Trial Outcomes & Findings for Aldesleukin and Pembrolizumab in Treating Patients With Stage III-IV Melanoma (NCT NCT02748564)

Last Updated: 2023-08-03

Results Overview

Estimated using OTD of IL-2 and pembrolizumab assessed by Response Evaluation Criteria in Solid Tumors version 1.1,for target lesions and assessed by CT or MRI imaging: 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) - At least a 20% increase in the sum of the longest diameter of target lesions; or Stable Disease (SD) - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. By testing increasing doses up to 600,000 IU. Receive IL-2 6,000 International Units per kilogram (IU/kg);in cycles 2, 3, 6,7,10 and 11, with follow up thirty days after the last dose of study drug

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

10 participants

Primary outcome timeframe

Four to six weeks later up to one year

Results posted on

2023-08-03

Participant Flow

All collected data for pre-specified Primary and Secondary Outcome Measures, and accurate Participant Flow, Baseline, and Adverse Events data is expected to be reported. Funding was lost so the second half of the study could not be completed.

Participant milestones

Participant milestones
Measure	Level 1 Treatment Pembrolizumab 200mg IV IL-2 6,000 Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 2 Pembrolizumab 200mg IV IL-2 60,000 Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 60,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 3 Pembrolizumab 200mg IV IL-2 600,000 Experimental 600,000 IU/kg of IL -2 Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 600,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug.
Overall Study STARTED	3	3	4
Overall Study COMPLETED	3	3	4
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Aldesleukin and Pembrolizumab in Treating Patients With Stage III-IV Melanoma

Baseline characteristics by cohort

PRIMARY outcome

Timeframe: Four to six weeks later up to one year

Outcome measures

Outcome measures
Measure	Level 1 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 6,000 Aldesleukin) n=3 Participants Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 2 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 60,000 n=3 Participants Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 60,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 3 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 600,000 n=4 Participants Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.
Best Overall Response Rate as Assessed by Response (BORR) Evaluation Criteria in Solid Tumors Version 1.1, With the Modification That Progressive Disease Must be Confirmed on a Subsequent Scan	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Four to six weeks later, up to three years

Population: The Number of Participants Analyzed for each Row should be specified in the Number Analyzed row, since it differs from the Overall Number of Participants Analyzed specified.

Participants are treated with pembrolizumab and the MTD of IL-2. Will be measured using the RECIST v 1.1. For all participants who experience a complete response, the date noted for disease response is the time of the scan when it was originally determined, and not the later date of the confirmatory scan.

Outcome measures

Outcome measures
Measure	Level 1 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 6,000 Aldesleukin) n=10 Participants Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 2 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 60,000 Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 60,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 3 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 600,000 Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.
Complete Response Rate Level 1	0 Participants	—	—
Complete Response Rate Level 2	0 Participants	—	—
Complete Response Rate Level 3	1 Participants	—	—

SECONDARY outcome

Timeframe: Thirty days after last dose of treatment, up to three years

Population: The Number of Participants Analyzed for each Row should be specified, since it differs from the Overall Number of Participants Analyzed specified.

Each participant will be assessed for potential or new worsening AE's. AE's will be graded and recorded through the study and during follow-up period according to National Cancer Institute Common Terminology Criteria for AE's, version 4.0. Grade 1-5 with grade 5 being the most severe.

Outcome measures

Outcome measures
Measure	Level 1 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 6,000 Aldesleukin) n=10 Participants Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 2 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 60,000 Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 60,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 3 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 600,000 Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.
Number of Adverse Effects (AE) as Evaluated by National Cancer Institute Common Terminology Criteria for AE's, Version 4.0 Level 1	0 Grade 3 or higher AE's	—	—
Number of Adverse Effects (AE) as Evaluated by National Cancer Institute Common Terminology Criteria for AE's, Version 4.0 Level 2	2 Grade 3 or higher AE's	—	—
Number of Adverse Effects (AE) as Evaluated by National Cancer Institute Common Terminology Criteria for AE's, Version 4.0 Level 3	3 Grade 3 or higher AE's	—	—

SECONDARY outcome

Timeframe: Baseline to end of follow-up, up to 3 years

Population: The Number of Participants Analyzed for each Row should be specified, since it differs from the Overall Number of Participants Analyzed specified.

Assess for survival status until death. Time to death measured in months.

Outcome measures

Outcome measures
Measure	Level 1 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 6,000 Aldesleukin) n=10 Participants Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 2 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 60,000 Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 60,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 3 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 600,000 Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.
Overall Survival Estimated Using Kaplan-Meier Curves Level 1	20.4 months Interval 4.0 to 56.0	—	—
Overall Survival Estimated Using Kaplan-Meier Curves Level 2	20.4 months Interval 4.0 to 56.0	—	—
Overall Survival Estimated Using Kaplan-Meier Curves Level 3	20.4 months Interval 4.0 to 56.0	—	—

SECONDARY outcome

Timeframe: Up to three years

Population: The Number of Participants Analyzed for each Row should be specified, since it differs from the Overall Number of Participants Analyzed specified.

As measured by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for targeted lesions; Partial response (PR) - \>= 30% increase in the sum of the longest diameter of target lesions; or stable (SD) - neither sufficient shrinkage to quality for PR nor Sufficient increase to quality PD. Descriptive statistical will be used. Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI).

Outcome measures

Outcome measures
Measure	Level 1 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 6,000 Aldesleukin) n=10 Participants Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 2 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 60,000 Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 60,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 3 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 600,000 Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.
Progressive Free Survival Retaining Progression-free Survival Status up to 36 Months Level 1	0 Participants	—	—
Progressive Free Survival Retaining Progression-free Survival Status up to 36 Months Level 2	0 Participants	—	—
Progressive Free Survival Retaining Progression-free Survival Status up to 36 Months Level 3	0 Participants	—	—

Adverse Events

Level 1 Treatment Pembrolizumab 200mg IV Q3 wk, IL-2 6,000

Serious events: 2 serious events

Other events: 3 other events

Deaths: 3 deaths

Level 2 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 60,000

Serious events: 1 serious events

Other events: 3 other events

Deaths: 2 deaths

Level 3 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 600,000

Serious events: 4 serious events

Other events: 4 other events

Deaths: 4 deaths

Serious adverse events

Serious adverse events
Measure	Level 1 Treatment Pembrolizumab 200mg IV Q3 wk, IL-2 6,000 n=3 participants at risk Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 2 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 60,000 n=3 participants at risk Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 60,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 3 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 600,000 n=4 participants at risk Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 600,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.
Respiratory, thoracic and mediastinal disorders Pleural effusion	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/4 • Up to 30 days after last dose of treatment and up to three years.
Respiratory, thoracic and mediastinal disorders Dyspnea	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/4 • Up to 30 days after last dose of treatment and up to three years.
Gastrointestinal disorders Vomiting	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	25.0% 1/4 • Number of events 2 • Up to 30 days after last dose of treatment and up to three years.
Cardiac disorders Ventricular tachycardia	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 2 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/4 • Up to 30 days after last dose of treatment and up to three years.
Respiratory, thoracic and mediastinal disorders Respiratory Failure	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	50.0% 2/4 • Number of events 2 • Up to 30 days after last dose of treatment and up to three years.
Infections and infestations Infection	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	25.0% 1/4 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.

Other adverse events

Additional Information

Adam Berger, MD

Cancer Institute of New Jersey

Phone: 215-235-8079

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Level 1 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 6,000 n=3 Participants Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 2 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 60,000z n=3 Participants Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 60,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 3 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 600,000 n=4 Participants Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Total n=10 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	8 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	6 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	10 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 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	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	10 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	3 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants	10 participants n=4 Participants

Measure	Level 1 Treatment Pembrolizumab 200mg IV Q3 wk, IL-2 6,000 n=3 participants at risk Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 6,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 2 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 60,000 n=3 participants at risk Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 60,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.	Level 3 Treatment Pembrolizumab 200mg IV Q3 wk IL-2 600,000 n=4 participants at risk Cohort 1: Participants were administered 200mg of Pembrolizumab by an infusion into a vein or central line every three weeks. The infusion time is 30 minutes. Additionally, participants receive IL-2 600,000 International Units per kilogram (IU/kg); in cycles 2, 3, 6,7,10 and 11, with follow up 30 days after the last dose of study drug. Participants will receive Pembrolizumab first followed by IL-2 every 8 hours up to a total of 14 doses.
Cardiac disorders Cardiac disorders - Other, specify	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 2 • Up to 30 days after last dose of treatment and up to three years.	25.0% 1/4 • Number of events 2 • Up to 30 days after last dose of treatment and up to three years.
General disorders General Disorders	100.0% 3/3 • Number of events 8 • Up to 30 days after last dose of treatment and up to three years.	100.0% 3/3 • Number of events 4 • Up to 30 days after last dose of treatment and up to three years.	75.0% 3/4 • Number of events 6 • Up to 30 days after last dose of treatment and up to three years.
Infections and infestations Infections	66.7% 2/3 • Number of events 2 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/4 • Up to 30 days after last dose of treatment and up to three years.
Gastrointestinal disorders Gastro disorder	100.0% 3/3 • Number of events 4 • Up to 30 days after last dose of treatment and up to three years.	66.7% 2/3 • Number of events 8 • Up to 30 days after last dose of treatment and up to three years.	50.0% 2/4 • Number of events 7 • Up to 30 days after last dose of treatment and up to three years.
Investigations Investigations	66.7% 2/3 • Number of events 3 • Up to 30 days after last dose of treatment and up to three years.	66.7% 2/3 • Number of events 16 • Up to 30 days after last dose of treatment and up to three years.	75.0% 3/4 • Number of events 21 • Up to 30 days after last dose of treatment and up to three years.
Metabolism and nutrition disorders Metabolism	33.3% 1/3 • Number of events 2 • Up to 30 days after last dose of treatment and up to three years.	66.7% 2/3 • Number of events 11 • Up to 30 days after last dose of treatment and up to three years.	50.0% 2/4 • Number of events 7 • Up to 30 days after last dose of treatment and up to three years.
Psychiatric disorders Psychiatic	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	75.0% 3/4 • Number of events 10 • Up to 30 days after last dose of treatment and up to three years.
Renal and urinary disorders Renal	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	25.0% 1/4 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.
Skin and subcutaneous tissue disorders skin	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	66.7% 2/3 • Number of events 3 • Up to 30 days after last dose of treatment and up to three years.	50.0% 2/4 • Number of events 6 • Up to 30 days after last dose of treatment and up to three years.
Vascular disorders Vascular	33.3% 1/3 • Number of events 2 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	25.0% 1/4 • Number of events 3 • Up to 30 days after last dose of treatment and up to three years.
Musculoskeletal and connective tissue disorders Muscular Skeleton	66.7% 2/3 • Number of events 3 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	25.0% 1/4 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.
Respiratory, thoracic and mediastinal disorders Respirtory	33.3% 1/3 • Number of events 7 • Up to 30 days after last dose of treatment and up to three years.	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	75.0% 3/4 • Number of events 12 • Up to 30 days after last dose of treatment and up to three years.
Reproductive system and breast disorders Reproductive	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/4 • Up to 30 days after last dose of treatment and up to three years.
Immune system disorders Immune	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/4 • Up to 30 days after last dose of treatment and up to three years.
Blood and lymphatic system disorders Blood	33.3% 1/3 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.	0.00% 0/3 • Up to 30 days after last dose of treatment and up to three years.	25.0% 1/4 • Number of events 1 • Up to 30 days after last dose of treatment and up to three years.