| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| METASTATIC CASTRATION-RESISTANT PROSTATE CANCER OR ESTROGEN RECEPTOR-POSITIVE, HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2-NEGATIVE ADVANCED BREAST CANCER |
|
| E.1.1.1 | Medical condition in easily understood language |
| METASTATIC CASTRATION-RESISTANT PROSTATE CANCER OR ADVANCED BREAST CANCER |
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| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast 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:
Primary objectives are
- to evaluate the safety and tolerability of ODM-209;
- to define the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of ODM-209, if feasible;
- to define the recommended dose of ODM-209 for prostate cancer and breast cancer and replacement therapy for Part 2 of the study.
Part 2:
- to further evaluate the safety and tolerability of ODM-209;
- to evaluate the preliminary anticancer activity of ODM-209. |
|
| E.2.2 | Secondary objectives of the trial |
Part 1:
- to characterise the pharmacokinetics (PK) of ODM-209 and its major metabolite ORM-38045 after single and repeated administrations;
- to evaluate the dosing schedule of ODM-209.
Part 2:
- to evaluate the recommended dose of ODM-209 for further clinical studies. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
PC patients
1Signed written IC obtained
2Male aged ≥18 years
3Patients with histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
4Metastatic disease documented with a biopsy and/or imaging using CTor MRI
5CRPC with serum testosterone < 50 ng/dl (< 1.7 nmol/l)
6Have documented disease progression by one or more of the following criteria
a.PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ≥ 1 week between each assessment with serum PSA at the time of screening ≥ 2 ng/ml b.Soft tissue disease progression as defined by the RECIST 1.1 criteria c.Bone disease progression as defined by the PCWG3 criteria
7Patients must maintain ongoing androgen deprivation therapy with a gonadotropin releasing hormone analogue (either an agonist or an antagonist) or have had bilateral orchiectomy
8Performance status 0-1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
9Have had treatment with at least 1 line of chemotherapy for advanced disease or be ineligible for chemotherapy
10Have had treatment with targeted endocrine therapy (defined as a second-generation antiandrogen therapy with e.g. abiraterone, enzalutamide, apalutamide, darolutamide) for castration-sensitive prostate cancer (CSPC) and/or for CRPC
11Adequate marrow, liver, and kidney function defined as follows
•hemoglobin ≥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)•serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x the upper limit of normal (ULN) (≤5.0 x ULN if liver metastases present)•serum total bilirubin ≤1.5 x ULN (< 3 ULN if Gilbert's syndrome)•serum albumin ≥3.0 g/dl•serum/plasma creatinine ≤1.5 ULN•serum potassium and sodium within the institutional normal reference range limits
12Resolution of the acute toxic effects from prior cancer therapy or surgical procedures to the NCI CTCAE v4.03 Grade ≤1 (except for alopecia, nail changes, and grade 2 peripheral neuropathy)
13Able to follow the study instructions, to comply with the replacement therapy dosing and regimen, and other study requirements
14Able to swallow tablets
14Able to swallow tablets
15AR mutation positive cohorts
BC patients
1 Signed written IC obtained
2 Female aged ≥18 years who are either
•Postmenopausal, as defined by at least one of the following criteria: age ≥ 60 years;age < 60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females documented bilateral oophorectomy
medically confirmed ovarian failure•Pre/peri-menopausal (i.e not meeting the criteria for being postmenopausal) if amenable to be treated
with the GnRH agonist or antagonist. Patients must have commenced treatment with GnRH agonist or antagonist at least 4 weeks prior to start of study treatment
3 Patients with histologically confirmed breast carcinoma4. ER-positive breast cancer (defined as >1% cancer cell nuclei stain positively) based on a biopsy
5 HER2-negative breast cancer (defined as immunohistochemistry [IHC] status 0 or 1+ or negative in situ hybridization [ISH] test) based on the most recent biopsy. If HER2 IHC is 2+ a negative ISH test is required. HER2 3+ (IHC) do not need ISH confirmation 6. Performance status 0-1 on the ECOG Performance Scale
7 In Part 1: Either measurable or non-measurable disease by RECIST 1.1, or bone-only metastatic disease confirmed by CT or MRI. In Part 2Measurable disease by the RECIST
8 Have documented disease progression after treatment with at least 2 lines of systemic treatment for advanced breast cancer. Of these, at least
one line must have been endocrine treatment
9 Adequate marrow, liver, and kidney function defined as follows •hemoglobin ≥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)•serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x the upper limit of normal (ULN) (≤5.0 x ULN if liver metastases present) •
serum total bilirubin ≤1.5 x ULN (< 3 ULN if Gilbert's syndrome)•serum albumin ≥3.0 g/dl•serum/plasma creatinine ≤1.5 ULN•serum potassium and sodium within the institutional normal reference range limits
10 Resolution of acute side effects from prior cancer therapy or surgical procedures to the NCI CTCAE v4.03 Grade ≤1 (except for alopecia, nail
changes, and grade 2 peripheral neuropathy)
11 Able to follow the study instructions, to comply with the replacement therapy dosing and regimen, and other study requirements
12 Able to swallow tablets
13 ESR1 mutation–negative cohort(s):absence of somatic mutation in the LBD of ESR1
|
|
| E.4 | Principal exclusion criteria |
Prostate cancer patients
1. History of pituitary dysfunction
2. Known brain metastases or active leptomeningeal disease
3. Concurrent other invasive malignancy; patients who have undergone potentially curative therapy for a prior invasive malignancy are eligible provided there is no evidence of disease for ≥ 5 years after the diagnosis
4. Active or uncontrolled autoimmune disease requiring concurrent corticosteroid therapy
5. Active infection or other medical condition that would make corticosteroids contraindicated
6. Use of aldosterone antagonist or phenytoin within 4 weeks prior to start of study treatment
7. Patients with an unstable dose of thyroid hormone replacement therapy within 6 months prior to the start of the study treatment
8. Chemotherapy (or CDK4/6 inhibitor therapy in Breast cancer patients)
within 3 weeks prior to the start of the study treatment
9. Radiotherapy within 2 weeks prior to start of the study treatment
10. 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 agonists/antagonists) within 3 weeks prior to the start of the study treatment. Use of immune checkpoint inhibitor within 12 weeks prior to start of the study treatment.
11. Use of any investigational second-generation antiandrogen therapy (prostate cancer) in phase 2
12. GI disease that may interfere with absorption of the study treatment
13. Poorly controlled diabetes or other diseases that may interfere with the study treatment
14. History of seizure or any condition that may predispose to seizure
15. Clinically significant cardiovascular disease, e.g. myocardial infarction, arterial thrombotic events, or pulmonary embolism in the past 6 months, unstable angina, or congestive heart failure (NYHA class II-IV)
16. Recent symptomatic cerebrovascular accident within one month e.g. TIA, stroke or cerebral hemorrhage
17. Hypotension: supine systolic BP < 110 mmHg, or uncontrolled hypertension: supine systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg, in 2 out of 3 recordings with optimized antihypertensive therapy
18. History or family history of the long QTc syndrome. Repeatable prolongation of the QTcF interval > 450 ms or any clinically significant abnormality in the ECG
19. Sexually active subject, who does not agree to use condoms during the study and until 3 months after the last dose of ODM-209 (prostate cancer)
20. Major surgery within 4 weeks before the start of the study treatment
21. Severe or uncontrolled concurrent medical condition or psychiatric illness
22. Known history of HIV infection
23. Acute or chronic hepatitis B or hepatitis C infection
24. Use of any investigational drug 4 weeks (immune checkpoint inhibitors 12 weeks) prior to the start of the study treatment
For breast cancer only:
10. Administration of endocrine therapy other than GnRH therapy for breast cancer in premenopausal women within 2 weeks (except for fulvestrant within 4 weeks), or ovarian ablation therapy within 8 weeks prior to the start of the study treatment
22. Subject is pregnant or breast-feeding. Subject with childbearing potential (i.e. menstruating, or less than 12 months from the last menstruation) must have a negative pregnancy test
23. Subject of childbearing potential who does not agree to use highly effective contraception (e.g. hormonal contraception, intrauterine device [IUD] or surgical sterilization during the study and until 3 months after the last dose of ODM-209
24. Use of any investigational drug 4 weeks (immune checkpoint inhibitors 12 weeks) prior to the start of the study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Safety: (serious) adverse events, vital signs including blood pressure, heart rate, body temperature and orthostatic test, 12-lead ECGs, physical exams, laboratory assessments: hematology, chemistry, urinalysis.
- Efficacy assessments: Serum total PSA (only PC patients), soft tissue response by CT or MRI scan, bone scan (only PC patients), ECOG performance score, bone mineral density
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Safety: Determined at several time-points (continuously/every visit)
- 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
|
|
| E.5.2 | Secondary end point(s) |
- Pharmacokinetic assessments: Part 1: Multiple blood samples for PK; additional single samples; Part 2 single samples
- Plasma samples for protein binding;
Metabolite screening: Multiple blood samples; urine collection
- Pharmacodynamic assessments: Testosterone level or estradiol and estrone level and other steroid hormones
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Pharmacokinetic assessments: Part 1: Multiple blood samples for PK on study days 1 and 8; additional single samples on days 15 and 29 and week 16; Part 2 single samples on Day 1 and 15 and at week 16
- Plasma samples for protein binding at 2 time points on Day 8;
Metabolite screening: Multiple blood samples on study days 1 and 8, and a single sample on Day29; urine collection on study days 1 and 8
- Pharmacodynamic assessments: Testosterone level or estradiol and estrone level and other steroid hormones: Multiple blood samples on study days 1 and 8. PD patients single samples on day 29, wk 16, wk 24, and every 12 weeks thereafter
|
|
| 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.8.3 |
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 | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 23 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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