Safety and pharmacokinetics of ODM-204 in patients with metastatic castration -resistant prostate cancer: an open-label, non - randomised, uncontrolled, multicentre, dose escalation, first-in- man study with additional expansion phase with a dose selected in the escalation phase

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2014-003642-26-LV
• Date of registration: 07/11/2014
• Prospective Registration: Yes
• Primary sponsor: Orion Corporation Orion Pharma
• Public title: Safety and pharmacokinetics of ODM-204 in patients with metastatic castration -resistant prostate cancer: an open-label, non - randomised, uncontrolled, multicentre, dose escalation, first-in- man study with additional expansion phase with a dose selected in the escalation phase
• Scientific title: SAFETY AND PHARMACOKINETICS OF ODM-204 IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (CRPC): OPEN, NONRANDOMISED, UNCONTROLLED, MULTICENTRE, DOSE ESCALATION, FIRST-IN-MAN STUDY WITH A DOSE EXPANSION - Dualides phase 1/2 study
• Date of first enrolment: 23/01/2015
• Target sample size: 75
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-003642-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Finland, Latvia, United Kingdom

Contacts

• Name: Virpi Mononen
• Affiliation: Orion Corporation Orion Pharma

• Name: Virpi Mononen
• Affiliation: Orion Corporation Orion Pharma

Key inclusion & exclusion criteria

Inclusion criteria:
1. Written informed consent (IC) obtained.
2. Male aged = 18 years.
3. Histologically or cytologically confirmed adenocarcinoma of prostate.
4. Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dl, 0.5 ng/ml, 0.5 ng/ml]) on GnRH agonist or antagonist therapy, or after bilateral orchiectomy.
Patients who have not undergone bilateral orchiectomy must continue GnRH therapy during the study.
5. Metastatic disease documented by bone scan, CT or magnetic resonance imaging (MRI).
6. Prostate cancer progression documented by one or more of the following criteria:
PSA progression defined by a minimum of 3 rising PSA levels with an interval of at least 1 week between each determination. The PSA value at the screening visit should be = 2 ng/ml.
- soft tissue disease progression as defined by RECIST 1.1 criteria
- bone disease progression defined by PCWG2 criteria (2 or more new lesions on bone scan compared with prior scan).
7. ECOG performance status 0-2.
8. Estimated life expectancy of at least 3 months.
9. Blood counts at screening:
- haemoglobin = 10 g/dl
- absolute neutrophil count = 1500/µl (1.5x10?/l)
- platelet count = 100,000/µl (100x10?/l )
The subject must not have received any growth factor or blood transfusion within 7 days of the haematology laboratory values obtained at the screening visit.
10. Liver, renal and albumin values at screening:
- ALT and AST = 2.5 x ULN
- total bilirubin = 1.5 x ULN (except for subjects with a diagnosis of Gilbert’s disease)
- creatinine = 1.5 x ULN
- albumin > 3.0 g/dl.
11. Serum potassium = 3.5 mmol/l.
12. Able to swallow study treatments and comply with study requirements.
13. Acceptable and regular bowel movements in the judgement of the investigator without any acute, subacute or chronic gastrointestinal (GI) obstruction or other GI disorder or procedure which may interfere significantly with absorption of study treatment.
14. Sexually active subjects, unless surgically sterile, must agree to use condoms and an additional effective contraception method during the study treatment and for 3 months after the end of the study treatment.
15. Patients on systemic glucocorticoids for the treatment of prostate cancer or control of symptoms must have documented PSA progression by PCWG2 criteria prior start of study treatment. Patients with confirmed PSA progression while on systemic corticosteroids
other than Prednison® are required to switch to Prednison® 5 mg (once or twice a day depending on the previous glucocorticoid dose) prior the start of study treatment, but PSA progression does not have to be reconfirmed.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 35
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 40

Exclusion criteria:
1. History of pituitary or adrenal dysfunction.
2. Known brain metastases.
3. Active infection or other medical condition that would make prednisone (corticosteroid) contraindicated.
4. Poorly controlled diabetes as judged by the investigator.
5. Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 4 weeks before the start of the study treatment.
6. Prior therapy with any investigational CYP17A1i (e.g. TAK-700, TOK-001) or any investigational second-generation AR inhibitors (e.g. ARN-509, ODM-201).
7. Depending upon patient’s prior treatment, the following apply:
- prior chemotherapy: not more than 2 prior chemotherapy treatments are allowed; chemotherapy is not allowed within 4 weeks before the start of the study treatment
- prior CYP17A1i therapy must have been stopped at minimum 4 weeks and at maximum 6 months before the start of the study treatment
- prior second-generation AR inhibitor therapy must have been stopped at minimum 4 weeks and at maximum 6 months before the start of the study treatment.
8. Use of first-generation AR inhibitor within 4 weeks (within 6 weeks for bicalutamide and nilutamide) before start of the study treatment.
9. Systemic therapy with ketoconazole, or any other azole drug (e.g. fluconazole, itraconazole) within 4 weeks before the start of the study treatment.
10. Use of estrogens, cyproterone acetate, 5-a reductase inhibitors (finasteride, dutasteride) or biologic treatment within 4 weeks before the start of the study treatment. Prior radiotherapy within 4 weeks or palliative radiotherapy within 2 weeks before start of study treatment.
11. Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not resolved to a NCI CTCAE (version 4.03) grade of = 1. Chemotherapy induced alopecia and grade 2 peripheral neuropathy is allowed.
12. Initiation of an osteoclast-targeted therapy (bisphosphonate or denosumab) within 4 weeks before the start of the study treatment. Patients on a stable dose of osteoclast-targeted therapy for at least 4 weeks before the start of the study treatment can continue the
treatment during the study.
13. Participation in another interventional clinical trial and any concurrent treatment with any other investigational drug except those mentioned in exclusion criterion 7 within 4 weeks before start of the study treatment.
14. Uncontrolled hypertension
? systolic BP = 160 mmHg or
? diastolic BP = 95 mmHg.
Subjects with history of hypertension can be included, provided that BP is controlled by
anti-hypertensive therapy.
15. Clinically significant heart disease as judged by the investigator, e.g. congestive heart
failure New York Heart Association (NYHA) class = 3, myocardial infarction, arterial
thrombotic events in the past 6 months, or unstable angina.
16. Prolonged QTc interval as evidenced by:
? history or family history of long QTc syndrome
? prolonged QT interval corrected by the Fridericia correction formula (QTcF) > 450 ms
on the cent

Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Metastatic castration resistant prostate cancer (mCRPC)
MedDRA version: 18.0 Level: PT Classification code 10036909 Term: Prostate cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 18.0 Level: LLT Classification code 10036916 Term: Prostate cancer stage D System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Product Name: ODM-204 50 mg
Product Code: ODM-204 50 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ODM-204
Current Sponsor code: ODM-204
Other descriptive name: ODM-204
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Product Name: ODM-204 100 mg
Product Code: ODM-204 100 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ODM-204
Current Sponsor code: ODM-204
Other descriptive name: ODM-204
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Main Objective: To evaluate safety and tolerability of ODM-204 including dose limiting
toxicities (DLTs) and the maximum tolerated dose (MTD), if possible

Secondary Objective: To evaluate:
- PK profile of ODM-204 and its metabolites ORM-24178, ORM-25367, ORM-26343 and possible other metabolites after a single and repeated administration in fed condition at different dose levels
- PD profile of ODM-204 (including hormone and circulating tumour cell [CTC] measurements)
- preliminary antitumour activity of ODM-204 in different populations to be studied (see section 4.1) according to the following criteria:
PSA response; response in bone and soft tissue; time on treatment;
the dose of ODM-204 for further clinical studies; long term safety and tolerability of ODM-204; time to PSA and radiological progression

Primary end point(s): Achieving a maximum tolerated dose (MTD) or dose limiting toxicity (DLT).

Timepoint(s) of evaluation of this end point: MTD is the dose level at which 2 or more out of 6 subjects in a cohort experience a DLT and those subjects who have received study treatment for 28 days or who had to discontinue study treatment earlier than 28 days because of DLT.
DLT is defined as any of the following toxicities with grade:
- = 3 toxicity, excluding haematological toxicities, nausea, vomiting and diarrhoea
- = 3 nausea, vomiting and diarrhoea uncontrolled with antiemetic and/or antidiarrheal therapy
- = 3 haematological toxicity lasting for = 7 days
- = 4 thrombocytopenia and neutropenia
- Other laboratory values of = grade 3 which are judged clinically significant by the investigator
- any other toxicity which in the judgement of the investigator and/or sponsor is viewed as a DLT.

Secondary Outcome(s)

Secondary end point(s): PK profile; hormone assessment and circulating tumour cells (CTC).
For preliminary antitumour activity a serum total PSA concentration (PSA response and progression) and soft tissue response and progression will be evaluated (chest, abdomen and pelvic CT or MRI will be performed); bone response and progression will be evaluated by a radionuclide bone scan.

Timepoint(s) of evaluation of this end point: - Serum total PSA concentration will be determined every 4 weeks until 24 weeks and every 12 weeks thereafter. In case of PSA progression a confirmatory test should be obtained 3-4 weeks later.
- Chest, abdomen and pelvic CT or MRI will be performed at screening, week 12 and every 12 weeks thereafter.
- Radionuclide bone scan will be performed at screening, week 12 and every 12 weeks thereafter, except for subjects with no bone metastasis or bone pain at week 12 the scan should be performed every 24 weeks. In case of bone progression, a confirmatory scan should be
performed in 6 weeks.

Secondary ID(s)

3116001

2014-003642-26-FI

Source(s) of Monetary Support

Orion Corporation Orion Pharma

Ethics review

Status: Approved
Approval date:
Contact: