| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-Resistant Prostate Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Prostate 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 | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
| To determine the efficacy of HC 1119 as compared to enzalutamide as assessed by overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) until 24 Weeks |
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| E.2.2 | Secondary objectives of the trial |
To determine the efficacy of HC-1119 as compared to enzalutamide as assessed by PSA50 (decline of ≥50% from baseline);) at 24 weeks.
To determine the efficacy of HC-1119 as compared to enzalutamide as assessed by (radiographic) progression-free survival (rPFS);
To determine the efficacy of HC-1119 as compared to enzalutamide as assessed by overall survival (OS);
To determine the efficacy of HC-1119 as compared to enzalutamide as assessed by duration of response;
To determine the efficacy of HC-1119 as compared to enzalutamide as assessed by time to prostate-specific antigen (PSA) progression;
To determine the safety and tolerability of orally administered HC-1119 as compared to enzalutamide |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. ECG sub-study consisting of 100 patients is included to assess safety of HC-1119.
Triplicate 12-lead ECGs will be taken pre-dose on Day 1 and prior to dosing on Days 8 (Week 2), 15 (Week 3) and 22 (Week 4), 29 (Week 5), 57 (Week 9), 85 (Week 13) and Day 169 (Week 25). ECG recordings will be read both locally and by a central lab.
2. Individual PK substudy - in a subset of 24 patients (Caucasian) will be collected at pre-dose (0 h) and 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 and 24 h postdose on Day 1 and at Week 9 (optionally Week 13). |
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| E.3 | Principal inclusion criteria |
1. Age 18 or older and willing and able to give informed consent.
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without significant and relevant neuroendocrine differentiation or small cell features, per investigator's judgment.
3. Ongoing ADT with a GnRH analogue, antagonist or bilateral orchiectomy (i.e., surgical or medical castration).
4. For patients who have not had a bilateral orchiectomy, there must be a plan to maintain effective GnRH-analogue or antagonist therapy for the duration of the trial.
5. Serum testosterone level < 1.7 nmol/L (50 ng/dL) at the Screening visit.
6. Patients receiving bisphosphonate or denosumab therapy must have been on stable doses for at least four weeks (from Day 1 visit).
7. Progressive disease at study entry defined as one or more of the following three criteria that occurred while the patient was on ADT as defined in eligibility criterion #3:
a. PSA progression defined by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination. Patients who received an anti-androgen agent must have progression after withdrawal (≥ 4 weeks since last flutamide or ≥ 6 weeks since last bicalutamide or nilutamide). The PSA value at the Screening visit should be ≥ 2 µg/L (2 ng/mL)
b. Soft tissue disease progression defined by RECIST 1.1
c. Bone disease progression defined by PCWG3 with two or more new lesions on bone scan
8. Metastatic disease documented by measurable soft tissue disease by CT/MRI per RECIST 1.1 criteria. Patients are allowed to have any metastatic disease (i.e. bone metastasis) as long as they also have measurable soft tissue lesions per RECIST 1.1.
9. No prior cytotoxic chemotherapy for prostate cancer.
10. Asymptomatic or mildly symptomatic from prostate cancer.
11. ECOG performance status of 0–1 per the Investigators’ clinical assessment
12. Estimated life expectancy of ≥ 6 months
13. Able to swallow the study drug and comply with study requirements
14. All sexually active patients are required to use a condom as well as meet 1 of the following:
a. Patient is non-fertile (orchiectomy) or has a female partner of non-childbearing potential (i.e., post-menopausal, surgically sterilized, hysterectomy)
b. Patient and his female partner use must agree to use an adequate contraceptive method from the first day of dosing until 3 months after the last dose to prevent pregnancies. Adequate contraceptive method is defined as:
i. Established use of oral, injected, or implanted hormonal methods of contraception.
ii. Placement of an intra-uterine device or intra-uterine system.
iii. Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
iv. Tubal ligation for at least 6 months prior to screening.
15.Male patient engaged in sexual activity with a pregnant female is required to use a condom from the first day of dosing until 3 months after the last dose of treatment with study drugs.
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| E.4 | Principal exclusion criteria |
1. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the investigator, would make the patient inappropriate for enrollment.
2. Known or suspected brain metastasis or active leptomeningeal disease.
3. Regular daily use of opiate analgesics for pain from prostate cancer within four weeks of enrollment (Day 1 visit).
4. WBC count < 3,000/µL, or absolute neutrophil count < 1,500/µL, or platelet count < 100,000/µL, or hemoglobin < 5.6 mmol/L (9 g/dL) at the Screening visit (NOTE: patients may not have received any growth factors or blood transfusions or any therapeutic invention within 14 days of the hematologic laboratory values obtained at the Screening visit).
5. Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal at the Screening visit; no therapeutic invention within 14 days before screening.
6. Creatinine clearance < 30 mL/min as calculated using the Cockcroft-Gault equation at the at the Screening visit.
Creatinine Clearance (mL/min) = [[140-Age (years)] * Weight (kg)] / [72 * Serum Creatinine (mg/dL)]
7. Albumin < 30 g/L (3.0 g/dL) at the Screening visit, no therapeutic invention within 14 days before screening.
8. History of another malignancy within the previous two years other than curatively treated non melanomatous skin cancer.
9. Treatment with flutamide within four weeks of enrollment (Day 1 visit).
10. Treatment with bicalutamide or nilutamide within six weeks of enrollment (Day 1 visit).
11. Treatment with 5-α reductase inhibitors (finasteride, dutasteride), estrogens, within four weeks of enrollment (Day 1 visit).
12. Treatment with systemic biologic therapy for prostate cancer (other than approved bone targeted agents) within four weeks of enrollment (Day 1 visit).
13. Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone/prednisolone per day within four weeks of enrollment (Day 1 visit).
14. Prior use, or participation in a clinical trial, of an agent that blocks androgen synthesis (e.g., abiraterone) or blocks the AR (e.g., apalutamide, darolutamide, enzalutamide, proxalutamide).
15. Participation in a previous clinical trial of HC-1119.
16. Use of an investigational agent within four weeks of enrollment (Day 1 visit).
17. Radiation therapy for treatment of the primary tumor within three weeks of enrollment (Day 1 visit).
18. Radionuclide therapy (Radium 223) for treatment of metastasis within four weeks of enrollment (Day 1 visit).
19. Clinically significant cardiovascular disease or condition including:
• Myocardial infarction within six months
• Uncontrolled angina within three months
• Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or with history of congestive heart failure NYHA class 3 or 4, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months results in a left ventricular ejection fraction that is ≥ 45%
• History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
• History of Mobitz II third degree heart block without a permanent pacemaker in place
• Bradycardia as indicated by a heart rate of < 50 beats per minute on the Screening ECG
• Patients with manifest hypertension at the Screening visit
•QTc prolongation and any other clinically significant ECG abnormalities as per Investigator criteria
20.Treatment with strong CYP2C8 inhibitors and inducers, CYP3A4 inducers, medications which are known to prolong the QT interval (see Appendix C).
21.History of seizure or any condition that may predispose to seizure.
22.Conditions that predispose subjects to increased risk for falls or fractures according to the discretion of the Investigator.
23.Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last three months).
24.Major surgery within four weeks prior to enrollment (Day 1 visit).
25.Have active infection with HBV measured by hepatitis B surface antigen (HBsAg) test, HCV measured by RNA test and HIV measured by antibody test.
26.Have known active tuberculosis.
27.Known hypersensitivity to HC-1119, enzalutamide, or any of the excipients.
28.Rare hereditary problems of fructose intolerance due to sorbitol
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate by RECIST 1.1. until 24 weeks is the primary endpoint for this study. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| The key secondary endpoint is the proportion of patients showing a PSA decline of ≥ 50% from baseline at 24 weeks. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| China |
| United States |
| Austria |
| Finland |
| France |
| Poland |
| Netherlands |
| Spain |
| Germany |
| Italy |
| Belgium |
| Denmark |
| Russian Federation |
| United Kingdom |
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| 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
|
| Last Patient Last Visit (LPLV) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 0 |
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