Trial Outcomes & Findings for Volasertib + Decitabine in Patients With Acute Myeloid Leukemia (AML) (NCT NCT02003573)

NCT ID: NCT02003573

Last Updated: 2019-01-31

Results Overview

The primary objective of the dose-escalation part of this study was to determine the MTD of volasertib in combination with decitabine. The MTD was to be identified based on the DLT information collected during the first treatment cycle of each dosing schedule. DLT was defined as a non-haematological drug-related toxicity of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3. The MTD corresponded to the highest dose of volasertib and decitabine at which the incidence of DLT was ≤17% (i.e. 1/6 patients) during Cycle 1.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

13 participants

Primary outcome timeframe

4 weeks

Results posted on

2019-01-31

Participant Flow

It was originally planned to enter 127 patients into this trial; however, the development of volasertib was discontinued during the conduct of the study.

Participant milestones

Participant milestones
Measure	Volasertib 300 mg + Decitabine Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 300 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 350 mg + Decitabine Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 350 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 400 mg + Decitabine Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 400 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.
Overall Study STARTED	3	4	6
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	3	4	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Volasertib 300 mg + Decitabine Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 300 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 350 mg + Decitabine Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 350 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 400 mg + Decitabine Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 400 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.
Overall Study Progressive disease	2	0	1
Overall Study Other Adverse event	0	1	1
Overall Study Refuse to take trial medication	0	1	1
Overall Study Other than specified	1	2	3

Baseline Characteristics

Volasertib + Decitabine in Patients With Acute Myeloid Leukemia (AML)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Volasertib 300 mg + Decitabine n=3 Participants Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 300 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 350 mg + Decitabine n=4 Participants Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 350 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 400 mg + Decitabine n=6 Participants Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 400 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Total n=13 Participants Total of all reporting groups
Age, Continuous	71.0 years n=99 Participants	76.0 years n=107 Participants	69.5 years n=206 Participants	73.0 years n=7 Participants
Sex: Female, Male Female	3 Participants n=99 Participants	1 Participants n=107 Participants	2 Participants n=206 Participants	6 Participants n=7 Participants
Sex: Female, Male Male	0 Participants n=99 Participants	3 Participants n=107 Participants	4 Participants n=206 Participants	7 Participants n=7 Participants

PRIMARY outcome

Timeframe: 4 weeks

Population: TS. One patient treated with volasertib 350 mg + decitabine had to be excluded because they did not receive all planned doses of volasertib and could therefore not be included in the calculation of MTD. Thus overall 12 patients were analysed instead of 13 patients.

Outcome measures

Outcome measures
Measure	Volasertib + Decitabine n=12 Participants Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 350 mg + Decitabine Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 350 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 400 mg + Decitabine Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 400 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.
Determination of the Maximum Tolerated Dose (MTD) Based on the Occurrence of Dose-limiting Toxicity (DLT) in Cycle 1	400 Milligram (mg)	—	—

PRIMARY outcome

Timeframe: 4 weeks

Population: TS. One patient treated with volasertib 350 mg + decitabine had to be excluded because they did not receive all planned doses of volasertib and could therefore not be included in the calculation of MTD. Thus 3 patients were analysed instead of 4 patients for volasertib 350 mg + decitabine arm.

Number of subjects with Dose Limiting Toxicities (DLT) in Cycle 1 is presented

Outcome measures

Outcome measures
Measure	Volasertib + Decitabine n=3 Participants Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 350 mg + Decitabine n=3 Participants Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 350 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 400 mg + Decitabine n=6 Participants Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 400 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.
Number of Subjects With Dose Limiting Toxicities (DLT) in Cycle 1	0 participant	0 participant	1 participant

Adverse Events

Volasertib 300 mg + Decitabine

Serious events: 3 serious events

Other events: 3 other events

Deaths: 0 deaths

Volasertib 350 mg + Decitabine

Serious events: 4 serious events

Other events: 4 other events

Deaths: 0 deaths

Volasertib 400 mg + Decitabine

Serious events: 6 serious events

Other events: 6 other events

Deaths: 0 deaths

Total

Serious events: 13 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	Volasertib 300 mg + Decitabine n=3 participants at risk Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 300 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 350 mg + Decitabine n=4 participants at risk Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 350 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Volasertib 400 mg + Decitabine n=6 participants at risk Patients were treated according to dosing Schedule A in which decitabine (Dacogen®; solution for infusion) 20 mg/m2 was to be administered (Intravenous infusion) for the first 5 consecutive days of the treatment cycle (Day 1 to Day 5). Volasertib 400 mg (solution for infusion) was administered (Intravenous infusion) on Days 1 and 15 of the treatment cycle. The duration of a treatment cycle was 28 days. Number of treatment cycles was unlimited until the patient met criteria for stopping study medication.	Total n=13 participants at risk Total of all arms
Blood and lymphatic system disorders Anaemia	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	50.0% 2/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Blood and lymphatic system disorders Leukopenia	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Blood and lymphatic system disorders Thrombocytopenia	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Cardiac disorders Sinus tachycardia	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Eye disorders Conjunctival haemorrhage	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Eye disorders Dry eye	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Eye disorders Retinal haemorrhage	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Abdominal tenderness	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Constipation	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	33.3% 2/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	23.1% 3/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Diarrhoea	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	33.3% 2/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	30.8% 4/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Dyspepsia	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Dysphagia	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	50.0% 2/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Flatulence	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Gingival bleeding	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Gingival pain	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Melaena	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Mouth haemorrhage	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Nausea	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	50.0% 2/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	30.8% 4/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Oral mucosa haematoma	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Oral pain	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Gastrointestinal disorders Vomiting	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	33.3% 2/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	23.1% 3/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Asthenia	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	50.0% 2/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	23.1% 3/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Chest pain	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Chills	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Face oedema	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Fatigue	66.7% 2/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	23.1% 3/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Mucosal inflammation	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Oedema	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Oedema peripheral	66.7% 2/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Pain	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
General disorders Pyrexia	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	25.0% 1/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Infections and infestations Anal infection	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Infections and infestations Bacteraemia	66.7% 2/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	15.4% 2/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Infections and infestations Bacterial infection	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Infections and infestations Enterococcal bacteraemia	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Infections and infestations Hordeolum	33.3% 1/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days
Infections and infestations Klebsiella bacteraemia	0.00% 0/3 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	0.00% 0/4 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	16.7% 1/6 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days	7.7% 1/13 • All Adverse events with an onset after the first dose of study medication up to a period of 30 days after the last administration of study medication; up to 333 days