| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
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| 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:
To evaluate the safety and tolerability, define the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) if possible, and define the recommended doses and dosing schedules of ODM-207 for Part 2 of the study.
Part 2:
To further evaluate the safety and tolerability, and preliminary antitumour activity of ODM-207 at the dose levels recommended for further clinical studies in patient populations with selected tumour types.
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| E.2.2 | Secondary objectives of the trial |
Part 1:
To characterise the pharmacokinetics (PK) of ODM-207 and its main metabolite ORM-32469 after single and repeated administration, evaluate the effect of food on bioavailability and to generate preliminary biomarker evidence of non-tumour target inhibition and antitumour activity.
Part 2:
To evaluate the doses and the dosing schedules of ODM-207 recommended for further clinical studies.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent obtained
2. Male or female patients of age ≥18 years in Part 1A or ≥15 years in Part 1B and Part 2
3. Life expectancy >12 weeks
4. Availability of tumour tissue sample
5. Patients with histologically or cytologically confirmed locally advanced or metastatic cancer for which no effective standard therapy exists or are refractory or resistant to conventional therapy, or the patient actively refuses use of chemotherapy which would be regarded standard and/or if in the judgment of the investigator, experimental treatment is clinically and ethically acceptable.
8. Adequate haemopoietic, hepatic, renal and coagulation function. Functionality may be judged clinically adequate even if some of the measures deviate marginally from the followings. Such cases should be discussed with the medical monitor prior to making decision on eligibility.
• ANC ≥ 1.5 x 109/l
• platelet count ≥ 100 x 109/l
• haemoglobin ≥ 9 g/dl in the absence of transfusions within 2 weeks before the start of study treatment
• bilirubin ≤ 1.5 x upper limit of normal (ULN) and for patients with a diagnosis of Gilbert’s disease ≤ 3 x ULN;
• AST and ALT ≤ 3 x ULN; alternatively ≤ 5 x ULN may be accepted if liver metastases are present after agreement with the sponsor and the medical monitor
• albumin ≥ 3.0 g/dl
• serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 ml/min/1.73 m2 for patients with creatinine levels above normal limit.
• adequate coagulation function as defined by partial thromboplastin time (PTT) ≤ 1.5 ULN
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Patients with an ECOG of 2 who are considered to have significantly greater likelihood of response to ODM-207 (e.g. based on mechanism of action, biomarker information, ex-vivo pre-screening or other supporting evidence) may be considered eligible if otherwise judged clinically eligible. Such cases should be discussed with the medical monitor prior to making decision on eligibility.
10. Recovery from adverse events of previous systemic anti-cancer therapies to normal or grade 1 level except for alopecia or stable neuropathy of grade 2 induced by prior cancer treatment.
Diagnosis-specific criteria |
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| E.4 | Principal exclusion criteria |
1. History of bleeding disorder or significant bleeding episode (e.g. from the gastrointestinal tract) within 6 months prior to study treatment.
2. Patients receiving anticoagulants (e.g. warfarin) or medications that durably inhibit platelet function (e.g. aspirin, clopidogrel, tirofiban). Wash-out period for these agents is 7 days prior to study treatment. Use of low molecular weight heparins (LMWH) is allowed if the patient has a stable coagulation profile.
3. History or current leptomeningeal or brain metastasis or spinal cord compression.
Patients previously treated for these conditions that have had stable CNS disease for >1 month, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted in Part 1B and Part 2 of the study.
4. Significant cardiovascular conditions or circumstances as listed below. The condition may be judged not clinically significant even if it deviates marginally from the following criteria. Such cases should be discussed with the medical monitor prior to making decision on eligibility.
• Active or unstable cardio/cerebro-vascular disease including thromboembolic event. 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).
• Uncontrolled hypertension: systolic blood pressure (BP) ≥ 160 mmHg or diastolic BP ≥ 90 mmHg with optimised antihypertensive therapy.
• History of severe arrhythmia, familial arrhythmia, clinically significant conduction abnormality or congenital long QT syndrome.
• Repeatable prolongation of QTcF interval ≥ 470 ms in 2 out of 3 recordings or any clinically significant abnormality in the ECG at screening period.
• Concomitant therapies known to prolong QT interval and associated with a risk of Torsades de Pointes (TdP) are not permitted between 7 days before the first dose and until last study treatment dose. Amiodarone is not permitted for 90 days before the first dose of ODM-207.
• In Part 1A only, patients with ventricular pacemaker or left bundle branch block.
5. Patients who received systemic anticancer treatment before the first dose of study treatment within the following time-frames given that treatment related AEs have been resolved to at least grade 1. Luteinizing hormone-releasing hormone [LHRH] agonists or antagonists are allowed.
• less than 21 days since the last dose of anticancer chemotherapy or less than 5 half-lives of a small molecule, whichever is the shorter
• less than 6 weeks since the last dose of immunotherapy antibody therapies or Mitomycin C or nitrosoureas
• less than 28 days of wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) or 14 days of limited field radiation for palliation.
6. Major surgery or serious infection within 21 days of the first dose of study treatment or known history of HIV or hepatitis B or C infection.
7. Known gastrointestinal disease or a procedure that may affect absorption of study treatment. Use of acid-reducing agents such as proton-pump inhibitors, H2-receptor antagonists, or antacids is allowed.
8. Serious concurrent medical condition or psychiatric illness.
9. Known active or history (within the last 2 years prior to screening) of other primary malignancy - unless treated with a curative intent (non-melanoma skin cancers, superficial bladder cancer, or in situ breast or cervical cancer are allowed).
10. Patient is pregnant or breast-feeding. Female patient of childbearing potential (i.e., menstruating or less than 2 years postmenopausal) must have negative pregnancy test before the first dose of study treatment.
11. Female patient of childbearing potential or male patient with female partner of childbearing potential who does not agree to use effective contraception for the duration of the study and 3 months after last dose of study medication. Sexual abstinence is defined as true abstinence, when this is in line with the preferred and usual lifestyle of the subject.
12. Known hypersensitivity to the study treatment excipients.
13. Any condition that, in the opinion of the investigator would impair the patient’s ability to comply with study procedures (e.g. uncontrolled diabetes mellitus, infection/inflammation, intestinal obstruction, unable to swallow study treatment, etc.).
14. Concurrent participation in another interventional clinical study or treatment with any IMP within 4 weeks before the start of study treatment.
15. Use of biologic response modifiers, such as granulocyte colony-stimulating factor and other hematopoietic growth factors within 3 weeks before the first dose of study drug. Patients with chronic erythropoietin use consistent with institutional guidelines are allowed.
16. If a response to ODM-207 is expected the patients eligibility to be discussed with Sponsor
17. Certain glioma pts |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. To evaluate safety and tolerability determining maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) by assessing the adverse events using NCI CTCAE.
2. For preliminary antitumour activity circulating markers of antitumour activity (e.g. prostate specific antigen [PSA]) will be assessed. Antitumour activity in soft tissue will be assessed using criteria applicable for the type of tumour (RECIST 1.1, RANO, PCWG3 or Lugano) based on computed tomography (CT), magnetic resonance
imaging (MRI) or positron emission tomography-computed tomography (PET-CT). Antitumour activity in bone will be assessed with radionuclide bone scan if applicable. Clinical disease progression will be evaluated (e.g. by the patient’s ECOG score and decrease in weight or any other clinical sign). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Safety will be assessed through entire study and pre-planned study visits by adverse events (AEs), laboratory tests, physical examination, vital signs, 12-lead electrocardiograms (ECGs) and 24-h continuous (Holter) ECGs.
2. Preliminary antitumour activity will be evaluated through entire study and during the pre-planned study visits. Survival status will be evaluated for patients in Part 2. |
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| E.5.2 | Secondary end point(s) |
1. The PK parameters (Cmax, tmax, AUCt, AUC∞, Vz/F, Cl/F and t½) will be determined.
2. Predictive and resistance molecular biomarkers will be explored in fresh tumour biopsies, archival tissue samples and exploratory plasma samples. Assessments will be done by targeted approach
and non-targeted approach (e.g. whole exome sequencing). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The PK parameters (Cmax, tmax, AUCt, AUC∞, Vz/F, Cl/F and t½) will be derived from the concentration-time data after single dose administration on day 1, and calculated on day 15 after repeated dosing. The average concentration in plasma after repeated administration (Cav) calculated as AUC0-24h divided by the dosing interval of 24 h for once daily dosing, will also be calculated on day 15. Pre-dose concentrations (C0) of ODM-207 in plasma
will be evaluated at several visits up to 12 weeks. If feasible, C0 concentrations of ODM-207 will also be evaluated from tumour biopsies in Part 1B.
2. Biomarkers evaluation will be executed at pre-planed study visits |
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| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | No |
| 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
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Patients will continue study treatment as long as it is considered beneficial to the patient, until unacceptable toxicity, or until any other study treatment discontinuation reason is met.
For all patients there is a 28 day (minimum) post treatment period after the end of the study treatment. After this, the end-of-study visit will take place. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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