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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Orion Corporation

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Mar 2018 → 28 Apr 2026

Decision date (initial)

2024-10-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Orion Corporation

External identifiers

EU CT number

2024-517439-39-00

EudraCT number

2017-002534-23

WHO UTN

U1111-1312-5050

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacogenomic, Pharmacogenetic, Dose response, Efficacy, Pharmacokinetic, Safety

Part 1/Phase 1:
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 and without mutated androgen receptor (AR) ligand-binding domain (LBD) who have progressed after novel AR targeted therapy and taxane-based chemotherapy
- to evaluate potential for DDI due to time-dependent inhibition of CYP3A4 by ODM-208 (added in Amendment 13).

Secondary objectives 2

1. 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.
2. Part 2/Phase 2: Secondary objectives are: - to evaluate different AR LBD mutations and their association with antitumour activity of ODM-208

Conditions and MedDRA coding

Metastatic castration-resistant prostate cancer.

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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/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.
6. Metastatic disease documented either by a positive bone scan, CT, PET/CT or MRI scan.
7. Castration-resistant prostate cancer with serum testosterone < 50ng/dl (< 0.5 ng/ml,< 1.7 nmol/l).
8. Patients must maintain ongoing androgen deprivation therapy with a gonadotropinreleasing hormone (GnRH) analogue (agonist oantagonist), 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/Phase1). - 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). 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.
14. Obsolete inclusion criteria removed in Amendment 12.

Exclusion criteria 17

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.
7. 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.
8. 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.
9. For Part 1/Phase 1 only: Known gastrointestinal (GI) disease or GI procedure that may interfere with absorption of study treatment.
10. 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.
11. 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).
12. 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.
13. 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).
14. 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.
15. 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).
16. For Part 2 DDI cohort: Use of opioids or benzodiazepines within 2 weeks prior to the start of the study treatment.
17. For Part 2 DDI cohort: Known sensitivity to midazolam or other anxiolytics, or concern for inability to tolerate 1 mg of oral midazolam.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. - 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)

Secondary endpoints 3

1. - 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.
2. 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)
3. Exploratory: - molecular biomarkers at genomic, protein and metabolite level from plasma/serum - overall survival assessment (Part 2/Phase 2 only)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Orion Corporation

Sponsor organisation

Orion Corporation

Address

P. O. Box 65

City

Espoo

Postcode

02101

Country

Finland

Scientific contact point

Organisation

Orion Corporation

Contact name

Clinical Trial Director

Public contact point

Organisation

Orion Corporation

Contact name

Clinical Trial Director

Third parties 8

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications