| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with metastatic castrate resistent prostate cancer (CRPC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with prostate cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the safety and tolerability profile of enzalutamide in combination with BI 836845 and to evaluate the anti-tumour activity of the combination treatment, versus enzalutamide alone, in patients with CRPC. |
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| E.2.2 | Secondary objectives of the trial |
| To determine prostate serum antigen (PSA) response and progression in combination with anti-tumour activity, changes in circulating tumour cells (CTC), plus overall survival (in phase II only) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- 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 more than 50% as determined by ECHO or MUGA.
- International normalized ratio (INR) ≤ 2 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%.
Inclusion criteria only for patients entering phase Ib escalation and phase II:
- 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.
Inclusion criterion only for patients entering phase Ib expansion cohort:
- Patients must be receiving continuous enzalutamide treatment and be failing this treatment prior to entering the study, as indicated by a rise in 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.
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| E.4 | Principal exclusion criteria |
- 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.
Exclusion criterion only for patients entering phase Ib expansion cohort:
- Patients that have received prior taxane-based therapy or abiraterone in any setting will not be eligible for the expansion cohort.
- Patients that are in immediate need of chemotherapy (e.g. for visceral disease, or
intractable pain) should be excluded.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1: Number of patients with dose limiting toxicities (phase Ib escalation)
2: Maximum tolerated dose (phase Ib escalation)
3: PSA response - defined as a decline in PSA value >50%, which is confirmed by a second value 3-4 weeks apart (phase Ib expansion)
4: Radiological progression free survival - defined as time from randomisation to disease progression based on investigator asessment in bone based on PCWG2 or soft tissue based on modified RECIST 1.1 where applicable, or death (phase II)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1: 6 months
2: 6 months
3: Up to 3 years
4: Up to 3 years
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| E.5.2 | Secondary end point(s) |
1: Changes in circulating tumour cells (CTC) response - CTC reduction compared to baseline for at least one time point after treatment defined as CTC decline from 5 to <5 cells per 7.5ml blood (phase Ib expansion)
2: Radiological progression free survival - defined as time from randomisation to disease progression based on investigator assessment in bone based on PCWG2 or soft tissue based on modified RECIST 1.1 where applicable, or death (phase Ib expansion)
3: Overall survival - defined as the time from randomisation to death from any cause (phase II)
4: Time to PSA progression - defined as the date that a 25% or greater increase in PSA, and an absolute increase of 2 ng/mL or more from the nadir, is documented, which is confirmed by a second value 3 or more weeks later (phase II)
5: Maximum decline in PSA - compared to baseline that occurs at any point after treatment start (phase II)
6: Percentage change in PSA - from baseline to week 12 of treatment (phase II)
7: PSA response - defined as a decline in PSA value >50%, which is confirmed by a second value 3 to 4 weeks apart (phase II)
8: Changes in circulating tumour cells (CTC) response - CTC reduction compared to baseline for at least one time point after treatment start assessed by CTC decline from, equal to, or more than, 5 to <5 cells per 7.5ml blood (phase II)
9: Changes in circulating tumour cells (CTC) response-CTC reduction compared to baseline for at least one time point after treatment start assessed by maximum change in CTC counts compared to baseline that occurs at any point after treatment start (phase II)
10: Radiological progression free survival - defined as time from randomisation to disease progression based on central review in bone based on PCWG2 or soft tissue based on modified RECIST 1.1 where applicable, or death (phase II)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: Up to 3 years
2: Up to 3 years
3: Up to 3 years
4: Up to 3 years
5: Up to 3 years
6:Up to 3 years
7: Up to 3 years
8: Up to 3 years
9: Up to 3 years
10:Up to 3 years
6: Up to 3 years
7: Up to 3 years
8: Up to 3 years
9: Up to 3 years
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First in human to combine BI 836845 with enzalutamide to find a safe and tolerable dose |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Hong Kong |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The trial will end when the last patient in both the phase Ib expansion and phase II trial has completed at least the last follow-up visit and an adequate number of overall survival events have been recorded while patients are still in the observation phase of the trial in phase II. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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