Safety and pharmacokinetics of odm-208 in patients with metastatic castration-resistant prostate cancer

Prior treatment

• 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).
• 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.
• 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).
• For Part 2 DDI cohort: Use of opioids or benzodiazepines within 2 weeks prior to the start of the study treatment.
• Active or uncontrolled autoimmune disease requiring concurrent corticosteroid therapy.
• Use of aldosterone antagonist (e.g. spironolactone, eplerenone) and phenytoin within 4 weeks prior start of the study treatment.
• 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.
• 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.

Other illness

• History of pituitary dysfunction.
• 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.
• 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).
• For Part 1/Phase 1: Known brain metastases or active leptomeningeal disease. For Part 2/Phase 2: Known brain metastases.
• Active infection or other medical condition that would make corticosteroid contraindicated.
• For Part 1/Phase 1 only: Known gastrointestinal (GI) disease or GI procedure that may interfere with absorption of study treatment.

Lab values

• 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.

Age

• 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.

Other

• For Part 2 DDI cohort: Known sensitivity to midazolam or other anxiolytics, or concern for inability to tolerate 1 mg of oral midazolam.

• Written informed consent (IC) obtained.
• 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).
• [Obsolete inclusion criterion removed in Amendment 7.]
• 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.
• 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.
• Obsolete inclusion criteria removed in Amendment 12.
• Males aged ≥ 18 years.
• Life expectancy > 3 months.
• ECOG performance status 0-1.
• 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.
• Metastatic disease documented either by a positive bone scan, CT, PET/CT or MRI scan.
• Castration-resistant prostate cancer with serum testosterone < 50ng/dl (< 0.5 ng/ml,< 1.7 nmol/l).
• Patients must maintain ongoing androgen deprivation therapy with a gonadotropinreleasing hormone (GnRH) analogue (agonist oantagonist), or have had bilateral orchiectomy.
• 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.