E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Castration-refractory prostate cancer (CRPC) |
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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 | 14.1 |
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 objective of the study is to determine the safety and tolerability of orally-administered VT-464 in chemotherapy-naïve patients with castration-refractory prostate cancer (CRPC). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To describe the pharmacokinetics (PK) of VT-464.
• To describe the pharmacodynamics (PD) of VT-464 based on changes in PSA levels from baseline.
• To describe the PD of VT-464 based on radiographic and clinical tumor responses in patients with evaluable and/or measureable metastases.
• To describe the PD of VT-464 based on adrenal, pituitary, and testicular hormone level responses. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must have documented histological or cytological evidence of adenocarcinoma of the prostate.
2. Patients must have a minimum serum PSA level of >2 ng/ml that is rising based on the Prostate Cancer Working Group 2 criteria.
3. Patients must be >18 years of age.
4. Patients must have castrate levels of testosterone (<50 ng/ml).
5. Patients must have undergone orchiectomy, or have been on LHRH agonists or antagonists, for at least 3 months prior to study entry. Patients on LHRH agonists/antagonists must remain on these agents for the duration of the study.
6. Patients must have an ECOG Performance Score of 0 or 1.
7. Patients must have adequate hematopoietic function as evidenced by:
- WBC >3,000/μl
- ANC >1,500/μl
- Platelet count >100,000/μl
- HGB >10 g/dl
8. Patients must have adequate hepatic function as evidenced by AST/ALT levels <3X the ULN and bilirubin levels of <2.0 mg/dl.
9. Patients must have adequate renal function as evidenced by a serum creatinine of <2.0 mg/dl
10. Patients must have K+ >3.5 mEq/l.
11. Patients or their legal representatives must be able to provide written informed consent. |
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E.4 | Principal exclusion criteria |
1. Patients who have received prior cytotoxic chemotherapy for prostate cancer.
2. Patients who have received second-line antihormonal therapy, including ketoconazole, aminoglutethimide, or high-dose estrogen within 30 days of study entry.
3. Patients who have completed sipuleucel-T treatment within 30 days of study entry
4. Patients who have received abiraterone, TAK-700 (Orteronel), TOK-001, or MDV3100, or any other investigational product directed towards the androgen receptor or androgen biosynthesis.
5. Patients who have received antiandrogens such as flutamide (EULEXIN®), bicalutamide (CASODEX®), or nilutamide (NILANDRON®) for > 3 months must be off treatment for 6 weeks and demonstrate a continued rise in PSA after withdrawal. Patients on antiandrogens for < 3 months must be off medication for 2 weeks. Patients on 5 alpha reductase inhibitors such as finasteride (PROSCAR®, PROPECIA®), or dutasteride (AVODART®) must stop medication at least 3 months from study entry.
6. Patients who require pharmacological or replacement doses of systemic corticosteroids or who have received systemic corticosteroids within 30 days of study entry; use of topical, inhaled or ophthalmic steroids is permitted.
7. Patients who have received any investigational agent within 2 weeks of study entry.
8. Patients who have received radiotherapy to their primary prostate cancer within 6 weeks of study entry.
9. Patients with hepatic or other soft tissue visceral (other than pulmonary) or CNS metastases from prostate cancer.
10. Patients with a history of adrenal insufficiency.
11. Patients with a history within the last 3 years of another invasive malignancy.
12. Patients with a QTcF interval of >470 msec; if the Screening ECG QTc interval is >470 msec, itmay be repeated, and if repeat < 470 msec, the patient may be enrolled.
13. Patients who have started on bisphosphonates within 3 months of study entry
14. Patients with any intercurrent conditions that could preclude their participation in the study, pose an undue medical hazard, or which could interfere with the interpretation of the study results, including, but not limited to, congestive heart failure (NYHA Class III or IV), unstable angina, cardiac arrhythmia, recent (within the preceding 6 months) myocardial infarction, acute coronary syndrome or stroke, hypertension requiring more than 2 medications for adequate control, or diabetes mellitus with more than 2 episodes of ketoacidosis in the preceding 12 months.
15. Patients who have known active HIV, Hepatitis B, or Hepatitis C infections
16. Patients with any other medical, psychiatric, or social condition, including substance abuse, 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 VT-464 when administered orally to patients with castration-refractory prostate cancer. The MTD is defined as the highest dose-level of VT-464 at which no more than 1 out of 6 evaluable subjects experience a dose-limiting toxicity (DLT) 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 VT-464 within the Single-Dose stage of the study or the first continuous, 28-day dosing cycle (Cycle 1). The occurrence of DLTs in each cohort 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) |
Pharmacokinetics:
Pharmacokinetic parameters will be determined using plasma concentration-time data and will be summarized by dose. Data will be analyzed by non-compartmental methods. The following parameters will be determined:
• Cmax
• Tmax
• t1/2
• AUC0-24
• Vd
Pharmacodynamics:
Pharmacodynamic response to VT-464 will be evaluated through changes in PSA levels from baseline, radiographic and clinical tumor responses, and serum levels of various hormones including DHEA, DHEAS, androstenedione, testosterone, cortisol, corticosterone, progesterone, pregnenolone, and ACTH. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK: Plasma samples on Single-dose stage 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 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 | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
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 | 0 |