A Phase Ib/II, Multicentre, Open Label, Randomized Study of BI 836845 in Combination With Enzalutamide, versus Enzalutamide alone, in Metastatic Castration-Resistant Prostate Cancer (CRPC) Following Disease Progression on Docetaxel-Based Chemotherapy and Abiraterone

- The patient has histologically, or cytologically, confirmed adenocarcinoma of the prostate.
- Male patient aged, equal to, or more than,18 years old.
- Patients with radiographic evidence of metastatic prostate cancer (stage M1 or D2). Distant metastases evaluable by radionuclide bone scan, CT scan, or MRI within 28 days before the start of study treatment.
- Patients with a PSA, equal to, or more than, 5 ng/mL.
- Patients with prior surgical or chemical castration with a serum testosterone of <50 ng/mL. If the method of castration is luteinizing hormone releasing level hormone (LHRH) agonists, the patient must be willing to continue the use of LHRH agonists during protocol treatment.
- Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
- Cardiac left ventricular function with resting ejection fraction of at more than 50% as determined by ECHO or MUGA.
- International normalized ratio (INR) <= 2.0 and a partial thromboplastin time (PTT) <= 5 seconds above the ULN (unless on oral anticoagulant therapy). Patients receiving full-dose anticoagulation therapy are eligible provided they meet all other criteria, are on a stable dose of oral anticoagulant or low molecular weight heparin (except warfarin or coumarin-like anticoagulants, which are not permitted).
- Fasting plasma glucose <8.9 mmol/L (<160 mg/dL) and HbA1c <8.0%.
- Patients who have disease progression during, or after, receiving docetaxel and have had at least 12 weeks of treatment and in the opinion of the investigator are unlikely to derive significant benefit from additional docetaxel-based therapy, or were intolerant to therapy with this agent.
- Patients who have disease progression during, or after, receiving abiraterone treatment in any setting.
- Patients must have progressive disease defined as at least one of the following:
a. Progressive measurable disease: using conventional solid tumour criteria RECIST 1.1.
b. Bone scan progression: at least two new lesions on bone scan, plus a rising PSA as described in (c) below.
c. Increasing PSA level: at least two consecutive rising PSA values over a reference value (PSA #1) taken at least 1 week apart. A third PSA (PSA #3) is required to be greater than PSA #2; if not, a fourth PSA (PSA #4) is required to be greater than PSA #2.

- Prior therapy with agents targeting IGF and/or IGFR pathway.
- Patients that have been treated with any of the following within 4 weeks of starting trial treatment: chemotherapy, immunotherapy, biological therapies, molecular targeted, hormone therapy (except LHRH agonists and LHRH antagonists), radiotherapy (except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within 2 weeks prior to study treatment).
- Use of any investigational drug within 4 weeks before start of trial treatment or concomitantly with this trial.
- Patients that have been treated with strong CYP2C8 inhibitors, CYP2C8 inducers within 2 weeks of starting the trial treatment.
- QTcF prolongation >450 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome). The QTcF will be calculated as the mean of the 3 ECGs taken at screening.
- Patients with small cell or neuroendocrine tumours.
- Patients with known or suspected leptomeningeal metastases.
- Uncontrolled or poorly controlled hypertension.
- Patients with epilepsy, seizures, or predisposing factors for seizure as judged by the investigator.
- A history of allergy to human monoclonal antibodies.
- Previous or concomitant malignancies at any other site with the exception of the following:
a.) benign basal cell carcinoma
b.) benign low grade transitional cell carcinoma of the bladder
c.) other effectively treated malignancy that has been in remission for more than 5 years and is considered to be cured
Exclusion criteria only for patients entering phase Ib escalation and phase II:
- Patients that have received prior taxane-based therapy or enzalutamide in any setting will not be eligible.
- Patients who have received more than 2 prior non-docetaxel-containing cytotoxic chemotherapy regimens for Metastatic Castration-Resistant Prostate Cancer (mCRPC).
- Patients who have received a taxane based treatment or abiraterone, within 4 weeks before start of study treatment.