Trial Outcomes & Findings for Efficacy and Safety of BI 2536 in Advanced or Metastatic Non Small Cell Lung Cancer (NCT NCT00376623)

Last Updated: 2022-06-21

Results Overview

The best overall response was the best response recorded from start of treatment until the participant progressed, received any other anti-tumour therapy, died or until the individual participant's end of trial. Number of participants with 'Objective tumour response evaluated according to RECIST 1.0 by central review of the tumour images = Yes' are reported. Objective response is complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter). Changes in tumour measurements were confirmed by repeat assessments that had to be performed 6 weeks after the criteria for response had been first met.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

96 participants

Primary outcome timeframe

assessed at baseline, then every 6 weeks (every second treatment course) until disease progression or start of any other anti-tumour therapy or death or individual participant's end of trial, up to 533 days

Results posted on

2022-06-21

Participant Flow

An open-label, randomized, parallel-group, phase II clinical trial to investigate the efficacy, safety and pharmacokinetics of a single dose of 200 milligram (mg) BI 2536 administered intravenously in comparison to 50 / 60 mg BI 2536 administered intravenously on days 1, 2 and 3 in patients with advanced or metastatic non small cell lung cancer.

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated. Abbreviation: Common Terminology Criteria for Adverse Events version 3.0 (CTCAE)

Participant milestones

Participant milestones
Measure	200 Milligram (mg) BI 2536 (Day 1) A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Overall Study STARTED	49	26	21
Overall Study Treated With BI 2536	48	26	21
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	49	26	21

Reasons for withdrawal

Reasons for withdrawal
Measure	200 Milligram (mg) BI 2536 (Day 1) A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Overall Study Progressive disease	35	22	17
Overall Study Lost to Follow-up	0	1	0
Overall Study Adverse Event other than Dose Limiting Toxicity	6	1	2
Overall Study Not treated with BI 2536	1	0	0
Overall Study Investigator's and participant's decision to stop treatment with BI 2536 after 6 cycles	1	0	0
Overall Study Investigator's and participant's decision to stop treatment with BI 2536	1	0	0
Overall Study Investigator's decision to stop treatment with BI 2536 after 6 cycles	2	0	0
Overall Study Investigator's decision to stop treatment with BI 2536	0	1	0
Overall Study Participant's decision to stop treatment with BI 2536 after 6 cycles	0	0	1
Overall Study Participant's decision to stop treatment with BI 2536	2	0	1
Overall Study Increase of tumour markers	0	1	0
Overall Study Bone metastasis	1	0	0

Baseline Characteristics

Efficacy and Safety of BI 2536 in Advanced or Metastatic Non Small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Total n=95 Participants Total of all reporting groups
Age, Continuous	61.8 years STANDARD_DEVIATION 9.1 • n=5 Participants	61.2 years STANDARD_DEVIATION 9.1 • n=7 Participants	62.5 years STANDARD_DEVIATION 12.0 • n=5 Participants	61.8 years STANDARD_DEVIATION 9.7 • n=4 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	9 Participants n=7 Participants	4 Participants n=5 Participants	28 Participants n=4 Participants
Sex: Female, Male Male	33 Participants n=5 Participants	17 Participants n=7 Participants	17 Participants n=5 Participants	67 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	48 Participants n=5 Participants	25 Participants n=7 Participants	21 Participants n=5 Participants	94 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: assessed at baseline, then every 6 weeks (every second treatment course) until disease progression or start of any other anti-tumour therapy or death or individual participant's end of trial, up to 533 days

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=47 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Objective Tumour Response Evaluated According to the Response Evaluation Criteria in Solid Tumours (RECIST 1.0) by Central Review of the Tumour Images	2 Number of Participants	0 Number of Participants	0 Number of Participants	0 Number of Participants

SECONDARY outcome

Timeframe: every 6 weeks (every second treatment course), up to 419 days

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized.

Progression-free survival defined as time from date of randomisation until "date of imaging indicating progressive disease (PD) as assessed by the independent central imaging review (according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0)" or "date of investigator assessment of clinical progression" or "date of progressive disease recorded during the follow-up period" or "death date", whatever comes first. Participants without documented progression at the time of analysis were censored at the date of the last visit. Per RECIST version 1.0 for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): PD, At least a 20% increase in the sum of the longest diameter (SoD) of target lesions taking as reference the smallest SoD of target lesions recorded since the treatment started or the appearance of one or more new lesions.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=47 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Progression Free Survival	49 days Interval 44.0 to 85.0	51.5 days Interval 43.0 to 90.0	48 days Interval 43.0 to 95.0	49 days Interval 44.0 to 85.0

SECONDARY outcome

Timeframe: every 6 weeks (every second treatment course), up to 599 days

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized.

Overall survival defined as time from date of randomisation until date of death from any cause. Participants alive at the time of analysis were censored at the date of the last trial visit or last date of follow-up, whatever came last.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=47 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Overall Survival	237 days Interval 179.0 to 370.0	244 days Interval 189.0 to 391.0	179 days Interval 102.0 to 244.0	196 days Interval 176.0 to 275.0

SECONDARY outcome

Population: All participants who received at least one application of the BI drug BI 2536 (including treated participants who were not randomized) and who showed an 'overall tumour response of complete response or partial response'.

For participants who showed an overall tumour response of complete response (CR, disappearance of all target lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter), 'duration of overall response' was defined as the time from the first date where measurement criteria were met for CR or PR (whichever was first recorded) until the first date that recurrent or progressive disease (PD) was objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started). Tumour response was evaluated based on local radiological images according to RECIST version 1.0 (agreed upon by independent review). The number of participants with an CR or PR who experienced the event 'recurrent or PD' is reported instead of the time-to-event data with unit of time as the number analyzed was too small to perform a Kaplan-Meier analysis.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=2 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Duration of Overall Response	2 Participants	—	—	0 Participants

SECONDARY outcome

Population: All participants who received at least one application of the BI drug BI 2536 (including treated participants who were not randomized) and had at least one post-baseline response evaluation.

The best overall response was the best response recorded from start of treatment until the participant progressed, received any other anti-tumour therapy, died or until the individual participant's end of trial. 'Objective tumour response evaluated according to RECIST 1.0 by investigator' is 'Yes' if the best overall response is either complete response (CR, disappearance of all target lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter). Otherwise it is 'No'. To be assigned a status of 'partial response' or 'complete response', changes in tumour measurements were confirmed by repeat assessments that had to be performed six weeks after the criteria for response had been first met. Number of participants with 'Objective tumour response evaluated according to RECIST 1.0 by investigator = Yes' are reported.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=47 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=47 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Objective Tumour Response Evaluated According to the Response Evaluation Criteria in Solid Tumours (RECIST 1.0) by Investigator	3 Number of Participants	1 Number of Participants	0 Number of Participants	1 Number of Participants

SECONDARY outcome

Timeframe: baseline and every 3 weeks (prior to the first administration of BI 2536 in a treatment course comprising 3 weeks), up to 539 days

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized.

Time to deterioration for cough \[days\] was defined as the time from randomization to deterioration in score for the symptom 'cough'. Participants were considered to have deteriorated if a 10-point increase from the baseline score at any time point after baseline was observed. Participants who died before deteriorating were analyzed as having deteriorated at the time of death. Participants with disease progression without deterioration in score were censored at the time of the last scale measurement. Participants with no QoL assessments were censored at day 1. The score for symptom 'cough' was based on Question 1 on the lung cancer module QLQ LC13 of the EORTC QLQ C30 Version 3.0. A linear transformation was used to standardize the raw scores, so that scores range from 0 to 100. A high score represents a higher ("worse") level of the symptom 'cough'.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=47 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Time-to-deterioration for Symptom Score 'Cough' Assessed on Question 1 on the Lung Cancer Module QLQ LC13 of the European Organization for Research and Treatment Quality of Life (QoL) Questionnaire (EORTC QLQ) C30 Version 3.0	108 days Interval 63.0 to 201.0	127 days Interval 58.0 to 189.0	99 days Interval 74.0 to 179.0	102 days Interval 74.0 to 176.0

SECONDARY outcome

Timeframe: baseline and every 3 weeks (prior to the first administration of BI 2536 in a treatment course comprising 3 weeks), up to 539 days

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized.

Time to deterioration for dyspnoea \[days\] was defined as the time from randomization to deterioration in score for the symptom 'dyspnoea'. Participants were considered to have deteriorated if a 10-point increase from the baseline score at any time point after baseline was observed. Participants who died before deteriorating were analyzed as having deteriorated at the time of death. Participants with disease progression without deterioration in score were censored at the time of the last scale measurement. Participants with no QoL assessments were censored at day 1. The score for symptom 'dyspnoea' was based on the composite of Questions 3-5 on the lung cancer module QLQ LC13 of the EORTC QLQ C30 Version 3.0. A linear transformation was used to standardize the raw scores, so that scores range from 0 to 100. A high score represents a higher ("worse") level of the symptom 'dyspnoea'.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=47 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Time-to-deterioration for Symptom Score 'Dyspnoea' Assessed on the Composite of Questions 3-5 on the Lung Cancer Module QLQ LC13 of the European Organization for Research and Treatment Quality of Life (QoL) Questionnaire (EORTC QLQ) C30 Version 3.0	56 days Interval 32.0 to 89.0	176 days Interval 93.0 to 198.0	80 days Interval 32.0 to 118.0	118 days Interval 76.0 to 180.0

SECONDARY outcome

Timeframe: baseline and every 3 weeks (prior to the first administration of BI 2536 in a treatment course comprising 3 weeks), up to 539 days

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized.

Time to deterioration for pain \[days\] was defined as the time from randomization to deterioration in score for the symptom 'pain'. Participants were considered to have deteriorated if a 10-point increase from the baseline score at any time point after baseline was observed. Participants who died before deteriorating were analyzed as having deteriorated at the time of death. Participants with disease progression without deterioration in score were censored at the time of the last scale measurement. Participants with no QoL assessments will be censored at day 1. The score for symptom 'pain' was based on the composite of Questions 9 and 19 of the EORTC QLQ C30 Version 3.0. A linear transformation was used to standardize the raw scores, so that scores range from 0 to 100. A high score represents a higher ("worse") level of the symptom 'pain'.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=47 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Time-to-deterioration for Symptom Score 'Pain' Assessed on the Composite of Questions 9 and 19 of the European Organization for Research and Treatment Quality of Life (QoL) Questionnaire (EORTC QLQ) C30 Version 3.0	63 days Interval 32.0 to 108.0	93 days Interval 49.0 to 198.0	43 days Interval 22.0 to 102.0	76 days Interval 32.0 to 179.0

SECONDARY outcome

Timeframe: on day 1 in treatment course 1: 0.5 hour (h) , 1 h, 2 h, 4 h, 120 h post-dose (planned times)

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants that were not randomized. Plasma concentrations below the limit of quantification were not used.

BI 2536 plasma concentrations after intravenous infusion of 200 milligram BI 2536 on day 1 in treatment course 1. Geometric Coefficient of Variation reported in percentage \[%\].

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
BI 2536 Plasma Concentrations After Intravenous Infusion of 200 Milligram BI 2536 on Day 1 in Treatment Course 1 0.5 hour post-dose (planned time)	614 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 40.2	—	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 200 Milligram BI 2536 on Day 1 in Treatment Course 1 1 hour post-dose (planned time)	589 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 52.8	—	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 200 Milligram BI 2536 on Day 1 in Treatment Course 1 2 hour post-dose (planned time)	160 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 37.1	—	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 200 Milligram BI 2536 on Day 1 in Treatment Course 1 4 hour post-dose (planned time)	110 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 37.1	—	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 200 Milligram BI 2536 on Day 1 in Treatment Course 1 120 hour post-dose (planned time)	3.07 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 65.5	—	—	—

SECONDARY outcome

Timeframe: on day 1 in treatment course 1: 1 hour (h), 2 h, 23.92 h, 25 h, 47.92 h, 48.5 h, 49 h, 50 h, 52 h, 120 h post-dose (planned times)

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized. Plasma concentrations below the limit of quantification were not used.

BI 2536 plasma concentrations after intravenous infusion of 50 / 60 milligram BI 2536 on day 1 in treatment course 1. Geometric Coefficient of Variation reported in percentage \[%\].

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=26 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 1 hour post-dose (planned time)	114 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 38.7	139 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 70.6	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 2 hour post-dose (planned time)	35.9 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 54.6	39.8 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 56.7	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 23.92 hour post-dose (planned time)	4.89 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 36.6	5.88 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 49.5	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 25 hour post-dose (planned time)	122 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 49.4	152 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 76.3	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 47.92 hour post-dose (planned time)	7.21 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 37.6	10.2 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 82.4	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 48.5 hour post-dose (planned time)	134 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 32.4	170 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 33.5	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 49 hour post-dose (planned time)	121 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 61.1	172 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 63.8	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 50 hour post-dose (planned time)	41.4 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 34.6	51.2 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 59.3	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 52 hour post-dose (planned time)	29.2 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 30.7	41.2 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 92.0	—	—
BI 2536 Plasma Concentrations After Intravenous Infusion of 50 / 60 Milligram BI 2536 on Day 1 in Treatment Course 1 120 hour post-dose (planned time)	2.42 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 53.6	3.19 nanogram / milliliter (ng/mL) Geometric Coefficient of Variation 57.7	—	—

SECONDARY outcome

Timeframe: On-treatment period, that is, from first administration of the trial drug until 3 weeks after the last administration of the trial drug, up to 428 days

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized.

Number of participants with adverse events categorized by "common terminology criteria for adverse events (CTCAE) grades (version 3.0)" are reported.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=47 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Incidence of Adverse Events Categorized by Common Terminology Criteria for Adverse Events (CTCAE) Grades Grade 2	6 Participants	7 Participants	2 Participants	9 Participants
Incidence of Adverse Events Categorized by Common Terminology Criteria for Adverse Events (CTCAE) Grades Grade 1	7 Participants	6 Participants	2 Participants	8 Participants
Incidence of Adverse Events Categorized by Common Terminology Criteria for Adverse Events (CTCAE) Grades Grade 3	13 Participants	8 Participants	7 Participants	15 Participants
Incidence of Adverse Events Categorized by Common Terminology Criteria for Adverse Events (CTCAE) Grades Grade 4	14 Participants	4 Participants	6 Participants	10 Participants
Incidence of Adverse Events Categorized by Common Terminology Criteria for Adverse Events (CTCAE) Grades Grade 5	6 Participants	1 Participants	4 Participants	5 Participants

SECONDARY outcome

Timeframe: On-treatment period, that is, from first administration of the trial drug until 3 weeks after the last administration of the trial drug, up to 428 days

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized.

Dose limiting toxicity was defined as drug related common terminology criteria for adverse events (CTCAE) grade 3 or greater non haematological toxicity (excluding untreated nausea, vomiting or diarrhoea) or drug related CTCAE grade 4 neutropenia for seven or more days and / or complicated by infection or CTCAE grade 4 thrombocytopenia. Number of participants with DLT is reported.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=48 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=21 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=47 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Incidence of Dose Limiting Toxicity (DLT)	8 Participant	4 Participant	3 Participant	7 Participant

SECONDARY outcome

Timeframe: On-treatment period, that is, from first administration of the trial drug until 3 weeks after the last administration of the trial drug, up to 428 days

Population: The Treated Set comprised all participants who received at least one application of the BI drug BI 2536 including treated participants who were not randomized. Participants with laboratory values that were out of range for CTCAE grading and were deemed possible clinically significant abnormal were excluded from the analyses.

Number of participants with neutropenia of common terminology criteria for adverse events (CTCAE) grade 3 or 4.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=46 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=26 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=20 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=46 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Number of Participants With Neutropenia of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4	33 Number of Participants	6 Number of Participants	12 Number of Participants	18 Number of Participants

SECONDARY outcome

Timeframe: On-treatment period, that is, from first administration of the trial drug until 3 weeks after the last administration of the trial drug, up to 428 days

Number of participants with thrombocytopenia of common terminology criteria for adverse events (CTCAE) grade 3 or 4.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=42 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=24 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=20 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=44 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Number of Participants With Thrombocytopenia of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4	4 Number of Participants	1 Number of Participants	0 Number of Participants	1 Number of Participants

SECONDARY outcome

Timeframe: baseline, date of individual participant's end of trial visit which was 533 days after start of treatment at the latest

Population: All participants who received at least one application of the BI drug BI 2536 (including treated patients who were not randomized) and for whom data were collected for this endpoint at the end-of-trial visit.

Change from baseline in systolic/diastolic blood pressure at individual participant's end-of-trial visit.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=15 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=14 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=7 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=21 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Change From Baseline in Systolic/Diastolic Blood Pressure at Individual Participant's End-of-trial Visit Change from baseline in systolic blood pressure	2.4 millimetre of mercury (mmHg) Standard Deviation 16.6	-2.4 millimetre of mercury (mmHg) Standard Deviation 14.0	2.9 millimetre of mercury (mmHg) Standard Deviation 17.8	-0.7 millimetre of mercury (mmHg) Standard Deviation 15.1
Change From Baseline in Systolic/Diastolic Blood Pressure at Individual Participant's End-of-trial Visit Change from baseline in diastolic blood pressure	-2.0 millimetre of mercury (mmHg) Standard Deviation 14.7	0.8 millimetre of mercury (mmHg) Standard Deviation 13.7	-7.1 millimetre of mercury (mmHg) Standard Deviation 12.5	-1.9 millimetre of mercury (mmHg) Standard Deviation 13.5

SECONDARY outcome

Timeframe: baseline, date of individual participant's end of trial visit which was 533 days after start of treatment at the latest

Change from baseline in pulse rate at individual participant's end-of-trial visit.

Outcome measures

Outcome measures
Measure	200 Milligram (mg) BI 2536 (Day 1) n=14 Participants A single dose of 200 mg BI 2536 on day one of each treatment course (comprising 21 days including the day of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT occurred and only with a dose reduced by up to 50 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	50 Milligram BI 2536 (Day 1 - Day 3) n=13 Participants A single dose of 50 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	60 Milligram BI 2536 (Day 1 - Day 3) n=6 Participants After implementation of protocol amendment 2 a single dose of 60 mg BI 2536 on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.	Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)" n=19 Participants A single dose of 50 mg or 60 mg (following implementation of protocol amendment 2) on days 1, 2 and 3 of each treatment course (comprising 21 days including the days of administration) was administered as an intravenous infusion over a period of 60 minutes. Each participant was planned to receive at least 2 treatment courses, in case of clinical benefit (i.e., at least stable disease and acceptable tolerability) the participants could continue therapy with the trial drug. Trial drug administration was stopped temporarily in case of dose limiting toxicity (DLT). Participants could continue therapy only if recovery from DLT (to CTCAE levels which allowed further therapy) occurred and only with a dose reduced by up to 10 mg. Dose reduction was allowed only once for a participant during the whole trial. If a participant had experienced a second episode of DLT with the reduced dose or the participant had not recovered from DLT then the participant was withdrawn from the trial. A participant who continued therapy with BI 2536 beyond course 2 could be treated with a higher dose in case of non-progression and good tolerability.
Change From Baseline in Pulse Rate at Individual Participant's End-of-trial Visit	10.6 beats per minute (bpm) Standard Deviation 14.3	4.5 beats per minute (bpm) Standard Deviation 13.3	-8.0 beats per minute (bpm) Standard Deviation 14.1	0.5 beats per minute (bpm) Standard Deviation 14.4

Adverse Events

200 Milligram (mg) BI 2536 (Day 1)

Serious events: 20 serious events

Other events: 44 other events

Deaths: 35 deaths

50 Milligram BI 2536 (Day 1 - Day 3)

Serious events: 8 serious events

Other events: 24 other events

Deaths: 20 deaths

60 Milligram BI 2536 (Day 1 - Day 3)

Serious events: 12 serious events

Other events: 19 other events

Deaths: 16 deaths

Combination of Treatment Group "50 mg BI 2536 (Day 1 - Day 3)" and "60 mg BI 2536 (Day 1 - Day 3)"

Serious events: 20 serious events

Other events: 43 other events

Deaths: 36 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