OPEVESOSTAT for Metastatic castration-resistant prostate cancer

Inclusion criteria

• {"criterion_text":"- Written informed consent (IC) obtained.\n- 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).\n- [Obsolete inclusion criterion removed in Amendment 7.]\n- 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/Phase1). - soft tissue disease progression as defined by RECIST 1.1 criteria. - bone disease progression as defined by PCWG3 criteria.\n- 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). For Part 2 DDI cohort: AST and ALT ≤ 1.5 x ULN. - total bilirubin ≤ 1.5 x ULN (< 3 ULN if Gilbert's syndrome); \\ For Part 2 . DDI cohort: total bilirubin ≤ ULN -albumin ≥ 3.0 g/dl; For Part 2 DDI cohort: albumin ≥ 3.2 g/dl - creatinine clearance ≥ 60 ml/min using serum creatinine.\n- Obsolete inclusion criteria removed in Amendment 12.\n- Males aged ≥ 18 years.\n- Life expectancy > 3 months.\n- ECOG performance status 0-1.\n- For Part 1/Phase1: 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.\n- Metastatic disease documented either by a positive bone scan, CT, PET/CT or MRI scan.\n- Castration-resistant prostate cancer with serum testosterone < 50ng/dl (< 0.5 ng/ml,< 1.7 nmol/l).\n- Patients must maintain ongoing androgen deprivation therapy with a gonadotropinreleasing hormone (GnRH) analogue (agonist oantagonist), or have had bilateral orchiectomy.\n- 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."}

Exclusion criteria

• {"criterion_text":"- History of pituitary dysfunction.\n- 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.\n- 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).\n- 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.\n- Part 1/Phase 1 (Finland, France and UK) and Part 2/Phase 2 (France and UK): Known history of human immunodeficiency virus (HIV), or acute or chronic hepatitis B or hepatitis C disease. Part 2/Phase 2 (US and Finland): Patients with HIV on established antiretroviral therapy (ART) less than four weeks and/or an HIV viral load more than 400 copies/mL prior to enrolment (added in Amendment 8).\n- Participation in another interventional clinical trial with an investigational agent 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.\n- Part 2/Phase 2 (excluding DDI cohort): Systemic use of the following medications within 2 weeks prior to the start of study treatment (added in Amendment 8): -Strong CYP3A4 inducers: E.g. avasimibe, carbamazepine, lumacaftor, phenobarbital, rifampicin, rifapentine, St John's Wort -P-gp inhibitors: erythromycin, clarithromycin, rifampicin, ketoconazole, itraconazole, posaconazole, artesunate-pyronaridine, ritonavir, indinavir, nelfinavir, atazanavir, glecaprevir-pibrentasvir, simeprevir, ledipasvirsofosbuvir, verapamil, diltiazem, dronedarone, propafenone, quinidine, cyclosporine, valspodar, milk thistle (Silybum marianum) For Part 2 DDI cohort: Systemic use of the following medications within 3 weeks prior to the start of study treatment (added in Amendment 13): •moderate and strong CYP3A4 inducers and inhibitors (the duration of the wash-out should be discussed with the Sponsor) •mild CYP3A4 inducers and inhibitors •P-gp inhibitors: erythromycin, clarithromycin, rifampicin, ketoconazole, itraconazole, posaconazole, artesunate-pyronaridine, ritonavir, indinavir, nelfinavir, atazanavir, glecaprevir-pibrentasvir, simeprevir, ledipasvirsofosbuvir, verapamil, diltiazem, dronedarone, propafenone, quinidine, cyclosporine, valspodar, milk thistle (Silybum marianum).\n- For Part 2 DDI cohort: Use of opioids or benzodiazepines within 2 weeks prior to the start of the study treatment.\n- For Part 2 DDI cohort: Known sensitivity to midazolam or other anxiolytics, or concern for inability to tolerate 1 mg of oral midazolam.\n- For Part 1/Phase 1: Known brain metastases or active leptomeningeal disease. For Part 2/Phase 2: Known brain metastases.\n- 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.\n- Active or uncontrolled autoimmune disease requiring concurrent corticosteroid therapy.\n- Active infection or other medical condition that would make corticosteroid contraindicated.\n- Use of aldosterone antagonist (e.g. spironolactone, eplerenone) and phenytoin within 4 weeks prior start of the study treatment.\n- 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.\n- 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.\n- For Part 1/Phase 1 only: Known gastrointestinal (GI) disease or GI procedure that may interfere with absorption of study treatment."}

Primary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Safety assessed by adverse events, vital signs (blood pressure, heart rate, body temperature), orthostatic test (Part 1 only), 12-lead ECGs, physical exams and laboratory assessments (hematology, chemistry, urinalysis) at multiple scheduled time-points."}
• {"endpoint_text":"- MTD/DLTs","definition_or_measurement_approach":"Maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) determined in Part 1/Phase 1 using dose-escalation rules to identify MTD/DLTs and to define the recommended dose for Part 2."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Efficacy measured by serum total PSA, imaging response (soft tissue response by CT or MRI using RECIST 1.1), bone scan assessments (PCWG3 criteria), ECOG performance status, and circulating tumour cell (CTC) response (Part 2 only)."}

Secondary endpoints

• {"endpoint_text":"- 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. - evaluate different AR LBD activating mutations and their association with antitumour activity of ODM-208.","definition_or_measurement_approach":"Pharmacokinetics assessed with multiple blood samples for PK, plasma samples for protein binding; metabolite screening via blood and urine collections. Includes determination of recommended dose for further studies and evaluation of association between AR LBD activating mutations and antitumour activity."}
• {"endpoint_text":"Exploratory: - Pharmacodynamic assessments: Testosterone level and other steroid hormones; - Biomarker assessments: Biomarkers in plasma may be performed on the steroid hormone samples; Germline DNA and pharmacogenomics. - to evaluate the relationship between AR-V7 splicing variant and antitumor activity of ODM-208 (Part 2/Phase 2 only)","definition_or_measurement_approach":"Pharmacodynamic assessments include measurement of testosterone and other steroid hormones. Biomarker assessments may include plasma biomarkers from steroid hormone samples, germline DNA and pharmacogenomics analyses, and evaluation of AR-V7 splicing variant relationship with antitumor activity (Part 2 only)."}
• {"endpoint_text":"Exploratory: - molecular biomarkers at genomic, protein and metabolite level from plasma/serum - overall survival assessment (Part 2/Phase 2 only)","definition_or_measurement_approach":"Exploratory molecular biomarker assessments at genomic, protein and metabolite levels from plasma/serum. Overall survival assessed in Part 2/Phase 2."}

Other endpoints

• {"endpoint_text":"- Pharmacodynamic assessments: Testosterone level and other steroid hormones; - Biomarker assessments: Biomarkers in plasma may be performed on the steroid hormone samples; Germline DNA and pharmacogenomics. - to evaluate the relationship between AR-V7 splicing variant and antitumor activity of ODM-208 (Part 2/Phase 2 only)","definition_or_measurement_approach":"See secondary/exploratory definitions: PD assessments (testosterone and steroid hormones), biomarker assessments in plasma, germline DNA and pharmacogenomics; evaluation of AR-V7 relationship with antitumor activity (Part 2)."}
• {"endpoint_text":"- molecular biomarkers at genomic, protein and metabolite level from plasma/serum - overall survival assessment (Part 2/Phase 2 only)","definition_or_measurement_approach":"Exploratory molecular biomarker analyses on plasma/serum (genomic, protein, metabolite) and overall survival assessment in Part 2."}

Finland

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

29-10-2024

Processing Time Days

15

Number Of Sites

2

Number Of Participants

13

France

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

07-11-2024

Processing Time Days

24

Number Of Sites

6

Number Of Participants

116

Primary sponsor

Full Name

Orion Corporation

Organisation Type

Pharmaceutical company

Country Of Registered Address

Finland

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

Vendor management (Labcorp, Clario=eRT)

Third parties

• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Central laboratory for safety labs; Central laboratory for PD assessments","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Ardena Bioanalysis B.V.","duties_or_roles":"Bioanalytical laboratory","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"Central laboratory for safety labs; Central laboratory for PD assessments","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Central ECG","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Eurofins Genomics Europe Applied Genomics GmbH","duties_or_roles":"DNA extraction","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Guardant Health Inc.","duties_or_roles":"AR mutation testing for patient pre-screening purpose","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"Vendor management (Labcorp, Clario=eRT)","organisation_type":"Pharmaceutical company"}
• {"country":"Finland","full_name":"Orion Corporation","duties_or_roles":"Exploratory analytics","organisation_type":"Pharmaceutical company"}