Trial Outcomes & Findings for BIBW 2992 and Letrozole in Hormonoresistant Metastatic Breast Cancer (NCT NCT00708214)

Last Updated: 2013-12-30

Results Overview

Progression was defined according to 1 of the following criteria: New bone lesion(s) on bone scan or on magnetic resonance imaging; Progression or occurrence of new lesion(s) according to the Response Evaluation Criteria In Solid Tumours version 1.0 (RECIST); an increase in tumour marker CA 15.3 of more than 20 percent,compared with baseline, at 2 consecutive examinations; occurrence of disease-related skeletal events. If a patient did not fulfil any criteria and was withdrawn because of clinical deterioration amounting to PD according to the Investigator, they were considered as having PD.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

28 participants

Primary outcome timeframe

16 weeks

Results posted on

2013-12-30

Participant Flow

According to the protocol the starting dose of Afatinib was 50mg/day. This dose was reduced according to the protocol to first 40mg/day and then to 30mg/day due to skin toxicity.

Participant milestones

Participant milestones
Measure	Afatinib 50 mg With Letrozole Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Overall Study STARTED	7	13	8
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	7	13	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Afatinib 50 mg With Letrozole Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Overall Study Other Adverse Event	3	6	2
Overall Study Other	0	1	1
Overall Study Progressive Disease	4	6	5

Baseline Characteristics

BIBW 2992 and Letrozole in Hormonoresistant Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Afatinib 50 mg With Letrozole n=7 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=13 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole n=8 Participants Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Total n=28 Participants Total of all reporting groups
Age, Continuous	63.0 years STANDARD_DEVIATION 14.7 • n=5 Participants	64.8 years STANDARD_DEVIATION 7.2 • n=7 Participants	58.5 years STANDARD_DEVIATION 9.0 • n=5 Participants	62.5 years STANDARD_DEVIATION 10.0 • n=4 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	13 Participants n=7 Participants	8 Participants n=5 Participants	28 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: 16 weeks

Population: Treated set (TS). TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=7 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=13 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole n=8 Participants Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Percentage of Progression Free Participants After 16 Weeks of Treatment	28.57 Percentage of participants Interval 3.67 to 70.96	0.00 Percentage of participants Interval 0.0 to 24.71	25.00 Percentage of participants Interval 3.19 to 65.09

SECONDARY outcome

Timeframe: Baseline till progression

Population: TS

OR was defined as complete response (CR) or partial response (PR) and was assessed according to RECIST criteria regardless of treatment status.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=7 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=13 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole n=8 Participants Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Number of Participants With Confirmed Objective Response (OR)	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 16 weeks and 24 weeks

Population: TS

CB was defined as CR, PR or stable disease (SD) and was assessed according to RECIST criteria regardless of treatment status.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=7 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=13 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole n=8 Participants Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Number of Participants With Clinical Benefit (CB) Participants with CB at 16 weeks	2 Participants	2 Participants	2 Participants
Number of Participants With Clinical Benefit (CB) Participants with CB at 24 weeks	2 Participants	0 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline till progression

Population: TS. Median time to RECIST tumour response was not calculable as there was no OR observed.

The time to OR was the duration from the first treatment to the time when the measurement criteria for CR and/or PR were met according to RECIST criteria.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=7 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=13 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole n=8 Participants Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Time to RECIST Tumour Reponse	NA days Median time to RECIST tumour response was not calculable as there was no OR observed.	NA days Median time to RECIST tumour response was not calculable as there was no OR observed.	NA days Median time to RECIST tumour response was not calculable as there was no OR observed.

SECONDARY outcome

Timeframe: First occurence or OR till progression or death

Population: TS. Median duration of RECIST tumour response was not calculable as there was no OR observed.

Duration of confirmed OR is measured from the time of first OR to the time of progression or death (or date of censoring for progression free survival).

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=7 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=13 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole n=8 Participants Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Duration of Confirmed OR	NA days Median duration of RECIST tumour response was not calculable as there was no OR observed.	NA days Median duration of RECIST tumour response was not calculable as there was no OR observed.	NA days Median duration of RECIST tumour response was not calculable as there was no OR observed.

SECONDARY outcome

Timeframe: Baseline till progression, death or data cut-off (04 Jan 2010)

Population: TS

PFS was defined as the time from the first treatment to the occurrence of tumour progression or death, whichever came first. Progression was assessed according to RECIST criteria.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=7 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=13 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole n=8 Participants Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Progression-free Survival (PFS)	60.0 days Interval 51.0 to 443.0	107.0 days Interval 44.0 to 163.0	79.0 days Interval 21.0 to 230.0

SECONDARY outcome

Timeframe: Baseline till progression, death or data cut-off

Population: TS. Estimation of median time to death was not feasible, due to the small number of patients who died during the trial.

OS was defined as the time from first treatment to death.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=7 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=13 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole n=8 Participants Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Overall Survival (OS)	NA days Interval 208.0 to Estimation of median time to death was not feasible, due to the small number of patients who died during the trial.	NA days Interval 288.0 to Estimation of median time to death was not feasible, due to the small number of patients who died during the trial.	NA days Interval 137.0 to Estimation of median time to death was not feasible, due to the small number of patients who died during the trial.

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.

AUCtau,ss represents the area under the concentration curve of afatinib in plasma over a uniform dosing interval tau at steady state.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=4 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=5 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss)	660 ng*h/mL Geometric Coefficient of Variation 41.3	579 ng*h/mL Geometric Coefficient of Variation 62.8	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.

Cmax,ss represents the maximum measured concentration of afatinib in plasma at steady state.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=4 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=5 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss)	43.8 ng/mL Geometric Coefficient of Variation 42.0	33.9 ng/mL Geometric Coefficient of Variation 79.4	—

SECONDARY outcome

Timeframe: Day 57

Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.

Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=5 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=8 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 57 (Cpre,ss,57)	21.4 ng/mL Geometric Coefficient of Variation 42.3	15.8 ng/mL Geometric Coefficient of Variation 42.1	—

SECONDARY outcome

Timeframe: Day 85

Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.

Cpre,ss,85 represents the pre-dose concentration of afatinib in plasma at steady state on day 85.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=4 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=5 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Pre-dose Concentration of Afatinib in Plasma at Steady Stateon Day 85 (Cpre,ss,85)	16.9 ng/mL Geometric Coefficient of Variation 55.7	17.3 ng/mL Geometric Coefficient of Variation 46.5	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Population: Data were particularly sparse for the 50 mg starting dose group and were not summarised.

tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=4 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=5 Participants Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss)	2.00 hours Full Range 2.00-4.00 • Interval 2.0 to 4.0	4.00 hours Full Range 0.917-7.67 • Interval 0.917 to 7.67	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Population: Analysis of all treatment arms combined, as Letrozole dose was the same in all arms.

AUC0-tau,ss represents the area under the concentration curve of letrozole in plasma over a uniform dosing interval tau at steady state.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=10 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Area Under Curve of Letrozole Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss)	2420 ng*h/mL Geometric Coefficient of Variation 76.2	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Population: Analysis of all treatment arms combined, as Letrozole dose was the same in all arms.

Cmax,ss represents the maximum measured concentration of letrozole in plasma at steady state.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=10 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Maximum Concentration of Letrozole in Plasma at Steady State (Cmax,ss)	135 ng/mL Geometric Coefficient of Variation 70.0	—	—

SECONDARY outcome

Timeframe: 0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Population: Analysis of all treatment arms combined, as Letrozole dose was the same in all arms.

tmax,ss represents the time from dosing to the maximum concentration of letrozole in plasma at steady state.

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=10 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Time From Dosing to the Maximum Concentration of Letrozole in Plasma at Steady State (Tmax,ss)	1.00 hours Interval 0.917 to 23.8	—	—

SECONDARY outcome

Timeframe: baseline and day 29

Population: Analysis of all treatment arms combined for tumor marker analysis.

Change from baseline in Ca15.3 tumor marker levels

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=21 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Change From Baseline in Ca15.3	-4.35 percentage of baseline level Interval -28.4 to 41.8	—	—

SECONDARY outcome

Timeframe: baseline till end of treatment

Best change from baseline in ECOG (Eastern Cooperative Oncology Group) performance status. ECOG is measured as score between 0 (fully active) and 5 (dead). Improvement is a decrease in ECOG score from baseline of at least 1. Deterioration is an increase in ECOG score from baseline of at least 1

Outcome measures

Outcome measures
Measure	Afatinib 50 mg With Letrozole n=28 Participants Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Best Change From Baseline in ECOG Performance Status Improved	4 participants	—	—
Best Change From Baseline in ECOG Performance Status Deteriorated	6 participants	—	—
Best Change From Baseline in ECOG Performance Status Unchanged	16 participants	—	—
Best Change From Baseline in ECOG Performance Status Not done	2 participants	—	—

Adverse Events

Afatinib 50 mg With Letrozole

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

Afatinib 40 mg With Letrozole

Serious events: 3 serious events

Other events: 13 other events

Deaths: 0 deaths

Afatinib 30 mg With Letrozole

Serious events: 5 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Publication restrictions are in place

Restriction type: OTHER

Measure	Afatinib 50 mg With Letrozole n=7 participants at risk Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 40 mg With Letrozole n=13 participants at risk Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Afatinib 30 mg With Letrozole n=8 participants at risk Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Diarrhoea	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Nausea	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Vomiting	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Asthenia	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Mucosal inflammation	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Obstruction	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Oedema peripheral	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Arthritis bacterial	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Erysipelas	14.3% 1/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Pneumococcal sepsis	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Post precedural sepsis	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Sinusitis	14.3% 1/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Metabolism and nutrition disorders Dehydration	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
Musculoskeletal and connective tissue disorders Spinal disorder	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Melanocytic naevus	14.3% 1/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm progression	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
Psychiatric disorders Depression	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
Psychiatric disorders Mood altered	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/13 • First administration of trial medication until 28 days after last administration of trial medication	12.5% 1/8 • First administration of trial medication until 28 days after last administration of trial medication
Renal and urinary disorders Renal failure acute	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication
Vascular disorders Jugular vein thrombosis	0.00% 0/7 • First administration of trial medication until 28 days after last administration of trial medication	7.7% 1/13 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/8 • First administration of trial medication until 28 days after last administration of trial medication