A Multi-centre 3-arm Randomised Phase II Trial of BIBF 11... | NCT00706628

Measure	Description	Time Frame
Progression Free Rate (PFR) at 12 Weeks	PFR is defined as a composite endpoint for disease progression. If patients met one of the following criteria they were counted as having progressive disease (PD): Prostate serum antigen (PSA) progression according to Prostate-Specific Antigen Working Group (PSAWG) criteria Bone metastasis progression- development of new lesions on bone scan or development of disease-related skeletal related events (SREs) Disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0	12 weeks

Measure	Description	Time Frame
Progression Free Rate at 24 and 48 Weeks	PFR is defined as a composite endpoint for disease progression. If patients met one of the following criteria they were counted as having progressive disease (PD): Prostate serum antigen (PSA) progression according to Prostate-Specific Antigen Working Group (PSAWG) criteria Bone metastasis progression- development of new lesions on bone scan or development of disease-related skeletal related events (SREs) Disease progression according to RECIST version 1.0

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Age >18 years.
Signed informed consent.
Able to comply with protocol requirements.
Histologically, cytologically or biochemically documented adenocarcinoma of the prostate, clinically refractory or resistant to hormone therapy, as documented by progression following at least one hormonal therapy, which must include orchidectomy or gonadotropin releasing hormone agonist (GnRHa).
Progressive Disease (PD) is defined as a minimum of three consecutive serum PSA measurements obtained at least 7 days apart within the previous 3 months of start of trial, which document progressively increasing values. Patients with progression of measurable disease (RECIST) or progression of bone disease must also fit the criterion for PSA progression.
Patients must have documented progression (as defined above) following anti-androgen withdrawal of 4 weeks duration for flutamide and 6 weeks for bicalutamide or nilutamide. For a patient who has withdrawn from anti-androgen therapy less than 6 months prior to inclusion in trial one of the following criteria is also required:
Following the completion of the anti-androgen withdrawal period one PSA higher than the last pre-withdrawal PSA.
Or Following the completion of the anti-androgen withdrawal period if the PSA value has decreased, he can still qualify if 2 increases in PSA are documented after the post- withdrawal nadir.
PSA > 5ng/mL.
Life expectancy of at least 12 weeks.
ECOG performance status 0-1 (see appendix 11.2).
Stable analgesia requirements.
Adequate hepatic function: total bilirubin < 26µmol/L, ALT and/or AST < 1.5x upper limit of normal (ULN).
Adequate renal function: serum creatinine < 1.5 x ULN.
INR Prothrombin time (PT) and partial thromboplastin time (PTT) <1.5 upper limit of normal.
Absolute neutrophil count (ANC) > 1.5 x 109l, Platelets > 100 x 109/l.
Haemoglobin > 9.0 g/dl.
LVEF > 50 % on MUGA scan or echocardiogram.
Castrate testosterone level [< 20ng/dl or <0.69nM (nM/L x 28.8 = ng/dl)], which must be maintained during the duration of the trial by orchidectomy or medical castration.
Patient on oral or intravenous bisphosphonates are allowed to enter the trial as long as they have been on bisphosphonates for a minimum of 3 months.

Exclusion Criteria:

Prior treatment with inhibitors of EGFR, HER 2 and/or VEGF receptors.
Prior treatment with cytotoxic chemotherapy.
Known hypersensitivity to the trial drugs or their excipients.
Systemic corticosteroids 28 days before screening (inhaled corticosteroids prescribed for bronchospasm are allowed). Patients on long-term stable-dose steroids for concurrent illness are not excluded.
Treatment with any investigational drug within 28 days of trial onset.
History of other malignancies which could affect compliance with the protocol or interpretation of results within 5-years. Patients with adequately treated basal or squamous cell skin cancer are generally eligible.
Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the trial.
Major injuries and/or surgery within 4 weeks of trial onset or bone fracture and planned surgical procedures during the trial period.
Significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within past 9 months, congestive heart failure > NYHA II) (see appendix 11.5).
History of haemorrhagic or thrombotic event in the past 12 months. Known inherited predisposition to bleeds or to thrombosis.
Patient with history or clinical evidence of CNS disease or brain metastases.
Patients with symptoms of impending or established spinal cord compression.
Gastrointestinal disorders or abnormalities that would inhibit absorption of the trial drug.
Patients who require full-dose anticoagulation.
Radio- or immunotherapy within the past four weeks prior to treatment with the trial drug.
Patients unable to comply with the protocol.
Active alcohol or drug abuse.

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
1239.3.4402 Boehringer Ingelheim Investigational Site		Belfast			United Kingdom
1239.3.4406 Boehringer Ingelheim Investigational Site

ID	Title	Description
FG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
FG001	BIBW 2992 Monotherapy

ID	Title	Description
BG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
BG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
BG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression
BG003	ComBI 70	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
BG004	Total	Total of all reporting groups

Units	Counts
Participants	BG00046 BG00120 BG00216 BG0033 BG00485

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Progression Free Rate (PFR) at 12 Weeks

PFR is defined as a composite endpoint for disease progression.

If patients met one of the following criteria they were counted as having progressive disease (PD):

Prostate serum antigen (PSA) progression according to Prostate-Specific Antigen Working Group (PSAWG) criteria
Bone metastasis progression- development of new lesions on bone scan or development of disease-related skeletal related events (SREs)
Disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0

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

Posted

Number

95% Confidence Interval

percentage of participants

12 weeks

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression
OG003	ComBI 70	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.

Units	Counts
Participants	OG00027 OG00112 OG00210 OG003

Title

Denominators

Categories

Title	Measurements
	OG00025.9(13.17 to 44.68) OG0010.0(0.00 to 24.25) OG0020.0(0.00 to 27.75) OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Fisher Exact		0.0577													No	Superiority or Other
OG000 OG002		Fisher Exact		0.0863

Secondary

Progression Free Rate at 24 and 48 Weeks

PFR is defined as a composite endpoint for disease progression.

If patients met one of the following criteria they were counted as having progressive disease (PD):

Prostate serum antigen (PSA) progression according to Prostate-Specific Antigen Working Group (PSAWG) criteria
Bone metastasis progression- development of new lesions on bone scan or development of disease-related skeletal related events (SREs)
Disease progression according to RECIST version 1.0

Full analysis set (FAS), which consisted of all patients who received at least

1 dose of study medication and for whom progression status could be determined at 12 weeks.

Posted

Number

95% Confidence Interval

percentage of participants

24 weeks and 48 weeks

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40

Secondary

Number of Patients Showing Prostate Serum Antigen (PSA) Response

PSA response was evaluated according to the PSAWG guidelines. All patients achieving a fall in PSA of ≥50% from baseline (confirmed with a second value at least 4 weeks later) fulfilled the criteria for PSA response. The confirmatory value had to be at least 50% lower than the baseline value, but could be higher than the original drop in PSA (first PSA value).

However, the confirmatory value could not be 50% higher than the first PSA value. If it was ≥50% higher than the first PSA, another sample was taken to determine if response had been achieved.

FAS

Posted

Number

percentage of participants

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

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40

Secondary

Duration of PSA Response

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

Duration of PSA response expressed in median number of days.

FAS

Posted

Median

Inter-Quartile Range

days

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

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40

Secondary

Time to PSA Progression

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

Time is expressed in median number of days.

FAS

Posted

Median

95% Confidence Interval

days

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

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression

Secondary

RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks

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

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

Posted

Number

percentage of participants

12, 24, 36, and 48 weeks

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression

Secondary

Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks

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

FAS (RECIST evaluable set)

Posted

Number

percentage of participants

12, 24, 36 and 48 weeks

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40

Secondary

Duration of RECIST Response

Time from first observation of response (PR, CR, confirmed or unconfirmed) until progression according to RECIST (version 1.0) or death.

Duration is expressed in Median number of days.

FAS (RECIST evaluable set)

Posted

Median

Inter-Quartile Range

days

Up to 48 weeks

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression

Secondary

Time to Progression

Time from first administration of study drug until disease progression according to composite endpoint.

Time is expressed in Median number of days.

FAS

Posted

Median

95% Confidence Interval

days

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

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression

Secondary

Overall Survival (Time to Death)

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

FAS

Posted

Median

95% Confidence Interval

days

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

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression

Secondary

Incidence and Worst Intensity of Adverse Events With Grading According CTCAE

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

Treated Set

Posted

Number

percentage of participants

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

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression

Secondary

Changes in Safety Laboratory Parameters

Changes in safety laboratory Parameters reported as adverse events

Treated Set

Posted

Number

percentage of participants

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

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression

Secondary

Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy

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

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

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 15, Day 29 and Day 57

ID	Title	Description
OG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.
OG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.

Units	Counts

Secondary

Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy

C12,14: plasma concentration at 12 hours Day 14

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

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day7, Day 14

ID	Title	Description
OG000	Combination Therapy of BIBF 1120 and BIBW 2992	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. C12,14 values of BIBF 1120 BS after sequential alternating 7-days administration of 250 mg BIBF 1120 bid; C24,7, C24,14 and C24,42 values of BIBW 2992 BS after sequential alternating 7-days administration of 40 mg BIBW 2992 qd

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Pancytopenia	Blood and lymphatic system disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG0030 affected3 at risk
Myocardial ischaemia	Cardiac disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Rectal haemorrhage	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Death	General disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA 12.0	Systematic Assessment	EG0002 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Spinal compression fracture	Injury, poisoning and procedural complications	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0011 affected20 at risk EG0020 affected16 at risk EG003
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0011 affected20 at risk EG0020 affected16 at risk EG003
Prostate cancer metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0011 affected20 at risk EG0020 affected16 at risk EG003
Cauda equina syndrome	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Cerebrovascular accident	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Spinal cord compression	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0022 affected16 at risk EG003
Haematuria	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Urinary retention	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0003 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Urinary tract obstruction	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Prostatitis	Reproductive system and breast disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA 12.0	Systematic Assessment	EG0002 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Asthenopia	Eye disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG0030 affected3 at risk
Conjunctivitis	Eye disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0013 affected20 at risk EG0020 affected16 at risk EG003
Dry eye	Eye disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Abdominal discomfort	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0004 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0011 affected20 at risk EG0020 affected16 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0009 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Anal fissure	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0009 affected46 at risk EG0012 affected20 at risk EG0025 affected16 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG00035 affected46 at risk EG00120 affected20 at risk EG00215 affected16 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0004 affected46 at risk EG0015 affected20 at risk EG0021 affected16 at risk EG003
Dyschezia	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0004 affected46 at risk EG0012 affected20 at risk EG0020 affected16 at risk EG003
Flatulence	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0004 affected46 at risk EG0011 affected20 at risk EG0020 affected16 at risk EG003
Gastritis	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0022 affected16 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Glossodynia	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0011 affected20 at risk EG0021 affected16 at risk EG003
Mouth ulceration	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0014 affected20 at risk EG0025 affected16 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG00029 affected46 at risk EG0015 affected20 at risk EG0026 affected16 at risk EG003
Oedema mouth	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Oral pain	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0015 affected20 at risk EG0021 affected16 at risk EG003
Rectal haemorrhage	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0003 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Stomatitis	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0012 affected20 at risk EG0021 affected16 at risk EG003
Toothache	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 12.0	Systematic Assessment	EG00016 affected46 at risk EG0014 affected20 at risk EG0024 affected16 at risk EG003
Chest pain	General disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Fatigue	General disorders	MedDRA 12.0	Systematic Assessment	EG0007 affected46 at risk EG0019 affected20 at risk EG0023 affected16 at risk EG003
Feeling drunk	General disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Influenza like illness	General disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0012 affected20 at risk EG0020 affected16 at risk EG003
Mucosal haemorrhage	General disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Mucosal inflammation	General disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0012 affected20 at risk EG0020 affected16 at risk EG003
Pain	General disorders	MedDRA 12.0	Systematic Assessment	EG0003 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Ear infection	Infections and infestations	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 12.0	Systematic Assessment	EG0002 affected46 at risk EG0011 affected20 at risk EG0021 affected16 at risk EG003
Rhinitis	Infections and infestations	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0011 affected20 at risk EG0022 affected16 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0011 affected20 at risk EG0022 affected16 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA 12.0	Systematic Assessment	EG0008 affected46 at risk EG0011 affected20 at risk EG0023 affected16 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA 12.0	Systematic Assessment	EG0005 affected46 at risk EG0010 affected20 at risk EG0023 affected16 at risk EG003
Blood urea increased	Investigations	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0012 affected20 at risk EG0020 affected16 at risk EG003
Ejection fraction decreased	Investigations	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Electrocardiogram ST-T segment abnormal	Investigations	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Gamma-glutamyltransferase increased	Investigations	MedDRA 12.0	Systematic Assessment	EG0002 affected46 at risk EG0010 affected20 at risk EG0022 affected16 at risk EG003
Anorexia	Metabolism and nutrition disorders	MedDRA 12.0	Systematic Assessment	EG0005 affected46 at risk EG0011 affected20 at risk EG0023 affected16 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA 12.0	Systematic Assessment	EG0003 affected46 at risk EG0016 affected20 at risk EG0022 affected16 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG0002 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG00010 affected46 at risk EG0012 affected20 at risk EG0023 affected16 at risk EG003
Bursitis	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG0002 affected46 at risk EG0011 affected20 at risk EG0021 affected16 at risk EG003
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG0005 affected46 at risk EG0011 affected20 at risk EG0021 affected16 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 12.0	Systematic Assessment	EG0003 affected46 at risk EG0013 affected20 at risk EG0021 affected16 at risk EG003
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Ageusia	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Cauda equina syndrome	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Dizziness	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0004 affected46 at risk EG0012 affected20 at risk EG0021 affected16 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0003 affected46 at risk EG0014 affected20 at risk EG0021 affected16 at risk EG003
Headache	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0005 affected46 at risk EG0013 affected20 at risk EG0020 affected16 at risk EG003
Lethargy	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0009 affected46 at risk EG0015 affected20 at risk EG0027 affected16 at risk EG003
Peripheral sensory neuropathy	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0011 affected20 at risk EG0021 affected16 at risk EG003
Sciatica	Nervous system disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Affect lability	Psychiatric disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Depressed mood	Psychiatric disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0012 affected20 at risk EG0020 affected16 at risk EG003
Dysuria	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0022 affected16 at risk EG003
Haematuria	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0003 affected46 at risk EG0012 affected20 at risk EG0022 affected16 at risk EG003
Nocturia	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0006 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Pollakiuria	Renal and urinary disorders	MedDRA 12.0	Systematic Assessment	EG0002 affected46 at risk EG0012 affected20 at risk EG0021 affected16 at risk EG003
Gynaecomastia	Reproductive system and breast disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0002 affected46 at risk EG00110 affected20 at risk EG0025 affected16 at risk EG003
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Nasal discomfort	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Nasal mucosal disorder	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Pleural fibrosis	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Acne	Skin and subcutaneous tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Dermatitis acneiform	Skin and subcutaneous tissue disorders	MedDRA 12.0	Systematic Assessment	EG0001 affected46 at risk EG0012 affected20 at risk EG0021 affected16 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0016 affected20 at risk EG0022 affected16 at risk EG003
Erythema	Skin and subcutaneous tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0012 affected20 at risk EG0020 affected16 at risk EG003
Ingrowing nail	Skin and subcutaneous tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA 12.0	Systematic Assessment	EG0002 affected46 at risk EG00110 affected20 at risk EG0025 affected16 at risk EG003
Skin exfoliation	Skin and subcutaneous tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Skin fissures	Skin and subcutaneous tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Skin induration	Skin and subcutaneous tissue disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003
Hypertension	Vascular disorders	MedDRA 12.0	Systematic Assessment	EG0004 affected46 at risk EG0010 affected20 at risk EG0020 affected16 at risk EG003
Peripheral coldness	Vascular disorders	MedDRA 12.0	Systematic Assessment	EG0000 affected46 at risk EG0010 affected20 at risk EG0021 affected16 at risk EG003

Name	Type	Description	Arm Group Labels	Other Names
BIBF 1120	Drug
BIBW 2992	Drug
Sequential BIBF 1120 + BIBW 2992	Drug

ID	Term
D005834	Genital Neoplasms, Male
D014565	Urogenital Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D005832	Genital Diseases, Male
D000091662	Genital Diseases
D000091642	Urogenital Diseases
D011469	Prostatic Diseases
D052801	Male Urogenital Diseases

ID	Term
C530716	nintedanib
D000077716	Afatinib

ID	Term
D000577	Amides
D009930	Organic Chemicals
D011799	Quinazolines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	BIBF 1120 Monotherapy	250 mg soft gelatine capsules administered orally twice a day (BID). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	11	46	46	46
EG001	BIBW 2992 Monotherapy	40 mg tablets administered orally once a day (QD). Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	2	20	20	20
EG002	ComBI 40	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and 15 to 21, BIBW 2992 40 mg QD on Days 8 to 14 and 22 to 28. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression	4	16	16	16
EG003	ComBI 70	Sequential alternating BIBF 1120 and BIBW 2992 combination therapy. Treatment regimen: BIBF 1120 250 mg BID on Days 1 to 7 and Days 15 to 21 of each treatment cycle; BIBW 2992 70 mg QD on Days 8 to 14 and Days 22 to 28 of each treatment cycle. The starting dose of BIBW 2992 was reduced due to an unexpectedly high incidence of severe (Grade 3) Adverse Events reported for the first 3 patients treated with ComBI 70. As the reported Adverse Events were attributed to BIBW 2992, the starting dose of BIBW 2992 in subsequent patients in this treatment arm was reduced to 40mg QD (ComBI 40); the dose of BIBF 1120 remained unchanged. Continuous daily dosing in 28-day cycles. Patients were eligible for repeated treatment cycles for 48 weeks in the absence of clinical disease progression.	1	3	3	3