Trial Outcomes & Findings for Trial of Afatinib (BIBW 2992) + Cetuximab in Advanced Solid Tumours (NCT NCT02020577)

NCT ID: NCT02020577

Last Updated: 2017-06-22

Results Overview

Maximum Tolerated Dose (MTD) of Afatinib in combination with cetuximab based on the number of patients with dose limiting toxicity (DLT) during the first treatment cycle (Dose escalation part). The MTD is defined as the highest dose level at which less than 33% of the patients experience DLT in first treatment cycle.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

58 participants

Primary outcome timeframe

First 21 days treatment cycle

Results posted on

2017-06-22

Participant Flow

Uncontrolled, open label, 3+3 dose escalation (Part A) study of afatinib in combination with cetuximab, followed by an expansion phase in 3 cohorts of patients (Part B). Adverse Event (AE). CTCAE: Common Terminology Criteria for Adverse Events

Participant milestones

Participant milestones
Measure	Afatinib 30mg+Cetuximab 250 mg/m² In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.
Overall Study STARTED	3	55
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	3	55

Reasons for withdrawal

Reasons for withdrawal
Measure	Afatinib 30mg+Cetuximab 250 mg/m² In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.
Overall Study Progressive disease	3	38
Overall Study Other AE or clinical progression	0	15
Overall Study Withdrawal by Subject	0	1
Overall Study Other than stated above	0	1

Baseline Characteristics

Trial of Afatinib (BIBW 2992) + Cetuximab in Advanced Solid Tumours

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=55 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Total n=58 Participants Total of all reporting groups
Age, Continuous	63.3 Years STANDARD_DEVIATION 7.6 • n=5 Participants	61.0 Years STANDARD_DEVIATION 11.4 • n=7 Participants	61.1 Years STANDARD_DEVIATION 11.2 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	20 Participants n=7 Participants	20 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	35 Participants n=7 Participants	38 Participants n=5 Participants

PRIMARY outcome

Timeframe: First 21 days treatment cycle

Population: Dose finding cohort treated set: This patient set includes all patients enrolled in part A of the trial who were documented to have taken at least one dose of study medication.

Outcome measures

Outcome measures
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=6 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
MTD of Afatinib in Combination With Cetuximab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib).	NA mg MTD was not determined for this dose group.	40 mg	—

PRIMARY outcome

Timeframe: First 21-day treatment cycle

Population: Dose finding cohort treated set.

Number of Patients With Dose Limiting Toxicity (DLT) Occurring during Cycle 1. The following drug related AEs qualified as DLT: 1\) CTCAE Grade ≥2 decrease in cardiac left ventricular function 2) CTCAE Grade 2 diarrhoea lasting for ≥7 days, despite appropriate use of standard antidiarrheal therapy based on Protocol Amendment 1 dated 22 Oct 2013 3) CTCAE Grade ≥3 diarrhoea despite appropriate use of standard anti-diarrheal therapy for at least 2 days. 4) CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days 5) CTCAE Grade ≥3 rash despite standard medical management. 6) CTCAE Grade ≥3 fatigue lasting more than 7 days. 7) All other AEs of CTCAE Grade ≥3 (except alopecia and allergic reaction) that led to an interruption of afatinib and/or cetuximab dosing for more than 14 days until recovery to baseline or Grade 1, whichever was higher. 8) CTCAE Grade 4 hypomagnesemia or Grade 3 hypomagnesemia with clinically-significant sequelae

Outcome measures

Outcome measures
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=6 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
Dose Limiting Toxicities During Cycle 1	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: First treatment cycle

Population: Dose finding cohort treated set

Maximum Tolerated Dose (MTD) of Afatinib in combination with cetuximab based on the number of patients with DLTs during the first treatment cycle (Dose escalation part).

Outcome measures

Outcome measures
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=6 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
MTD of Afatinib in Combination With Cetuximab Based on the Number of Patients With DLTs During the First Treatment Cycle (Cetuximab).	NA mg/m2 MTD was not determined for this dose group.	250 mg/m2	—

SECONDARY outcome

Timeframe: All treatment cycle (each treatment cycle of 21 days)

Population: Treated Set

Number of patients with DLT occuring during all treatment cycle is presented

Outcome measures

Outcome measures
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=55 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients n=58 Participants Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
Dose Limiting Toxicities During All Treatment Cycles	0 Participants	9 Participants	9 Participants

SECONDARY outcome

Timeframe: All treatment cycle (each treatment cycle of 21 days)

Population: Treated Set

MTD was deemed the recommended Phase II dose based on the number of patients with dose limiting toxicity events at all treatment cycles.

Outcome measures

Outcome measures
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=55 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
Recommended Phase II Dose Based on the Number of Patients With Dose Limiting Toxicity Events (Cetuximab)	NA mg/m2 MTD was not determined for this dose group.	250 mg/m2	—

SECONDARY outcome

Timeframe: Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 19 months

Population: Treated set

Best overall response (according to RECIST version 1.1) was defined as the best response recorded at any time from the first administration of afatinib or cetuximab to the End of Treatment (EOT). As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

Outcome measures

Outcome measures
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=55 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients n=58 Participants Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
Best Overall Response Complete Response (CR)	0.0 Percentage of participants	0.0 Percentage of participants	0.0 Percentage of participants
Best Overall Response Partial Response (PR)	0.0 Percentage of participants	0.0 Percentage of participants	0.0 Percentage of participants
Best Overall Response Stable Disease (SD)	66.7 Percentage of participants	52.7 Percentage of participants	53.4 Percentage of participants
Best Overall Response Progressive disease (PD)	33.3 Percentage of participants	34.5 Percentage of participants	34.5 Percentage of participants
Best Overall Response Not evaluable (NE)/Missing	0.0 Percentage of participants	12.7 Percentage of participants	12.1 Percentage of participants

SECONDARY outcome

Timeframe: Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 19 months

Population: Treated set

Objective response was defined as the proportion of patients with measurable disease having at least a best overall response of complete response (CR) or partial response (PR), according to RECIST version 1.1. As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

Outcome measures

Outcome measures
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=55 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients n=58 Participants Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
Objective Response	0.0 Percentage of participants	0.0 Percentage of participants	0.0 Percentage of participants

SECONDARY outcome

Timeframe: Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 19 months

Population: Treated set

For patients with measurable disease, disease control was defined as the proportion of patients having at least a best overall response of CR, PR or stable disease (SD). As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression

Outcome measures

Outcome measures
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=55 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients n=58 Participants Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
Disease Control Rate	66.7 Percentage of participants	52.7 Percentage of participants	53.4 Percentage of participants

SECONDARY outcome

Timeframe: All treatment cycle (each treatment cycle of 21 days)

Population: Treated Set

MTD was deemed the recommended Phase II dose based on the number of patients with dose limiting toxicity events at all treatment cycles.

Outcome measures

Outcome measures
Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 Participants In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=55 Participants In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
Recommended Phase II Dose Based on the Number of Patients With Dose Limiting Toxicity Events (Afatinib)	NA mg MTD was not determined for this dose group.	40 mg	—

Adverse Events

Afatinib 30mg+Cetuximab 250 mg/m²

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Afatinib 40mg+Cetuximab 250 mg/m²

Serious events: 31 serious events

Other events: 54 other events

Deaths: 0 deaths

All Patients

Serious events: 32 serious events

Other events: 57 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

Measure	Afatinib 30mg+Cetuximab 250 mg/m² n=3 participants at risk In each 21 day treatment cycle, patients were administered 30 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	Afatinib 40mg+Cetuximab 250 mg/m² n=55 participants at risk In each 21 day treatment cycle, patient were administered 40 mg Film-coated tablet daily afatinib in combination with cetuximab. An initial loading dose of cetuximab 400 mg/m2 was administered intravenously at Day1 Cycle1, followed by cetuximab 250mg/m² weekly dose.	All Patients n=58 participants at risk Patients who were administered Afatinib 30mg+cetuximab 250 mg/m² plus the patients who were administered Afatinib 40mg+cetuximab 250 mg/m².
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Blood and lymphatic system disorders Febrile bone marrow aplasia	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Ear and labyrinth disorders Deafness	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Ear and labyrinth disorders Deafness unilateral	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.6% 2/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.4% 2/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Gastrointestinal disorders Dysphagia	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Gastrointestinal disorders Gastrointestinal obstruction	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Gastrointestinal disorders Haematemesis	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Gastrointestinal disorders Vomiting	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
General disorders Asthenia	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.6% 2/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.4% 2/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
General disorders Mucosal inflammation	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Immune system disorders Hypersensitivity	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Infections and infestations Bacterial infection	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Infections and infestations Cellulitis	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Infections and infestations Device related infection	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Infections and infestations Respiratory tract infection	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.6% 2/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.4% 2/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Infections and infestations Sepsis	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	5.5% 3/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	5.2% 3/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Infections and infestations Urinary tract infection	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Injury, poisoning and procedural complications Upper limb fracture	33.3% 1/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	0.00% 0/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Metabolism and nutrition disorders Dehydration	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	5.5% 3/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	5.2% 3/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.6% 2/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.4% 2/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.6% 2/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.4% 2/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.6% 2/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.4% 2/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	33.3% 1/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	9.1% 5/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	10.3% 6/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lung	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour haemorrhage	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Nervous system disorders Cognitive disorder	33.3% 1/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	0.00% 0/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Nervous system disorders Nervous system disorder	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Renal and urinary disorders Acute kidney injury	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Renal and urinary disorders Proteinuria	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Renal and urinary disorders Renal failure	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Renal and urinary disorders Urinary retention	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Reproductive system and breast disorders Female genital tract fistula	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Respiratory, thoracic and mediastinal disorders Bronchostenosis	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.6% 2/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.4% 2/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Skin and subcutaneous tissue disorders Dermatitis acneiform	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Skin and subcutaneous tissue disorders Rash	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.6% 2/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.4% 2/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Vascular disorders Deep vein thrombosis	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Vascular disorders Lymphoedema	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.6% 2/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	3.4% 2/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Eye disorders Ophthalmoplegia	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.
Infections and infestations Staphylococcal infection	0.00% 0/3 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.8% 1/55 • From first drug administration until 28 days after last drug administration, up to 19 months.	1.7% 1/58 • From first drug administration until 28 days after last drug administration, up to 19 months.