| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Castration-Resistant Prostate Cancer |
|
| 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 | 18.1 |
| 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) |
|
| 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 I – Dose Escalation
The primary objective of Part I of the study is to evaluate the safety and tolerability of orally administered EPI-506.
Part II - Dose Expansion
The primary objective of Part II of the study is to evaluate the
PSA response rate defined as the proportion of patients with PSA decline of ≥ 50% from baseline after 12 weeks of daily dosing with EPI-506.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of Part I:
• To determine the maximum tolerated dose (MTD)
• To define the RP2D of EPI-506
• To evaluate the PK of EPI-506 and major metabolite
EPI-002 following single- and multiple-dose oral
administration
• Evaluate the food effect of EPI-506 on the PK
following single-dose administration.
• Evaluate prostate-specific antigen (PSA) as a
pharmacodynamic (PD) marker of response
• Evaluate biomarkers using circulating tumor cells
(CTCs) with a particular emphasis on androgen receptor (AR) splice variants including constitutively active, truncated AR splice variant V7
Secondary objectives for Part II:
• Evaluate the safety and tolerability of orally
administrated EPI-506
To evaluate the PK of EPI-506 and major metabolite
EPI-002 following multiple-dose oral administration.
• To evaluate the time to PSA progression
• To evaluate radiographic progression per modified
Response Evaluation Criteria in Solid Tumors
(mRECIST) v1.1
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Parts I and II
Inclusion Criteria
Patients are eligible for the study if all of the following apply:
1. Institutional Review Board (IRB)/Independent Ethics
Committee (IEC)-approved written informed consent and
privacy language as per national regulations must be
obtained from the patient prior to any study-related
procedures being performed.
2. Male 18 years of age or older.
3. Histologically confirmed adenocarcinoma of the prostate
without known neuroendocrine differentiation or small cell
features.
4. PSA progression within 8 weeks of study treatment
(requires a baseline and minimum of 2 sequentially rising
PSA levels at an interval of ≥ 1 week between each
determination while taking androgen deprivation therapy
[ADT])
5. Presence of metastatic disease at study entry documented
by 1 or more bone lesions on bone scan or by soft tissue
disease observed by CT/MRI.
6. Asymptomatic or minimally symptomatic patients defined
as reported pain score on BPI-SF question #3 (worst pain in
prior 24 hours) must be < 4 at screening.
7. Disease progression while receiving abiraterone or
enzalutamide as assessed by either:
a. PSA progression;
b. Radiographic progression with 2 new lesions on bone
scan or soft tissue progression on CT/MRI per
mRECISTv1.1.
8. The patient must have recovered from toxicities related to
any prior treatments, unless toxicities are assessed by the
Investigator as clinically non-significant (e.g., hot flashes
from luteinizing-hormone receptor hormone (LHRH)
therapy).
9. Castrate at screening:
a. Ongoing ADT with LHRH agonist/antagonist therapy
or history of bilateral orchiectomy.
b. Serum testosterone ≤ 1.7 nmol/L (50 ng/dL) at
screening.
10. Patients receiving bisphosphonates or other approved bonetargeting
therapy (e.g., denosumab) must be on a stable
dose for at least 4 weeks prior to the start of study drug.
11. PSA value at screening ≥ 2 ng/mL.
12. Life expectancy of ≥ 6 months according to the
Investigator’s judgment.
13. Eastern Cooperative Oncology Group (ECOG)
performance status score of 0 to 1.
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., postmenopausal,
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 intrauterine
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.
|
|
| E.4 | Principal exclusion criteria |
Parts I and II
Exclusion Criteria
Patients will be excluded from participation in the study if any
of the following apply:
1. Candidates for cytotoxic chemotherapy or have received a
biologic anti-cancer therapy (e.g., sipuleucel-T, docetaxel,
cabazitaxel, and estramustine) or a cytotoxic chemotherapy
within 4 weeks prior to the start of study drug.
2. Have received more than 1 line of chemotherapy for the
treatment of mCRPC.
3. Use of hormonal agents with anti-tumor activity against
prostate cancer including 5-alpha reductase inhibitors,
androgens (e.g., testosterone), cytoproterone acetate,
progestational agents, and estrogens/diethylstilbestrol
within 4 weeks prior to the start of study drug. Low-dose
hormonal agents (e.g., Megace) given for treatment of side
effects of LHRH therapy are allowed with prior approval
from the Medical Monitor.
4. Use of bicalutamide or nilutamide within 6 weeks prior to
the start of study drug, and flutamide within 4 weeks prior
to the start of study drug.
5. Use of an investigational agent that targets the AR axis (i.e.,
AR antagonists, AR signaling inhibitors, agents that target
alternative blockade of the AR, and androgen synthesis
inhibitory agents).
6. Enzalutamide and/or abiraterone use as follows:
a. Received more than 1 treatment course of
enzalutamide
b. Received more than 1 treatment course of abiraterone
c. Received either agent within 4 weeks prior to the start
of study drug.
d.
Received abiraterone and/or enzalutamide and
discontinued agent without evidence of radiographic
or PSA progression.
7. Use of systemic corticost eroids exceeding prednisone 10 mg/day within 4 weeks prior to the start of study drug.
Increased dose of inhaled steroids may be allowed with
approval by a study Medical Monitor.
8. Use of prior radionuclide (e.g., strontium-89 or samarium).
9. Use of radium-223 dichloride within 28 days prior to the
start of study drug.
10. Received limited-field palliative bone radiotherapy
> 5 fractions and/or any radiotherapy within 2 weeks prior
to the start of study drug.
11. Received a blood transfusion within 28 days of screening.
12. Major surgery within 2 months prior to screening.
13. Known intra-cerebral disease or brain metastasis.
14. Spinal cord compression as follows:
a. Candidates with spinal cord compression related to
prostate cancer that required treatment within 6
months prior to starting study drug.
b. Any symptoms of neurologic compromise with
radiographic evidence of potential spinal cord
compression within 4 weeks prior to starting study
drug.
15. Diagnosis of another invasive malignancy within the previous 3 years other than curatively treated
non-melanomatous skin cancer or superficial urothelial carcinoma.
16. Gastrointestinal disorder affecting absorption (e.g.,
gastrectomy).
17. Significant cardiovascular disease including any of the
following
• Myocardial infarction within 6 months prior to study entry.
• Uncontrolled angina within 3 months prior to study entry.
• Congestive heart failure New York Heart Association
(NYHA) class III or IV, or a history of congestive heart
failure NYHA class III or IV unless a screening
echocardiogram or multigated acquisition scan
(MUGA) performed within 3 months prior to study
entry results in a left ventricular ejection fraction that is ≥ 45%.
• QT interval corrected by the Fridericia correction
formula (QTcF) > 470 msec at screening.
• History of clinically significant ventricular
arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes).
• History of Mobitz II second degree or third degree
heart block.
• Uncontrolled hypertension as indicated by a resting
systolic blood pressure > 180 mm Hg or diastolic
blood pressure > 110 mm Hg at screening.
• Cardiac pacemakers.
18. Concurrent disease or any clinically significant abnormality following the Investigator’s review of the screening
physical examination findings, 12-lead ECG results, and clinical laboratory tests, which in the judgment of the Investigator would interfere with the patient’s participation
in this study or evaluation of study results.
19. Absolute neutrophil count (ANC) < 1500/µL, platelet count
< 100 000/µL; hemoglobin < 5.6 mmol/L (9.0 g/dL) at
screening;
Note: Patients must not have received any growth factors within 7 days or blood transfusions within 28 days prior to the hematologic laboratory values obtained at screening.
20. Total bilirubin > 1.5 × the upper limit of normal (ULN) at screening
21. Alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) > 2.5 × ULN at screening.
22. Creatinine > 1.5 × ULN at screening
23. Albumin ≤ 30 g/L at screening
24. Known or suspected hypersensitivity to any components of
the formulation used for EPI-506
25. Use of an investigational agent within 4 weeks prior to the first dose of EPI-506 or a period required by local
regulation, whichever is longer
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary end point for part I is safety as defined by occurrence of dose limiting toxicities.
Primary end point for part II is decline from baseline in PSA of greater/= 50%. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part I: all timepoints
Part II: screening and week 12 |
|
| E.5.2 | Secondary end point(s) |
Secondary end point for part I is safety as defined by TEAE's, Clinical laboratory parameters, vital sign measurements, and ECGs, PK parameter of EPI-506 and the major metabolite EPI-002, PSA.
Secondary end point for part II is efficacy as defined by time to PSA progression, time to radiographic progression, objective response |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part I: All timepoints
Part II: Screening and Week 12 |
|
| 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 | No |
| 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 | 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) | 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
| 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 | 4 |
| 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 |
| Canada |
| France |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 3 |
| 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 | 3 |
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