Trial Outcomes & Findings for A Multi-centre 3-arm Randomised Phase II Trial of BIBF 1120 Versus BIBW 2992 Versus Sequential Administration of BIBF 1120 and BIBW 2992 in Patients With Hormone-resistant Prostate Cancer (NCT NCT00706628)

Last Updated: 2015-01-15

Results Overview

PFR is defined as a composite endpoint for disease progression. If patients met one of the following criteria they were counted as having progressive disease (PD): * Prostate serum antigen (PSA) progression according to Prostate-Specific Antigen Working Group (PSAWG) criteria * Bone metastasis progression- development of new lesions on bone scan or development of disease-related skeletal related events (SREs) * Disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

87 participants

Primary outcome timeframe

12 weeks

Results posted on

2015-01-15

Participant Flow

Participant milestones

Participant milestones
Measure	BIBF 1120 Monotherapy 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events (AE) reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Overall Study STARTED	47	21	16	3
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	47	21	16	3

Reasons for withdrawal

Reasons for withdrawal
Measure	BIBF 1120 Monotherapy 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events (AE) reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Overall Study Other Adverse Event	16	5	5	2
Overall Study Non compliant with protocol	0	1	0	0
Overall Study Consent withdrawn	6	1	3	0
Overall Study Progressive disease	20	13	8	1
Overall Study Other than those stated above	4	0	0	0
Overall Study Not treated	1	1	0	0

Baseline Characteristics

A Multi-centre 3-arm Randomised Phase II Trial of BIBF 1120 Versus BIBW 2992 Versus Sequential Administration of BIBF 1120 and BIBW 2992 in Patients With Hormone-resistant Prostate Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BIBF 1120 Monotherapy n=46 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=20 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=16 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 n=3 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	Total n=85 Participants Total of all reporting groups
Age, Continuous	67.7 years STANDARD_DEVIATION 8.1 • n=93 Participants	68.4 years STANDARD_DEVIATION 5.4 • n=4 Participants	70.4 years STANDARD_DEVIATION 8.1 • n=27 Participants	68.3 years STANDARD_DEVIATION 0.6 • n=483 Participants	68.4 years STANDARD_DEVIATION 7.4 • n=36 Participants
Sex: Female, Male Female	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Sex: Female, Male Male	46 Participants n=93 Participants	20 Participants n=4 Participants	16 Participants n=27 Participants	3 Participants n=483 Participants	85 Participants n=36 Participants

PRIMARY outcome

Timeframe: 12 weeks

Population: Modified full analysis set(mFAS): Patients who received at least 1 dose of study medication and for whom progression status could be determined at 12 weeks,excluding patients who discontinued treatment before 12 weeks for reasons other than PD.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=27 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=12 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=10 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 n=1 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Progression Free Rate (PFR) at 12 Weeks	25.9 percentage of participants Interval 13.17 to 44.68	0.0 percentage of participants Interval 0.0 to 24.25	0.0 percentage of participants Interval 0.0 to 27.75	NA percentage of participants Not calculated to avoid reporting patient level data as only 1 patient had evaluable data

SECONDARY outcome

Timeframe: 24 weeks and 48 weeks

Population: Full analysis set (FAS), which consisted of all patients who received at least 1 dose of study medication and for whom progression status could be determined at 12 weeks.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=27 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=13 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=10 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Progression Free Rate at 24 and 48 Weeks 24 weeks	22.2 percentage of participants Interval 10.61 to 40.76	0.0 percentage of participants Interval 0.0 to 22.81	0.0 percentage of participants Interval 0.0 to 27.75	—
Progression Free Rate at 24 and 48 Weeks 48 weeks	18.5 percentage of participants Interval 8.18 to 36.7	0.0 percentage of participants Interval 0.0 to 22.81	0.0 percentage of participants Interval 0.0 to 27.75	—

SECONDARY outcome

Timeframe: End of trial visit, 29 ± 1 days after Day 1 of the last treatment cycle (Up to 48 weeks)

Population: FAS

PSA response was evaluated according to the PSAWG guidelines. All patients achieving a fall in PSA of ≥50% from baseline (confirmed with a second value at least 4 weeks later) fulfilled the criteria for PSA response. The confirmatory value had to be at least 50% lower than the baseline value, but could be higher than the original drop in PSA (first PSA value). However, the confirmatory value could not be 50% higher than the first PSA value. If it was ≥50% higher than the first PSA, another sample was taken to determine if response had been achieved.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=27 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=13 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=10 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Number of Patients Showing Prostate Serum Antigen (PSA) Response Response	3.7 percentage of participants	0.0 percentage of participants	10.0 percentage of participants	—
Number of Patients Showing Prostate Serum Antigen (PSA) Response No Response	96.3 percentage of participants	100.0 percentage of participants	90.0 percentage of participants	—

SECONDARY outcome

Timeframe: End of trial visit, 29 ± 1 days after Day 1 of the last treatment cycle (Up to 48 weeks)

Population: FAS

Duration of PSA response was calculated from the time of first 50% decline in PSA (compared to baseline) until the time at which there was an increase of 50% from the PSA nadir, provided that the absolute increase was at least 5 ng/mL. The increase had to be confirmed by a second consecutive measurement that was at least 50% above the nadir. If the PSA never showed a 50% increase over the nadir value, then the patient was censored at the last PSA measurement. Duration of PSA response expressed in median number of days.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=27 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=13 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=10 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Duration of PSA Response	NA days Not Applicable (NA) as only 1 patient had PSA response therefore the median and Inter-Quartile Range were not estimable using the Kaplan-Meier method. All other patients were censored.	NA days NA as all patients censored	NA days Not Applicable (NA) as only 1 patient had PSA response therefore the median and Inter-Quartile Range were not estimable using the Kaplan-Meier method. All other patients were censored.	—

SECONDARY outcome

Timeframe: Start of treatment until end of treatment (Up to 48 weeks)

Population: FAS

Time to PSA progression through 48 weeks was calculated as the number of days from first administration of study drug to the first time that there was an increase of 50% from the PSA nadir, provided the absolute increase was at least 5 ng/mL. Time is expressed in median number of days.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=27 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=13 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=10 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Time to PSA Progression	31.0 days Interval 29.0 to 84.0	29.0 days Interval 29.0 to 57.0	57.0 days Interval 29.0 to 84.0	—

SECONDARY outcome

Timeframe: 12, 24, 36, and 48 weeks

Population: FAS (RECIST evaluable set); RECIST evaluable set, which consisted of patients who had RECIST measurable disease at baseline.

RECIST (version 1.0) tumour progression rate at 12, 24, 36, and 48 weeks was calculated based on the occurrence of new lesions, or an increase in the sum of the longest lesion diameters of at least 20%.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=12 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=8 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=7 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks 12 weeks (N=12, 8, 7)	8.3 percentage of participants	50.0 percentage of participants	42.9 percentage of participants	—
RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks 24 weeks (N=6, 1, 1)	50.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants	—
RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks 36 weeks (N=3, 0, 0)	33.3 percentage of participants	NA percentage of participants Not Available (NA) as 0 participants analyzed	NA percentage of participants NA as 0 participants analyzed	—
RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks 48 weeks (N=2, 0, 0)	50.0 percentage of participants	NA percentage of participants NA as 0 participants analyzed	NA percentage of participants NA as 0 participants analyzed	—

SECONDARY outcome

Timeframe: 12, 24, 36 and 48 weeks

Population: FAS (RECIST evaluable set)

Objective response is defined as a Complete or Partial response Complete response \[CR\] for Target lesions: Disappearance of all target lesions. Complete response \[CR\] for Non- target lesions: Disappearance of all non-target lesions and normalization of tumour marker level Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=12 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=8 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=7 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks 12 weeks (N=12, 8, 7)	8.3 percentage of participants	0.0 percentage of participants	0.0 percentage of participants	—
Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks 24 weeks (N=6, 1, 1)	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants	—
Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks 36 weeks (N=3, 0, 0)	0.0 percentage of participants	NA percentage of participants Not Available (NA) as 0 participants analyzed	NA percentage of participants NA as 0 participants analyzed	—
Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks 48 weeks (N=2, 0, 0)	0.0 percentage of participants	NA percentage of participants NA as 0 participants analyzed	NA percentage of participants NA as 0 participants analyzed	—

SECONDARY outcome

Timeframe: Up to 48 weeks

Population: FAS (RECIST evaluable set)

Time from first observation of response (PR, CR, confirmed or unconfirmed) until progression according to RECIST (version 1.0) or death. Duration is expressed in Median number of days.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=12 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=8 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=7 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Duration of RECIST Response	116.0 days Interval 116.0 to 116.0	NA days Not Applicable (NA) as 0 patients had RECIST response therefore the median and Inter-Quartile Range were not estimable using the Kaplan-Meier method. All patients were censored.	NA days Not Applicable (NA) as 0 patients had RECIST response therefore the median and Inter-Quartile Range were not estimable using the Kaplan-Meier method. All patients were censored.	—

SECONDARY outcome

Timeframe: start of treatment until end of the treatment (Up to 48 weeks)

Population: FAS

Time from first administration of study drug until disease progression according to composite endpoint. Time is expressed in Median number of days.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=27 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=13 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=10 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Time to Progression	31.0 days Interval 29.0 to 84.0	29.0 days Interval 29.0 to 54.0	57.0 days Interval 29.0 to 78.0	—

SECONDARY outcome

Timeframe: start of treatment until 28 days after end of treatment (Up to 52 weeks)

Population: FAS

Overall survival (time to death) was calculated in days from baseline to the date of reporting of death. Time is expressed in Median number of days.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=27 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=13 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=10 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Overall Survival (Time to Death)	NA days Not Applicable (NA) as all patients censored	NA days NA as all patients censored	NA days NA as all patients censored	—

SECONDARY outcome

Timeframe: from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)

Population: Treated Set

Incidence and worst intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=46 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=20 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=16 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 n=3 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Incidence and Worst Intensity of Adverse Events With Grading According CTCAE CTCAE Grade 1	26.1 percentage of participants	0.0 percentage of participants	37.5 percentage of participants	0.0 percentage of participants
Incidence and Worst Intensity of Adverse Events With Grading According CTCAE CTCAE Grade 2	30.4 percentage of participants	55.0 percentage of participants	18.8 percentage of participants	33.3 percentage of participants
Incidence and Worst Intensity of Adverse Events With Grading According CTCAE CTCAE Grade 3	37.0 percentage of participants	40.0 percentage of participants	37.5 percentage of participants	66.7 percentage of participants
Incidence and Worst Intensity of Adverse Events With Grading According CTCAE CTCAE Grade 4	6.5 percentage of participants	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Incidence and Worst Intensity of Adverse Events With Grading According CTCAE CTCAE Grade 5	0.0 percentage of participants	5.0 percentage of participants	6.3 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)

Population: Treated Set

Changes in safety laboratory Parameters reported as adverse events

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=46 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=20 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=16 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 n=3 Participants Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Changes in Safety Laboratory Parameters Alanine aminotransferase increased	17.4 percentage of participants	5.0 percentage of participants	18.8 percentage of participants	33.3 percentage of participants
Changes in Safety Laboratory Parameters Gamma-glutamyltransferase increased	4.3 percentage of participants	0.0 percentage of participants	12.5 percentage of participants	33.3 percentage of participants
Changes in Safety Laboratory Parameters Aspartate aminotransferase increased	10.9 percentage of participants	0.0 percentage of participants	18.8 percentage of participants	0.0 percentage of participants
Changes in Safety Laboratory Parameters Blood urea increased	2.2 percentage of participants	10.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Changes in Safety Laboratory Parameters Blood creatinine increased	2.2 percentage of participants	5.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Changes in Safety Laboratory Parameters Blood potassium decreased	0.0 percentage of participants	5.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Changes in Safety Laboratory Parameters Transaminases increased	4.3 percentage of participants	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Changes in Safety Laboratory Parameters Blood alkaline phosphatase increased	2.2 percentage of participants	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Changes in Safety Laboratory Parameters Hepatic enzyme increased	2.2 percentage of participants	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: Day 15, Day 29 and Day 57

Population: Pharmacokinetics (PK) data set: All patients from whom PK samples were received in the bioanalytical laboratories were included in the PK analysis.

Trough plasma concentrations are defined either as pre-dose concentration of BIBF 1120 and BIBW 2992 in plasma at steady state immediately before administration of the next dose for the monotherapy treatment or as post dose concentrations taken after the dosing interval for the combination treatment

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=43 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=18 Participants 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy Cpre,ss,15 (N=28, 15)	10.2 ng/mL Geometric Coefficient of Variation 81.0	18.0 ng/mL Geometric Coefficient of Variation 81.2	—	—
Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy Cpre,ss,29 (N=35, 18)	11.8 ng/mL Geometric Coefficient of Variation 75.5	19.1 ng/mL Geometric Coefficient of Variation 92.6	—	—
Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy Cpre,ss,57 (N=27, 12)	11.8 ng/mL Geometric Coefficient of Variation 110.0	18.2 ng/mL Geometric Coefficient of Variation 81.5	—	—

SECONDARY outcome

Timeframe: Day7, Day 14

Population: Pharmacokinetics (PK) data set: All patients from whom PK samples were received in the bioanalytical laboratories were included in the PK analysis.

Outcome measures

Outcome measures
Measure	BIBF 1120 Monotherapy n=16 Participants 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy C 12,14 (N=14)	13.7 ng/mL Geometric Coefficient of Variation 50.5	—	—	—
Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy C 24,7 (N=13)	11.4 ng/mL Geometric Coefficient of Variation 216	—	—	—
Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy C 24,14 (N=12)	16.4 ng/mL Geometric Coefficient of Variation 53.7	—	—	—

Adverse Events

BIBF 1120 Monotherapy

Serious events: 11 serious events

Other events: 46 other events

Deaths: 0 deaths

BIBW 2992 Monotherapy

Serious events: 2 serious events

Other events: 20 other events

Deaths: 0 deaths

ComBI 40

Serious events: 4 serious events

Other events: 16 other events

Deaths: 0 deaths

ComBI 70

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

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Boehringer Ingelheim Pharmaceuticals

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	BIBF 1120 Monotherapy n=46 participants at risk 250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	BIBW 2992 Monotherapy n=20 participants at risk 40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	ComBI 40 n=16 participants at risk Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	ComBI 70 n=3 participants at risk Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	6.2% 1/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Cardiac disorders Myocardial ischaemia	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Gastrointestinal disorders Abdominal pain	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Gastrointestinal disorders Rectal haemorrhage	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
General disorders Death	0.00% 0/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	6.2% 1/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Infections and infestations Urinary tract infection	4.3% 2/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Injury, poisoning and procedural complications Spinal compression fracture	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Musculoskeletal and connective tissue disorders Back pain	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	6.2% 1/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	5.0% 1/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	5.0% 1/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer metastatic	0.00% 0/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	5.0% 1/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Nervous system disorders Cauda equina syndrome	0.00% 0/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	33.3% 1/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Nervous system disorders Cerebrovascular accident	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Nervous system disorders Spinal cord compression	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	12.5% 2/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	33.3% 1/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Renal and urinary disorders Haematuria	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Renal and urinary disorders Urinary retention	6.5% 3/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Renal and urinary disorders Urinary tract obstruction	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Reproductive system and breast disorders Prostatitis	2.2% 1/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Vascular disorders Deep vein thrombosis	4.3% 2/46 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/20 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/16 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)	0.00% 0/3 • from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)