Prostatic Neoplasms
Conditions
Brief summary
The primary objective of this trial is to estimate and compare the 12-week progression-free rate of BIBF 1120, BIBW 2992 or sequential administration of BIBF 1120 and BIBW 2992 in patients with HRPC as determined by radiographic, bone and PSA criteria.
Interventions
DRUGBIBF 1120
DRUGBIBW 2992
DRUGSequential BIBF 1120 + BIBW 2992
Sponsors
Boehringer Ingelheim
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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 For a patient who has withdrawn from anti-androgen therapy less than 6 months prior to inclusion in trial one of the following criteria is also required: * Following the completion of the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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Rate (PFR) at 12 Weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Showing Prostate Serum Antigen (PSA) Response | End of trial visit, 29 ± 1 days after Day 1 of the last treatment cycle (Up to 48 weeks) | 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. |
| Duration of PSA Response | End of trial visit, 29 ± 1 days after Day 1 of the last treatment cycle (Up to 48 weeks) | 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. |
| Time to PSA Progression | Start of treatment until end of treatment (Up to 48 weeks) | 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. |
| RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 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%. |
| Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 12, 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. |
| Duration of RECIST Response | Up to 48 weeks | 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. |
| Progression Free Rate at 24 and 48 Weeks | 24 weeks 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 |
| Overall Survival (Time to Death) | start of treatment until 28 days after end of treatment (Up to 52 weeks) | 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. |
| Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks) | Incidence and worst intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0). |
| Changes in Safety Laboratory Parameters | from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks) | Changes in safety laboratory Parameters reported as adverse events |
| Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy | Day 15, Day 29 and Day 57 | 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 |
| Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy | Day7, Day 14 | 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 (C12,14 for BIBF1120 ; C24,7 and C24,14 for BIBW2992) C12,14: plasma concentration at 12 hours Day 14 |
| Time to Progression | start of treatment until end of the treatment (Up to 48 weeks) | Time from first administration of study drug until disease progression according to composite endpoint. Time is expressed in Median number of days. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 46 |
| 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. | 20 |
| 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 | 16 |
| 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. | 3 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Consent withdrawn | 6 | 1 | 3 | 0 |
| Overall Study | Non compliant with protocol | 0 | 1 | 0 | 0 |
| Overall Study | Not treated | 1 | 1 | 0 | 0 |
| Overall Study | Other Adverse Event | 16 | 5 | 5 | 2 |
| Overall Study | Other than those stated above | 4 | 0 | 0 | 0 |
| Overall Study | Progressive disease | 20 | 13 | 8 | 1 |
Baseline characteristics
| Characteristic | BIBF 1120 Monotherapy | BIBW 2992 Monotherapy | ComBI 40 | ComBI 70 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 67.7 years STANDARD_DEVIATION 8.1 | 68.4 years STANDARD_DEVIATION 5.4 | 70.4 years STANDARD_DEVIATION 8.1 | 68.3 years STANDARD_DEVIATION 0.6 | 68.4 years STANDARD_DEVIATION 7.4 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 46 Participants | 20 Participants | 16 Participants | 3 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 46 / 46 | 20 / 20 | 16 / 16 | 3 / 3 |
| serious Total, serious adverse events | 11 / 46 | 2 / 20 | 4 / 16 | 1 / 3 |
Outcome results
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
Time frame: 12 weeks
Population: Modified full analysis set(mFAS): Patients who received at least 1 dose of study medication and for whom progression status could be determined at 12 weeks,excluding patients who discontinued treatment before 12 weeks for reasons other than PD.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIBF 1120 Monotherapy | Progression Free Rate (PFR) at 12 Weeks | 25.9 percentage of participants |
| BIBW 2992 Monotherapy | Progression Free Rate (PFR) at 12 Weeks | 0.0 percentage of participants |
| ComBI 40 | Progression Free Rate (PFR) at 12 Weeks | 0.0 percentage of participants |
| ComBI 70 | Progression Free Rate (PFR) at 12 Weeks | NA percentage of participants |
p-value: 0.0577Fisher Exact
p-value: 0.0863Fisher Exact
Secondary
Changes in Safety Laboratory Parameters
Changes in safety laboratory Parameters reported as adverse events
Time frame: from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIBF 1120 Monotherapy | Changes in Safety Laboratory Parameters | Aspartate aminotransferase increased | 10.9 percentage of participants |
| BIBF 1120 Monotherapy | Changes in Safety Laboratory Parameters | Hepatic enzyme increased | 2.2 percentage of participants |
| BIBF 1120 Monotherapy | Changes in Safety Laboratory Parameters | Blood creatinine increased | 2.2 percentage of participants |
| BIBF 1120 Monotherapy | Changes in Safety Laboratory Parameters | Blood urea increased | 2.2 percentage of participants |
| BIBF 1120 Monotherapy | Changes in Safety Laboratory Parameters | Blood alkaline phosphatase increased | 2.2 percentage of participants |
| BIBF 1120 Monotherapy | Changes in Safety Laboratory Parameters | Gamma-glutamyltransferase increased | 4.3 percentage of participants |
| BIBF 1120 Monotherapy | Changes in Safety Laboratory Parameters | Alanine aminotransferase increased | 17.4 percentage of participants |
| BIBF 1120 Monotherapy | Changes in Safety Laboratory Parameters | Transaminases increased | 4.3 percentage of participants |
| BIBF 1120 Monotherapy | Changes in Safety Laboratory Parameters | Blood potassium decreased | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Changes in Safety Laboratory Parameters | Blood creatinine increased | 5.0 percentage of participants |
| BIBW 2992 Monotherapy | Changes in Safety Laboratory Parameters | Alanine aminotransferase increased | 5.0 percentage of participants |
| BIBW 2992 Monotherapy | Changes in Safety Laboratory Parameters | Gamma-glutamyltransferase increased | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Changes in Safety Laboratory Parameters | Aspartate aminotransferase increased | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Changes in Safety Laboratory Parameters | Blood urea increased | 10.0 percentage of participants |
| BIBW 2992 Monotherapy | Changes in Safety Laboratory Parameters | Blood potassium decreased | 5.0 percentage of participants |
| BIBW 2992 Monotherapy | Changes in Safety Laboratory Parameters | Transaminases increased | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Changes in Safety Laboratory Parameters | Blood alkaline phosphatase increased | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Changes in Safety Laboratory Parameters | Hepatic enzyme increased | 0.0 percentage of participants |
| ComBI 40 | Changes in Safety Laboratory Parameters | Blood potassium decreased | 0.0 percentage of participants |
| ComBI 40 | Changes in Safety Laboratory Parameters | Blood creatinine increased | 0.0 percentage of participants |
| ComBI 40 | Changes in Safety Laboratory Parameters | Hepatic enzyme increased | 0.0 percentage of participants |
| ComBI 40 | Changes in Safety Laboratory Parameters | Blood alkaline phosphatase increased | 0.0 percentage of participants |
| ComBI 40 | Changes in Safety Laboratory Parameters | Gamma-glutamyltransferase increased | 12.5 percentage of participants |
| ComBI 40 | Changes in Safety Laboratory Parameters | Alanine aminotransferase increased | 18.8 percentage of participants |
| ComBI 40 | Changes in Safety Laboratory Parameters | Blood urea increased | 0.0 percentage of participants |
| ComBI 40 | Changes in Safety Laboratory Parameters | Transaminases increased | 0.0 percentage of participants |
| ComBI 40 | Changes in Safety Laboratory Parameters | Aspartate aminotransferase increased | 18.8 percentage of participants |
| ComBI 70 | Changes in Safety Laboratory Parameters | Transaminases increased | 0.0 percentage of participants |
| ComBI 70 | Changes in Safety Laboratory Parameters | Blood creatinine increased | 0.0 percentage of participants |
| ComBI 70 | Changes in Safety Laboratory Parameters | Blood potassium decreased | 0.0 percentage of participants |
| ComBI 70 | Changes in Safety Laboratory Parameters | Hepatic enzyme increased | 0.0 percentage of participants |
| ComBI 70 | Changes in Safety Laboratory Parameters | Gamma-glutamyltransferase increased | 33.3 percentage of participants |
| ComBI 70 | Changes in Safety Laboratory Parameters | Alanine aminotransferase increased | 33.3 percentage of participants |
| ComBI 70 | Changes in Safety Laboratory Parameters | Aspartate aminotransferase increased | 0.0 percentage of participants |
| ComBI 70 | Changes in Safety Laboratory Parameters | Blood alkaline phosphatase increased | 0.0 percentage of participants |
| ComBI 70 | Changes in Safety Laboratory Parameters | Blood urea increased | 0.0 percentage of participants |
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.
Time frame: End of trial visit, 29 ± 1 days after Day 1 of the last treatment cycle (Up to 48 weeks)
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BIBF 1120 Monotherapy | Duration of PSA Response | NA days |
| BIBW 2992 Monotherapy | Duration of PSA Response | NA days |
| ComBI 40 | Duration of PSA Response | NA days |
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.
Time frame: Up to 48 weeks
Population: FAS (RECIST evaluable set)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BIBF 1120 Monotherapy | Duration of RECIST Response | 116.0 days |
| BIBW 2992 Monotherapy | Duration of RECIST Response | NA days |
| ComBI 40 | Duration of RECIST Response | NA days |
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).
Time frame: from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks)
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIBF 1120 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 4 | 6.5 percentage of participants |
| BIBF 1120 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 2 | 30.4 percentage of participants |
| BIBF 1120 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 5 | 0.0 percentage of participants |
| BIBF 1120 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 3 | 37.0 percentage of participants |
| BIBF 1120 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 1 | 26.1 percentage of participants |
| BIBW 2992 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 3 | 40.0 percentage of participants |
| BIBW 2992 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 4 | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 5 | 5.0 percentage of participants |
| BIBW 2992 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 2 | 55.0 percentage of participants |
| BIBW 2992 Monotherapy | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 1 | 0.0 percentage of participants |
| ComBI 40 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 3 | 37.5 percentage of participants |
| ComBI 40 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 1 | 37.5 percentage of participants |
| ComBI 40 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 2 | 18.8 percentage of participants |
| ComBI 40 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 4 | 0.0 percentage of participants |
| ComBI 40 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 5 | 6.3 percentage of participants |
| ComBI 70 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 4 | 0.0 percentage of participants |
| ComBI 70 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 2 | 33.3 percentage of participants |
| ComBI 70 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 1 | 0.0 percentage of participants |
| ComBI 70 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 3 | 66.7 percentage of participants |
| ComBI 70 | Incidence and Worst Intensity of Adverse Events With Grading According CTCAE | CTCAE Grade 5 | 0.0 percentage of participants |
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.
Time frame: End of trial visit, 29 ± 1 days after Day 1 of the last treatment cycle (Up to 48 weeks)
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIBF 1120 Monotherapy | Number of Patients Showing Prostate Serum Antigen (PSA) Response | Response | 3.7 percentage of participants |
| BIBF 1120 Monotherapy | Number of Patients Showing Prostate Serum Antigen (PSA) Response | No Response | 96.3 percentage of participants |
| BIBW 2992 Monotherapy | Number of Patients Showing Prostate Serum Antigen (PSA) Response | Response | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Number of Patients Showing Prostate Serum Antigen (PSA) Response | No Response | 100.0 percentage of participants |
| ComBI 40 | Number of Patients Showing Prostate Serum Antigen (PSA) Response | Response | 10.0 percentage of participants |
| ComBI 40 | Number of Patients Showing Prostate Serum Antigen (PSA) Response | No Response | 90.0 percentage of participants |
95% CI: [1.1754, 1.7892]
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.
Time frame: 12, 24, 36 and 48 weeks
Population: FAS (RECIST evaluable set)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIBF 1120 Monotherapy | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 12 weeks (N=12, 8, 7) | 8.3 percentage of participants |
| BIBF 1120 Monotherapy | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 24 weeks (N=6, 1, 1) | 0.0 percentage of participants |
| BIBF 1120 Monotherapy | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 36 weeks (N=3, 0, 0) | 0.0 percentage of participants |
| BIBF 1120 Monotherapy | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 48 weeks (N=2, 0, 0) | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 48 weeks (N=2, 0, 0) | NA percentage of participants |
| BIBW 2992 Monotherapy | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 12 weeks (N=12, 8, 7) | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 36 weeks (N=3, 0, 0) | NA percentage of participants |
| BIBW 2992 Monotherapy | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 24 weeks (N=6, 1, 1) | 0.0 percentage of participants |
| ComBI 40 | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 48 weeks (N=2, 0, 0) | NA percentage of participants |
| ComBI 40 | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 24 weeks (N=6, 1, 1) | 0.0 percentage of participants |
| ComBI 40 | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 36 weeks (N=3, 0, 0) | NA percentage of participants |
| ComBI 40 | Overall Objective Response by RECIST Criteria (Version 1.0) (Complete Response [CR] or Partial Response [PR]) for Patients With Measurable Disease at 12, 24, 36 and 48 Weeks | 12 weeks (N=12, 8, 7) | 0.0 percentage of participants |
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.
Time frame: start of treatment until 28 days after end of treatment (Up to 52 weeks)
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BIBF 1120 Monotherapy | Overall Survival (Time to Death) | NA days |
| BIBW 2992 Monotherapy | Overall Survival (Time to Death) | NA days |
| ComBI 40 | Overall Survival (Time to Death) | NA days |
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
Time frame: 24 weeks and 48 weeks
Population: Full analysis set (FAS), which consisted of all patients who received at least~1 dose of study medication and for whom progression status could be determined at 12 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIBF 1120 Monotherapy | Progression Free Rate at 24 and 48 Weeks | 24 weeks | 22.2 percentage of participants |
| BIBF 1120 Monotherapy | Progression Free Rate at 24 and 48 Weeks | 48 weeks | 18.5 percentage of participants |
| BIBW 2992 Monotherapy | Progression Free Rate at 24 and 48 Weeks | 24 weeks | 0.0 percentage of participants |
| BIBW 2992 Monotherapy | Progression Free Rate at 24 and 48 Weeks | 48 weeks | 0.0 percentage of participants |
| ComBI 40 | Progression Free Rate at 24 and 48 Weeks | 24 weeks | 0.0 percentage of participants |
| ComBI 40 | Progression Free Rate at 24 and 48 Weeks | 48 weeks | 0.0 percentage of participants |
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%.
Time frame: 12, 24, 36, and 48 weeks
Population: FAS (RECIST evaluable set); RECIST evaluable set, which consisted of patients who had RECIST measurable disease at baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIBF 1120 Monotherapy | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 12 weeks (N=12, 8, 7) | 8.3 percentage of participants |
| BIBF 1120 Monotherapy | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 24 weeks (N=6, 1, 1) | 50.0 percentage of participants |
| BIBF 1120 Monotherapy | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 36 weeks (N=3, 0, 0) | 33.3 percentage of participants |
| BIBF 1120 Monotherapy | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 48 weeks (N=2, 0, 0) | 50.0 percentage of participants |
| BIBW 2992 Monotherapy | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 48 weeks (N=2, 0, 0) | NA percentage of participants |
| BIBW 2992 Monotherapy | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 12 weeks (N=12, 8, 7) | 50.0 percentage of participants |
| BIBW 2992 Monotherapy | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 36 weeks (N=3, 0, 0) | NA percentage of participants |
| BIBW 2992 Monotherapy | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 24 weeks (N=6, 1, 1) | 0.0 percentage of participants |
| ComBI 40 | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 48 weeks (N=2, 0, 0) | NA percentage of participants |
| ComBI 40 | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 24 weeks (N=6, 1, 1) | 0.0 percentage of participants |
| ComBI 40 | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 36 weeks (N=3, 0, 0) | NA percentage of participants |
| ComBI 40 | RECIST Tumour Progression Rate at 12, 24, 36, and 48 Weeks | 12 weeks (N=12, 8, 7) | 42.9 percentage of participants |
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.
Time frame: start of treatment until end of the treatment (Up to 48 weeks)
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BIBF 1120 Monotherapy | Time to Progression | 31.0 days |
| BIBW 2992 Monotherapy | Time to Progression | 29.0 days |
| ComBI 40 | Time to Progression | 57.0 days |
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.
Time frame: Start of treatment until end of treatment (Up to 48 weeks)
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BIBF 1120 Monotherapy | Time to PSA Progression | 31.0 days |
| BIBW 2992 Monotherapy | Time to PSA Progression | 29.0 days |
| ComBI 40 | Time to PSA Progression | 57.0 days |
Secondary
Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy
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 (C12,14 for BIBF1120 ; C24,7 and C24,14 for BIBW2992) C12,14: plasma concentration at 12 hours Day 14
Time frame: Day7, Day 14
Population: Pharmacokinetics (PK) data set: All patients from whom PK samples were received in the bioanalytical laboratories were included in the PK analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| BIBF 1120 Monotherapy | Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy | C 12,14 (N=14) | 13.7 ng/mL | Geometric Coefficient of Variation 50.5 |
| BIBF 1120 Monotherapy | Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy | C 24,7 (N=13) | 11.4 ng/mL | Geometric Coefficient of Variation 216 |
| BIBF 1120 Monotherapy | Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Combination Therapy | C 24,14 (N=12) | 16.4 ng/mL | Geometric Coefficient of Variation 53.7 |
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
Time frame: Day 15, Day 29 and Day 57
Population: Pharmacokinetics (PK) data set: All patients from whom PK samples were received in the bioanalytical laboratories were included in the PK analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| BIBF 1120 Monotherapy | Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy | Cpre,ss,15 (N=28, 15) | 10.2 ng/mL | Geometric Coefficient of Variation 81 |
| BIBF 1120 Monotherapy | Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy | Cpre,ss,29 (N=35, 18) | 11.8 ng/mL | Geometric Coefficient of Variation 75.5 |
| BIBF 1120 Monotherapy | Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy | Cpre,ss,57 (N=27, 12) | 11.8 ng/mL | Geometric Coefficient of Variation 110 |
| BIBW 2992 Monotherapy | Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy | Cpre,ss,15 (N=28, 15) | 18.0 ng/mL | Geometric Coefficient of Variation 81.2 |
| BIBW 2992 Monotherapy | Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy | Cpre,ss,29 (N=35, 18) | 19.1 ng/mL | Geometric Coefficient of Variation 92.6 |
| BIBW 2992 Monotherapy | Trough Plasma Concentrations for BIBF 1120 and BIBW 2992 for the Monotherapy | Cpre,ss,57 (N=27, 12) | 18.2 ng/mL | Geometric Coefficient of Variation 81.5 |