| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic castration-resistant prostate cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic castration-resistant prostate cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Part 1/Phase1:
Primary objectives are:
- to evaluate the safety and tolerability of ODM-208 in patients with metastatic castration-resistant prostate cancer (mCRPC),
- to define the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of ODM-208, if possible,
- to define the recommended dose of ODM-208 for Part 2 of the study.
Part 2/Phase 2:
Primary objectives are:
- to further evaluate the safety and tolerability of ODM-208,
- to further evaluate antitumour activity of ODM-208 in mCRPC patients with mutated androgen receptor (AR) ligand-binding domain (LBD) who have progressed after novel AR targeted therapy and taxane-based chemotherapy
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|
| E.2.2 | Secondary objectives of the trial |
Part 1/Phase 1:
Secondary objectives are:
- to characterise the pharmacokinetics (PK) of ODM-208 after single and repeated administration,
- to evaluate dosing schedule of ODM-208.
- to evaluate preliminary antitumour activity of ODM-208.
Part 2/Phase 2:
Secondary objectives are:
- to evaluate different AR LBD mutations and their association with antitumour activity of ODM-208 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent (IC) obtained.
2. Males aged ≥ 18 years.
3. Life expectancy > 3 months.
4. ECOG performance status 0-1.
5. For Part 1/Phase 1: Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.
For Part 2/Phase 2: Histologically confirmed adenocarcinoma of the prostate without pure small cell features.
6. Metastatic disease documented either by a positive bone scan, CT, PET/CT or MRI scan.
7.Castration-resistant prostate cancer with serum testosterone < 50 ng/dl (< 0.5 ng/ml,< 1.7 nmol/l).
8. Patients must maintain ongoing androgen deprivation therapy with a gonadotropinreleasing hormone (GnRH) analogue (agonist or antagonist), or have had bilateral orchiectomy.
9. For Part 1/Phase 1: Treatment with at least 1 line of chemotherapy or ineligibility for chemotherapy. For Part 2/Phase 2: Treatment with at least 1 line of taxane-based chemotherapy in castration-sensitive prostate cancer (CSPC) or in CRPC.
10. Treatment of at least 1 line of novel AR targeted hormonal therapy in CSPC or in CRPC for a minimum of 12 weeks (e.g. abiraterone, enzalutamide, darolutamide, apalutamide).
11. [Obsolete inclusion criterion removed in Amendment 7.]
12. Documented disease progression by one or more of the following criteria:
- PSA progression defined by a minimum of 2 elevated PSA levels with an interval of at least 1 week between the measurements. The PSA value at the screening visit should be >=1 ng/ml (For Part2/Phase 2), >=2 ng/ml (for Part 1/Phase 1).
- soft tissue disease progression as defined by RECIST 1.1 criteria.
- bone disease progression as defined by PCWG3 criteria.
13. Adequate marrow, liver and kidney function.
- haemoglobin ≥ 10 g/dl (in absence of blood transfusion within 7 days of value obtained)
- absolute neutrophil count (ANC) ≥ 1500/μl (1.5 x 10⁹/l)
- platelet count ≥ 100 000/μl (100 x 10⁹/l )
- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) (≤ 5.0 x ULN if liver metastases present)
- total bilirubin ≤ 1.5 x ULN (< 3 ULN if Gilbert's syndrome)
- albumin ≥ 3.0 g/dl
- creatinine ≤ 1.5 ULN or calculated creatinine clearance ≥ 60 ml/min/1.73 m2 for patients with creatinine levels above normal limit
17. For Part 2/Phase 2 only (added in Amendment 7): Patients with identified activating mutation in the LBD of AR in plasma ctDNA confirmed by the central testing |
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| E.4 | Principal exclusion criteria |
1. History of pituitary dysfunction.
2. For Part 1/Phase 1: Known brain metastases or active leptomeningeal disease. For Part 2/Phase 2: Known brain metastases.
3. Other concurrent malignancies, except adequately treated basal cell or squamous cell carcinoma of the skin. Patients who have undergone potentially curative therapy for a prior malignancy are eligible provided there is no evidence of disease for > 3 years (Part 2/Phase 2) or >=5 years (Part 1/Phase 1) and patient is deemed to be at low risk for recurrence.
4. Active or uncontrolled autoimmune disease requiring concurrent corticosteroid therapy.
5. Active infection or other medical condition that would make corticosteroid contraindicated.
6. Use of aldosterone antagonist (e.g. spironolactone, eplerenone) and phenytoin within 4 weeks prior start of the study treatment.
8. Prior radiotherapy, chemotherapy within the last 4 weeks (2 weeks for oral or weekly chemotherapy; 6 weeks for nitrosoureas and mitomycin C) prior to the start of the study treatment. Concurrent radiotherapy for palliation is allowed.
9. Part 1/Phase 1: Use of enzalutamide within 4 weeks and abiraterone acetate within 2 weeks prior to the start of study treatment. Use of other
anticancer therapy (excluding GnRH) within 4 weeks prior to the start of the study treatment. Use of immune checkpoint inhibitor within 12
weeks prior to the start of the study treatment (amendment 4)
Part 2/Phase 2: Use of enzalutamide and apalutamide within 3 weeks, use of darolutamide and abiraterone acetate within 2 weeks prior to the start of study treatment. Use of other anticancer therapy (excluding GnRH) within 4 weeks prior to the start of the study treatment. Use of immune checkpoint inhibitor within 12 weeks prior to the start of the study treatment.
10. For Part 1/Phase 1 only: Known gastrointestinal (GI) disease or GI procedure that may interfere with absorption of study treatment.
12. Hypotension: systolic BP < 110 mmHg, or uncontrolled hypertension: systolic ≥ BP 160 mmHg or diastolic ≥ BP 90 mmHg (for Part 2/Phase 2:
95 mmHg), in 2 out of 3 recordings with optimized antihypertensive therapy.
14. Active or unstable cardio/cerebro-vascular disease, including thromboembolic events. Examples include recent (within 6 months) myocardial infarction, coronary artery bypass graft or symptomatic cerebrovascular accident or congestive heart failure (New York Heart Association class III-IV) (for Part 1/Phase 1), III-IV (for Part 2/Phase 2).
15. History or family history of long QTc syndrome. Repeatable prolongation (2 out of 3 recordings) of QTcF interval > 450 ms (for Part 1/Phase 1), > 470 ms (for Part 2/Phase 2), or any clinically significant abnormality in the centrally-read ECG.
19. Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
21. Participation in another interventional clinical trial with an investigational agent or any concurrent treatment with any investigational drug 4 weeks (immune checkpoint inhibitors 12 weeks) prior to the start of the study treatment. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Safety: adverse events, vital signs including blood pressure, heart rate, body temperature and orthostatic test (part 1 only), 12-lead ECGs; physical exams, laboratory assessments: hematology, chemistry, urinalysis. Determined at several time-points
- MTD/DLTs
- Efficacy assessments: Serum total PSA, soft tissue response by CT or MRI scan, bone scan, ECOG performance score. Circulating tumour cell (CTC) response (Part 2 only) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Safety: Determined at several time-points
- Efficacy assessments: Serum total PSA (every 4 weeks for 24 weeks; every 12 weeks thereafter), soft tissue response by CT or MRI scan (every 8 weeks for 24 weeks; every 12 weeks thereafter), bone scan (every 8 weeks for 24 weeks; every 12 weeks thereafter), ECOG performance score at each visit. CTC response Day1 + Wk12
|
|
| E.5.2 | Secondary end point(s) |
- Pharmacokinetic assessments: Multiple blood samples for PK; Plasma samples for protein binding
- Metabolite screening: Multiple blood samples and urine collection
- Recommended dose for further studies.
Exploratory:
- Pharmacodynamic assessments: Testosterone level and other steroid hormones;
- Biomarker assessments: Biomarkers in plasma may be performed on the steroid hormone samples; Optional assessments on fresh and archival tumors biopsies; Germline DNA and pharmacogenomics.
- to evaluate the relationship between AR-V7 splicing variant and antitumor activity of ODM-208 (Part 2/Phase 2 only)
- molecular biomarkers at genomic, protein and metabolite level from plasma/serum
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Pharmacokinetic assessments: Multiple blood samples for PK on study days 1 and 8; Plasma samples for protein binding at 2 time points on Day 8;
- Metabolite screening: Multiple blood samples on study days 1 and 8; urine collection on study days 1 and 8
- Recommended dose for further studies.
Exploratory:
- Pharmacodynamic assessments: Testosterone level and other steroid hormones; Multiple blood samples on study days 1 and 8
- Biomarker assessments: Biomarkers in plasma may be performed on the steroid hormone samples; Optional assessments on fresh and archival tumors biopsies; Germline DNA and pharmacogenomics: at pre-dose on Day 1.
|
|
| 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 | No |
| 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 | Yes |
| 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 | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 end of the study is defined as the date of the last subject’s last visit or last contact with the study site. |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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