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

Study Overview
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Brief Summary
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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.

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

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: BIBF 1120
* Drug: BIBW 2992
* Drug: Sequential BIBF 1120 + BIBW 2992


Participation Criteria
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Eligibility Criteria
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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 For a patient who has withdrawn from anti-androgen therapy less than 6 months prior to inclusion in trial one of the following criteria is also required: Following the completion of the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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: BIBF 1120|nan|
|Drug: BIBW 2992|nan|
|Drug: Sequential BIBF 1120 + BIBW 2992|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 24 weeks and 48 weeks | 
| 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. | End of trial visit, 29 ± 1 days after Day 1 of the last treatment cycle (Up to 48 weeks) | 
| 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. | End of trial visit, 29 ± 1 days after Day 1 of the last treatment cycle (Up to 48 weeks) | 
| 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. | Start of treatment until end of treatment (Up to 48 weeks) | 
| 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%. | 12, 24, 36, and 48 weeks | 
| 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. | 12, 24, 36 and 48 weeks | 
| 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. | Up to 48 weeks | 
| 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. | start of treatment until end of the treatment (Up to 48 weeks) | 
| 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. | start of treatment until 28 days after end of treatment (Up to 52 weeks) | 
| 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). | from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks) | 
| Changes in Safety Laboratory Parameters | Changes in safety laboratory Parameters reported as adverse events | from first intake of treatment until 29 days after last intake of treatment (Up to 52 weeks) | 
| 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 | Day 15, Day 29 and Day 57 | 
| 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 | Day7, Day 14 |