Trial Outcomes & Findings for ADAM-Afatinib Diarrhea Assessment and Management (NCT NCT01814553)

NCT ID: NCT01814553

Last Updated: 2016-10-31

Results Overview

Overall incidence of patients who experienced diarrhea during the first three courses of afatinib treatment.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

40 participants

Primary outcome timeframe

From first drug administration until 28 days after the end of third treatment course, up to 84 days.

Results posted on

2016-10-31

Participant Flow

PD: Progressive Disease (PD)

Participant milestones

Participant milestones
Measure	Afatinib 40 mg + Loperamide (Cohort 1) Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours.	Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2.
Overall Study STARTED	18	22
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	18	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Afatinib 40 mg + Loperamide (Cohort 1) Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours.	Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2.
Overall Study PD per clinical progression	6	8
Overall Study Other Adverse Event	4	5
Overall Study Withdrawal by Subject	1	1
Overall Study Other than stated	7	8

Baseline Characteristics

ADAM-Afatinib Diarrhea Assessment and Management

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Afatinib 40 mg + Loperamide (Cohort 1) n=18 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours.	Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) n=22 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2.	Total n=40 Participants Total of all reporting groups
Age, Continuous	69.70 Years STANDARD_DEVIATION 10.80 • n=5 Participants	68.00 Years STANDARD_DEVIATION 6.50 • n=7 Participants	68.80 Years STANDARD_DEVIATION 8.62 • n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants	12 Participants n=7 Participants	24 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	10 Participants n=7 Participants	16 Participants n=5 Participants

PRIMARY outcome

Timeframe: From first drug administration until 28 days after the end of third treatment course, up to 84 days.

Population: Treated set

Overall incidence of patients who experienced diarrhea during the first three courses of afatinib treatment.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Loperamide (Cohort 1) n=18 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours.	Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) n=22 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2.
Occurence of CTCAE Grade >= 2 Diarrhea	72.20 Percentage of participants	31.80 Percentage of participants

SECONDARY outcome

Timeframe: From first drug administration until end of third treatment course, up to 84 days.

Population: Treated set

Time to initial onset of diarrhea grade 2 or higher

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Loperamide (Cohort 1) n=13 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours.	Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) n=7 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2.
Time to Initial Onset of Diarrhea Grade 2 or Higher	23.50 days Standard Deviation 22.64	15.40 days Standard Deviation 14.97

SECONDARY outcome

Timeframe: From first drug administration until end of third treatment course, up to 84 days.

Population: Treated set

Duration of first episode of diarrhea grade 2 or higher. Please note that the nine patients experienced diarrhea episodes that were not managed according to the protocol specified afatinib treatment interruptions and dose reductions. No patients were excluded from the primary analysis.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Loperamide (Cohort 1) n=13 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours.	Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) n=7 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2.
Duration of First Episode of Diarrhea Grade 2 or Higher	3.10 days Standard Deviation 4.09	7.60 days Standard Deviation 5.19

SECONDARY outcome

Timeframe: Up to 12 weeks (equivalent to 3 courses)

Population: Treated set

Percentage of participants with grade 2 or higher diarrhea each week for the first 3 cycles of afatinib treatment

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Loperamide (Cohort 1) n=18 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours.	Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) n=22 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2.
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 11 (N=0, 0)	0.00 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 1 (N=2, 1)	11.10 Percentage of participants	4.50 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 2 (N=4, 3)	22.20 Percentage of participants	13.60 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 3 (N=3, 3)	16.70 Percentage of participants	13.60 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 4 (N=6, 2)	33.30 Percentage of participants	9.10 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 5 (N=2, 0)	11.10 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 6 (N=0, 1)	0.00 Percentage of participants	4.80 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 7 (N=2, 1)	11.80 Percentage of participants	5.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 8 (N=3, 0)	17.60 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 9 (N=2, 0)	11.80 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 10 (N=0, 0)	0.00 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 11 (N=2, 0)	11.80 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade 2: Week 12 (N=1, 1)	5.90 Percentage of participants	6.30 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 1 (N=1, 1)	5.60 Percentage of participants	4.50 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 2 (N=2, 2)	11.10 Percentage of participants	9.10 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 3 (N=3, 1)	16.70 Percentage of participants	4.50 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 4 (N=0, 1)	0.00 Percentage of participants	4.50 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 5 (N=0, 0)	0.00 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 6 (N=0, 0)	0.00 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 7 (N=1, 0)	5.90 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 8 (N=0, 0)	0.00 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 9 (N=0, 0)	0.00 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 10 (N=1, 0)	5.90 Percentage of participants	0.00 Percentage of participants
Changes in Intensity of Diarrhea Over Time Grade >=3: Week 12 (N=0, 0)	0.00 Percentage of participants	0.00 Percentage of participants

SECONDARY outcome

Timeframe: Every 08 weeks during the first 6 months of treatment, and every 12 weeks thereafter until the end of treatment.

Population: Treated Set

Progression-free survival (PFS). PFS was defined as the time from the start of treatment to an event occurred. In the analyses for the PFS endpoint, an event was defined as disease progression or death, whichever occurred earlier. Data for patients who did not die or progress during the trial were censored at the time of afatinib discontinuation or transition to commercially available afatinib. Median PFS is estimated using Kaplan-Meier method. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1).

Outcome measures

Outcome measures
Measure	Afatinib 40 mg + Loperamide (Cohort 1) n=18 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours.	Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) n=22 Participants Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2.
PFS	15.40 Months Interval 5.5 to The upper limit was not evaluable due to insufficient patients.	9.90 Months Interval 5.5 to The upper limit was not evaluable due to insufficient patients.

Adverse Events

Afatinib 40 mg + Loperamide (Cohort 1)

Serious events: 10 serious events

Other events: 18 other events

Deaths: 0 deaths

Afatinib 40 mg + Loperamide Prophylactic (Cohort 2)

Serious events: 5 serious events

Other events: 22 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 40 mg + Loperamide (Cohort 1) n=18 participants at risk Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and if any diarrhea was experienced Common Terminology Criteria for Adverse Events (CTCAE Grade 1), 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2 mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours.	Afatinib 40 mg + Loperamide Prophylactic (Cohort 2) n=22 participants at risk Subjects were orally administered with the starting dose of Afatinib Film-coated tablets 40 mg once daily - with possible dose reductions to 30 mg and 20 mg and 2 tablets of loperamide 2 mg daily (i.e., 4 mg daily) starting on Course 1 Day 1. If any diarrhea was experienced (CTCAE Grade 1) by subjects, 2 tablets of loperamide 2 mg were to be taken immediately, followed by 1 tablet of loperamide 2mg with every subsequent loose bowel movement until bowel movements ceased for 12 hours. Subjects who experienced no diarrhea during Course 1 were allowed to reduce the loperamide dose to 2 mg daily and subjects who experienced no diarrhea during the first two courses discontinued daily prophylactic loperamide at the end of Course 2.
Gastrointestinal disorders Diarrhoea	16.7% 3/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Gastrointestinal disorders Diverticular perforation	0.00% 0/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	4.5% 1/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Gastrointestinal disorders Gastritis	0.00% 0/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	4.5% 1/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	4.5% 1/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Gastrointestinal disorders Vomiting	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
General disorders Asthenia	0.00% 0/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	4.5% 1/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
General disorders Oedema peripheral	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Hepatobiliary disorders Cholecystitis	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Infections and infestations Abscess limb	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Infections and infestations Cellulitis	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Infections and infestations Lung infection	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Infections and infestations Sepsis	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Metabolism and nutrition disorders Dehydration	0.00% 0/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	9.1% 2/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Metabolism and nutrition disorders Hypoglycaemia	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	0.00% 0/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	4.5% 1/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Psychiatric disorders Mental status changes	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Renal and urinary disorders Acute kidney injury	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	4.5% 1/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Respiratory, thoracic and mediastinal disorders Pleural effusion	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.
Vascular disorders Deep vein thrombosis	5.6% 1/18 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.	0.00% 0/22 • From first drug administration until 28 days after the end of third treatment course, up to 112 days.