| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Castration-resistant prostate cancer (CRPC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the prostate gland that has become hormone resistant |
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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 | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| 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 |
The primary objectives of the Phase 1 portion of the study are:
To determine the safety and tolerability of seviteronel in “treatment naïve” (not treated with previous abiraterone or enzalutamide) subjects with CRPC.
The primary objectives of the Phase 2 portion of the study are:
•Proportion of subjects who have ≥50% PSA decline at any time on study from the start of treatment with seviteronel
•Median time to radiographic disease progression evaluated by computerized tomography (CT scan) or magnetic resonance imaging (MRI) and radionuclide bone scans by RECIST 1.1 or Prostate Cancer Clinical Trials Working Group 3 (PCWG3; Scher et al, 2016)
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the Phase 1 portion of the study are:
•Pharmacokinetics (PK) of seviteronel
•Pharmacodynamics (PD) of seviteronel based on changes in prostate-specific antigen (PSA) levels from baseline
•PD of seviteronel based on radiographic and clinical tumor responses using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as modified in the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) (Scher et al, 2008) in subjects with evaluable and/or measurable metastases
•PD of seviteronel based on adrenal, pituitary, and testicular hormone level responses.
The secondary objectives of the Phase 2 portion of the study are:
•Radiographic response rate by RECIST 1.1 & PCWG3
•Safety of seviteronel with or without concurrent glucocorticoid administration
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.≥18 years of age
2.Able to provide written informed consent or have their legal representatives provide written informed consent
3.Documented histological or cytological evidence of adenocarcinoma of the prostate. Subjects whose pathology reports are no longer available may be enrolled if, in the opinion of the investigator, the subject has a clinical course consistent with prostatic adenocarcinoma
4.ECOG Performance Status of 0 or 1
5.Undergone orchiectomy, or have ongoing LHRH analogue therapy prior to C1D1. Subjects on LHRH analogues should remain on these agents for the duration of the study
6.Castrate levels of testosterone ≤50 ng/dl (or 1.7 nmol/L) and have progressive disease at Screening defined as PSA rise determined by a minimum of 2 rising PSA values ≥ 1 week between each assessment. The PSA value at the Screening visit must be ≥ 2ng/mL with or without:
•Soft tissue disease progression defined by RECIST 1.1 at Screening or ≤ 28 days of C1D1. Measurable disease is not required for entry. Lymph nodes ≥ 1.5cm (short axis) are considered measurable disease (PCWG3, Scher 2016)
•Bone disease progression defined by ≥2 new lesions on bone scan at Screening, or ≤ 28 days of C1D1
7.Have received abiraterone and/or enzalutamide. Subject must have received either abiraterone or enzalutamide for ≥12 weeks. Other second generation CYP17 inhibitors/androgen receptor antagonists including but not limited to TAK-700 (orteronel), TOK-001 (galeterone) may have been taken in place of abiraterone and ARN-509 (apalutamide) may have been taken in place of enzalutamide.
8.Adequate hematopoietic function as evidenced by:
•WBC ≥ 3,000/μl
•ANC ≥ 1,500/μl
•Platelet count ≥ 100,000/μl
•HGB ≥ 10 g/dl and not transfusion dependent
9.Adequate liver function, including all the following:
•Total serum bilirubin ≤2.0 x ULN unless the subject has documented Gilbert syndrome;
•Aspartate and alanine aminotransferase (AST & ALT) ≤3.0 x ULN or ≤5.0 x ULN if subject has liver metastasis;
•Alkaline phosphatase ≤3.0 x ULN or ≤5 x ULN in case of bone metastasis and/or hepatic metastasis
10.Subjects must have adequate renal function as evidenced by a serum creatinine of ≤2.0 mg/dl
11.Potassium (K+) ≥3.5 mEq/l
12.Subject and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at Screening and continuing throughout the study period and for 3 months after final study drug administration
13.Able to swallow study medication
14.Able to comply with study requirements
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| E.4 | Principal exclusion criteria |
1.Received sipuleucel-T (Provenge ®) treatment within 28 days of C1D1
2.Received 5-alpha reductase inhibitors such as finasteride (PROSCAR®, PROPECIA®), or dutasteride (AVODART®) within 28 days of C1D1
3.Received any investigational agent ≤ 28 days of C1D1
4.Received palliative radiotherapy ≤ 2 weeks of C1D1
5.Symptomatic CNS metastases
6.History of another invasive malignancy ≤ 3 years of C1D1
7.A QTcF interval of > 470 msec; if the Screening ECG QTcF interval is > 470 msec, it may be repeated, and if repeat < 470 msec, the subject may be enrolled
8.Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes, second degree or third degree atrioventricular heart block without a permanent pacemaker in place)
9.Started a bone modifying agent (e.g. bisphosphonates, denosumab) ≤ 28 days of C1D1 (note: ongoing bone modifying agents administered > 28 days are allowed)
10.Any medical condition that could preclude subject participation in the study, pose an undue medical hazard, or which could interfere with study results
11.Class III or IV Congestive Heart Failure (CHF) as defined by the New York Heart Association (NYHA) functional classification system within the previous 6 months
12.A history of loss of consciousness or transient ischemic attack ≤ 12 months of C1D1
13.Known active HIV, Hepatitis B, or Hepatitis C infections
14.Known or suspected hypersensitivity to seviteronel, or any components of the formulation
15.Any other condition which in the opinion of the investigator would preclude participation in the study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is the maximum tolerated dose (MTD) of INO-464 when administered orally to patients with castration-resistant prostate cancer. The MTD is defined as the highest dose-level of VT-464 in Phase 1 at which the incidence of dose-limiting toxicity (DLT) was less than 33% within the Single-Dose stage of the study or the first continuous 28-day dosing cycle. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A dose-limiting toxicity (DLT) is defined as any Grade 3 or greater adverse event possibly/probably/definitely related to INO-464 from the first dose of VT-464 through the first continuous, 28-day dosing cycle (Cycle 1). The occurrence of DLTs in each cohort of Phase 1 will be used to determine the MTD. DLTs will be reported by the study investigators to the sponsor as they occur. |
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| E.5.2 | Secondary end point(s) |
Secondary Objectives Phase 1
To describe the:
• Pharmacokinetics (PK) of seviteronel
• Pharmacodynamics (PD) of seviteronel based on changes in prostate-specific antigen (PSA) levels from baseline
• PD of seviteronel based on radiographic and clinical tumor responses using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as modified in the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) (Scher et al, 2008) in subjects with evaluable and/or measurable metastases
• PD of seviteronel based on adrenal, pituitary, and testicular hormone level responses
Secondary Objectives Phase 2
To determine the:
• Radiographic response rate by RECIST 1.1 & PCWG3
• Safety of seviteronel with or without concurrent glucocorticoid administration |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK: Plasma samples on Single-dose stage (Phase 1 only) Day 1 Predose, .5, 1, 2, 4, 6, 8, and 24 hours postdose; Cycle 1, Day 1 Predose, .5, 1, 2, 4, 6, and 8 hours postdose; Cycle 1, Day 14 predose; Cycle 2, Day 1 Predose, .5, 1, 2, 4, 6, and 8 hours postdose; and Day 1 of all subsequent cycles.
PD: PSA will be obtained at Screening, on Cycle 1, Days 1 and 14 and at all subsequent study visits. Extent of metastatic disease will be evaluated at Screening and on Day 1 of all 28-day cycles.
An endocrine panel will be obtained on Single-dose stage Day 1 (Phase 1 only) Pre-dose and 2, 4, and 24 hours postdose; Cycle 1, Day 1 Pre-dose; Cycle 2, Day 1 Pre-dose and 2, 4, and 8 hours postdose; all subsequent 28-day cycles Day 1 Pre-dose and 2, 4, and 8 hours postdose; and at the final visit. |
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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 | No |
| 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 | 2 |
| 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 |
| Greece |
| Switzerland |
| United States |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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