55 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Endocrine disorders Hypothyroidism	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Eye disorders Blurred vision	5.5% 3/55 • Number of events 3 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Eye disorders Dry eye	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Eye disorders Eye pain	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	3.4% 1/29 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Eye disorders Flashing lights	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Eye disorders Floaters	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Eye disorders Photophobia	1.8% 1/55 • Number of events 1 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.	0.00% 0/29 • Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent. "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.