Trial Outcomes & Findings for IL-12 Gene and in Vivo Electroporation-Mediated Plasmid DNA Vaccine Therapy in Patients With Merkel Cell Cancer (NCT NCT01440816)

Last Updated: 2023-05-15

Results Overview

The MAGPIX assay was used to assess differential expression of hIL-12 in patient tumor tissue before and after treatment with intratumoral (IT) tavo injections and in vivo electroporation (EP). Expression of hIL-12 was used to identify patients who met the primary endpoint of a 2-fold or higher increase in expression of hIL-12 in tumors after treatment. Fold change was taken as a comparison of hIL-12 expression at Week 3:pre-treatment, Week 6:pre-treatment, Week 8:pre-treatment, or Week 13:pre-treatment over baseline (pre- treatment). The fold change was calculated as log2 (time point/baseline).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

15 participants

Primary outcome timeframe

Pre-treatment up to Week 13

Results posted on

2023-05-15

Participant Flow

Participants were enrolled at 1 investigative site in the United States from 03 January 2012 to 10 April 2015.

Participant milestones

Participant milestones
Measure	Cohort A: Tavo-EP Patients in Cohort A received one cycle (3 daily treatments on Days 1, 5, and 8) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, after which they proceeded to definitive treatment (surgery and/or radiation therapy) which started between 2 and 4 weeks after the first injection.	Cohort B: Tavo-EP Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Overall Study STARTED	3	12
Overall Study COMPLETED	2	1
Overall Study NOT COMPLETED	1	11

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort A: Tavo-EP Patients in Cohort A received one cycle (3 daily treatments on Days 1, 5, and 8) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, after which they proceeded to definitive treatment (surgery and/or radiation therapy) which started between 2 and 4 weeks after the first injection.	Cohort B: Tavo-EP Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Overall Study Disease Progression	0	9
Overall Study To Be Seen By Local Oncologist	1	2

Baseline Characteristics

IL-12 Gene and in Vivo Electroporation-Mediated Plasmid DNA Vaccine Therapy in Patients With Merkel Cell Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort A: Tavo-EP n=3 Participants Patients in Cohort A received one cycle (3 daily treatments on Days 1, 5, and 8) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, after which they proceeded to definitive treatment (surgery and/or radiation therapy) which started between 2 and 4 weeks after the first injection.	Cohort B: Tavo-EP n=12 Participants Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.	Total n=15 Participants Total of all reporting groups
Age, Continuous	60.7 years STANDARD_DEVIATION 11.59 • n=5 Participants	68.7 years STANDARD_DEVIATION 12.08 • n=7 Participants	67.1 years STANDARD_DEVIATION 12.03 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	9 Participants n=7 Participants	12 Participants n=5 Participants
Region of Enrollment United States	3 Participants n=5 Participants	12 Participants n=7 Participants	15 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-treatment up to Week 13

Population: Efficacy Analysis Set, all patients from Cohort B who received any amount of the study drug (tavo).

Outcome measures

Outcome measures
Measure	Cohort B: Tavo-EP n=12 Participants Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.	Cohort B: Tavo-EP Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Percentage of Participants Who Experienced At Least 2-Fold Increase in Expression of IL-12 Protein in the Tumor Tissue After Intratumoral (IT) pIL-12 Injections and In Vivo Electroporation	83 percentage of participants	—

SECONDARY outcome

Timeframe: From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months)

Population: Safety Analysis Set, all patients who received any amount of the study drug (tavo).

An AE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, medical treatment or procedure and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could have, therefore, been any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, medical treatment or procedure whether or not considered related to the medicinal product. An SAE was defined an any untoward medical occurrence that at any dosage resulted in one or more of the following: death, A life-threatening adverse event (real risk of dying), inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly, required intervention to prevent permanent impairment of damage.

Outcome measures

Outcome measures
Measure	Cohort B: Tavo-EP n=3 Participants Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.	Cohort B: Tavo-EP n=12 Participants Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	100 percentage of participants	100 percentage of participants
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	0 percentage of participants	8.3 percentage of participants

SECONDARY outcome

Timeframe: 3-4 weeks after the first dose in each cycle and then every 3 months until disease progression, death or withdrawal of consent (up to 15 months)

Population: Efficacy Analysis Set, all patients from Cohort B who received any amount of the study drug (tavo) and had evaluable lesions.

ORR is defined as the percentage of participants with evaluable lesions that achieved a complete response (CR) or partial response (PR) as assessed by the investigator using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. The same method was used to assess response rate for treated lesions and response rate for non-treated lesions. The best response rate for non-treated lesions was based on the number of patients who had at least one non-treated lesion.

Outcome measures

Outcome measures
Measure	Cohort B: Tavo-EP n=12 Participants Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.	Cohort B: Tavo-EP Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Objective Response Rate (ORR) in Injected and Non-injected (Distant) Lesions Injected Lesions	33.3 percentage of participants	—
Objective Response Rate (ORR) in Injected and Non-injected (Distant) Lesions Non-Injected Lesions	20.0 percentage of participants	—

SECONDARY outcome

Timeframe: 3-4 weeks after the first dose in each cycle and then every 3 months until disease progression, death or withdrawal of consent (up to 15 months)

Population: Efficacy Analysis Set, all patients from Cohort B who received any amount of the study drug (tavo) and had document disease progression.

TTP is defined as the number of days between the treatment initiation date (Study Day 1) and the earliest date of documented disease progression as defined by RECIST 1.1 or death that is not associated with prior disease progression. 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.

Outcome measures

Outcome measures
Measure	Cohort B: Tavo-EP n=10 Participants Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.	Cohort B: Tavo-EP Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Time to Progression (TTP)	52.5 days Interval 42.0 to 84.0	—

SECONDARY outcome

Timeframe: From the start of study treatment until death (up to 15 months)

Population: Efficacy Analysis Set, all patients who received any amount of the study drug (tavo). Zero participants were analyzed for overall survival because all patients were alive at their study completion visit.

Overall survival is defined as the time in days from the date of first study drug administration to the date of death.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Pre-treatment up to Week 13

Population: Efficacy Analysis Set, all patients from Cohort B who received any amount of the study drug (tavo) and had evaluable lesions.

Nanostring analysis was performed to determine the expression (mRNA) of IL-12. For each study patient, the fold change (log2 transformed) in IL-12A mRNA as measured by Nanostring was determined using the pre-treatment (screening) biopsy as a reference for the post treatment biopsy. A log2 fold change \>=1 is a positive result.

Outcome measures

Outcome measures
Measure	Cohort B: Tavo-EP n=6 Participants Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.	Cohort B: Tavo-EP Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Immunologic Effects of IT pIL-12 Injection and In Vivo EP Measured By: Percentage of Participants With a Positive Fold Change (Log2) in IL-12A Messenger Ribonucleic Acid (mRNA) for Patient Pre- and Post IT pIL 12 EP	66.6 percentage of participants	—

SECONDARY outcome

Timeframe: 3-4 weeks after the first dose in each cycle and then every 3 months until disease progression, death or withdrawal of consent (up to 15 months)

Population: All patients from Cohorts A and B with evaluable lesions.

Local regression rate is defined as the percentage of participants with ≥30% regression (decrease in size) of at least one assessed local (injected) lesion.

Outcome measures

Outcome measures
Measure	Cohort B: Tavo-EP n=15 Participants Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.	Cohort B: Tavo-EP Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Local Regression Rate	45.5 percentage of participants	—

SECONDARY outcome

Timeframe: 3-4 weeks after the first dose in each cycle and then every 3 months until disease progression, death or withdrawal of consent (up to 15 months)

Population: All patients from Cohorts A and B with evaluable lesions.

Distant regression rate is defined as the percentage of participants with ≥30% regression (decrease in size) of at least one assessed distant (non-injected) lesion.

Outcome measures

Outcome measures
Measure	Cohort B: Tavo-EP n=12 Participants Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.	Cohort B: Tavo-EP Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Distant Regression Rate	22.2 percentage of participants	—

Adverse Events

Cohort A: Tavo-EP

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Cohort B: Tavo-EP

Serious events: 1 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Cohort A: Tavo-EP n=3 participants at risk Patients in Cohort A received one cycle (3 daily treatments on Days 1, 5, and 8) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, after which they proceeded to definitive treatment (surgery and/or radiation therapy) which started between 2 and 4 weeks after the first injection.	Cohort B: Tavo-EP n=12 participants at risk Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Infections and infestations Urinary tract infection	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).

Other adverse events

Additional Information

Sharron E Gargosky, Chief Clinical Regulatory Officer

OncoSec Medical Incorporated

Phone: +1 858-255-4729

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Cohort A: Tavo-EP n=3 participants at risk Patients in Cohort A received one cycle (3 daily treatments on Days 1, 5, and 8) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, after which they proceeded to definitive treatment (surgery and/or radiation therapy) which started between 2 and 4 weeks after the first injection.	Cohort B: Tavo-EP n=12 participants at risk Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 weeks planned between each cycle, lasting up to 12 months.
Injury, poisoning and procedural complications Procedural pain	100.0% 3/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	100.0% 12/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Injury, poisoning and procedural complications Contusion	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Injury, poisoning and procedural complications Seroma	33.3% 1/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	0.00% 0/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Injection site inflammation	66.7% 2/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	50.0% 6/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Injection site discolouration	33.3% 1/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	33.3% 4/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Fatigue	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	25.0% 3/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Injection site bruising	33.3% 1/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	16.7% 2/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Injection site erythema	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Injection site haematoma	33.3% 1/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	0.00% 0/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Injection site necrosis	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Oedema peripheral	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Pain	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Peripheral swelling	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
General disorders Pyrexia	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Infections and infestations Injection site cellulitis	33.3% 1/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	16.7% 2/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Infections and infestations Lung infection	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Infections and infestations Oral herpes	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Infections and infestations Pneumonia	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Gastrointestinal disorders Constipation	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Gastrointestinal disorders Vomiting	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatocellular carcinoma	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	33.3% 1/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	0.00% 0/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Blood and lymphatic system disorders Lymph node pain	33.3% 1/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	0.00% 0/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Cardiac disorders Atrial fibrillation	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Eye disorders Diplopia	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Metabolism and nutrition disorders Decreased appetite	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Psychiatric disorders Insomnia	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).
Vascular disorders Lymphoedema	0.00% 0/3 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).	8.3% 1/12 • From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months).