Trial Outcomes & Findings for A Study of Trastuzumab Emtansine (Trastuzumab-MCC-DM1, T-DM1) in Combination With Pertuzumab Administered to Patients With Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Locally Advanced or Metastatic Breast Cancer Who Have Previously Received Trastuzumab (NCT NCT00875979)

Last Updated: 2013-12-24

Results Overview

A patient had an objective response if they had a complete response or a partial response on 2 consecutive occasions ≥ 4 weeks apart. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

67 participants

Primary outcome timeframe

Baseline through the end of the study (up to 2 years 3 months)

Results posted on

2013-12-24

Participant Flow

There were 2 phases in the study, a Dose Escalation phase (Phase 1b) and a Dose Expansion phase (Phase 2a).

Participant milestones

Participant milestones
Measure	Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.
Dose Escalation Phase - 3.0 mg/kg STARTED	3	0
Dose Escalation Phase - 3.0 mg/kg COMPLETED	0	0
Dose Escalation Phase - 3.0 mg/kg NOT COMPLETED	3	0
Dose Escalation Phase - 3.6 mg/kg STARTED	0	6
Dose Escalation Phase - 3.6 mg/kg COMPLETED	0	0
Dose Escalation Phase - 3.6 mg/kg NOT COMPLETED	0	6
Dose Expansion Phase - 3.6 mg/kg STARTED	0	58
Dose Expansion Phase - 3.6 mg/kg COMPLETED	0	11
Dose Expansion Phase - 3.6 mg/kg NOT COMPLETED	0	47

Reasons for withdrawal

Reasons for withdrawal
Measure	Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.
Dose Escalation Phase - 3.0 mg/kg Disease Progression	1	0
Dose Escalation Phase - 3.0 mg/kg Physician Decision	1	0
Dose Escalation Phase - 3.0 mg/kg Patient/Legal Guardian Decision	1	0
Dose Escalation Phase - 3.6 mg/kg Disease Progression	0	6
Dose Expansion Phase - 3.6 mg/kg Disease Progression	0	37
Dose Expansion Phase - 3.6 mg/kg Physician Decision	0	3
Dose Expansion Phase - 3.6 mg/kg Patient/legal Guardian Decision	0	3
Dose Expansion Phase - 3.6 mg/kg Started Non-protocol Anti-Cancer Therapy	0	3
Dose Expansion Phase - 3.6 mg/kg Death	0	1

Baseline Characteristics

A Study of Trastuzumab Emtansine (Trastuzumab-MCC-DM1, T-DM1) in Combination With Pertuzumab Administered to Patients With Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Locally Advanced or Metastatic Breast Cancer Who Have Previously Received Trastuzumab

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg n=3 Participants Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg n=64 Participants Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Total n=67 Participants Total of all reporting groups
Age, Continuous	53.3 years STANDARD_DEVIATION 1.5 • n=5 Participants	52.7 years STANDARD_DEVIATION 10.8 • n=7 Participants	52.7 years STANDARD_DEVIATION 10.5 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	63 Participants n=7 Participants	66 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline through the end of the study (up to 2 years 3 months)

Population: Treated population: All enrolled patients who had baseline measureable disease.

Outcome measures

Outcome measures
Measure	Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg n=3 Participants Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg n=64 Participants Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.
Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)	66.7 Percentage of patients Interval 13.5 to 98.3	40.6 Percentage of patients Interval 28.5 to 53.6

SECONDARY outcome

Timeframe: Baseline through the end of the study (up to 2 years 3 months)

Population: Treated population: All enrolled patients who had baseline measureable disease. Only patients with an objective response were included in the analysis.

Duration of objective response was defined as the time from initial response to disease progression (PD) or death from any cause. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.

Outcome measures

Outcome measures
Measure	Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg n=2 Participants Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg n=26 Participants Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.
Duration of Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)	8.6 Months The confidence interval could not be estimated due to the small sample size.	13.9 Months Interval 6.93 to The upper limit of the confidence interval could not be estimated due to the small sample size.

SECONDARY outcome

Timeframe: Baseline through the end of the study (up to 2 years 3 months)

Population: Treated population: All enrolled patients.

Progression-free survival was defined as the time from randomization to first documented disease progression (PD) or death due to any cause within 30 days of the last treatment, whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.

Outcome measures

Outcome measures
Measure	Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg n=3 Participants Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg n=64 Participants Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.
Progression-free Survival Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)	13.8 Months The confidence interval could not be estimated due to the small sample size.	6.6 Months Interval 4.21 to 9.46

Adverse Events

Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg

Serious events: 22 serious events

Other events: 64 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg n=3 participants at risk Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg n=64 participants at risk Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.
Cardiac disorders Pericardial effusion	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Cardiac disorders Tachycardia	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Nausea	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	3.1% 2/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Vomiting	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	3.1% 2/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	3.1% 2/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Colitis	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Gastritis	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Ileus	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Fatigue	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Pyrexia	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Pain	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Hepatobiliary disorders Hepatic cirrhosis	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Cellulitis	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	4.7% 3/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Breast cellulitis	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Pneumonia	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	4.7% 3/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Osteomyelitis	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Localised infection	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Skin infection	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Staphylococcal bacteraemia	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Metabolism and nutrition disorders Diabetic foot	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Metabolism and nutrition disorders Failure to thrive	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour haemorrhage	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Nervous system disorders Cerebral haemorrhage	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Nervous system disorders Ataxia	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Nervous system disorders Aphasia	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Renal and urinary disorders Renal failure acute	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Renal and urinary disorders Haematuria	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	4.7% 3/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	4.7% 3/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Urinary tract infection	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	1.6% 1/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.

Other adverse events
Measure	Trastuzumab Emtansine 3.0 mg/kg + Pertuzumab 420 mg n=3 participants at risk Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Trastuzumab Emtansine 3.6 mg/kg + Pertuzumab 420 mg n=64 participants at risk Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	32.8% 21/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Blood and lymphatic system disorders Anaemia	66.7% 2/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	10.9% 7/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Blood and lymphatic system disorders Neutropenia	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	7.8% 5/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Eye disorders Lacrimation increased	33.3% 1/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	7.8% 5/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Eye disorders Dry eye	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	6.2% 4/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Nausea	66.7% 2/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	50.0% 32/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	33.3% 1/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	39.1% 25/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Constipation	33.3% 1/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	32.8% 21/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Vomiting	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	28.1% 18/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Dyspepsia	33.3% 1/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	17.2% 11/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	10.9% 7/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Dry mouth	33.3% 1/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	9.4% 6/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Gingival bleeding	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	9.4% 6/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	6.2% 4/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Fatigue	100.0% 3/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	60.9% 39/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Chills	66.7% 2/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	31.2% 20/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Pyrexia	33.3% 1/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	29.7% 19/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Mucosal inflammation	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	25.0% 16/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Asthenia	33.3% 1/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	17.2% 11/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Oedema peripheral	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	10.9% 7/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Chest pain	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	6.2% 4/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
General disorders Influenza like illness	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	6.2% 4/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Urinary tract infection	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	12.5% 8/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Upper respiratory tract infection	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	7.8% 5/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Sinusitis	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	7.8% 5/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Infections and infestations Cellulitis	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	6.2% 4/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Contusion	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	6.2% 4/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Investigations Aspartate aminotransferase increased	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	29.7% 19/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Investigations Alanine aminotransferase increased	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	28.1% 18/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Investigations Blood alkaline phosphatase increased	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	9.4% 6/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Investigations Blood bilirubin increased	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	6.2% 4/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Investigations Haemoglobin decreased	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	6.2% 4/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Metabolism and nutrition disorders Decreased appetite	66.7% 2/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	34.4% 22/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	9.4% 6/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	33.3% 1/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	20.3% 13/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	20.3% 13/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	18.8% 12/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	15.6% 10/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	14.1% 9/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Myalgia	33.3% 1/3 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.	10.9% 7/64 • From informed consent until treatment start (T), serious adverse events (SAE) related to protocol procedures were reported. From the start up to 30 days after the end of T, all AEs and SAEs were reported. Thereafter, only T-related SAEs were reported. Safety population: All patients who received at least 1 dose of study drug.