The goal of this clinical study is to determine the safety, pharmacokinetics,
pharmacodynamics and efficacy and activity of seviteronel, a lyase-selective inhibitor of
CYP17, in patients with advanced breast cancer.
This is an open-label, Phase 1/2 study of seviteronel in subjects with TNBC or ER +/HER2
normal unresectable locally advanced breast cancer. Only women will be enrolled in Phase 1
and both men and women enrolled into their respective cohorts in Phase 2. There will be a
dose confirmation Phase 1 portion of the study to establish the recommended Phase 2 dose
(RP2D) for women with breast cancer using a non-stratified, combined cohort of women with
TNBC or ER+ BC. Cohort expansion will occur in Phase 2 at the RP2D confirmed/established in
Phase 1 using separate TNBC and ER+ cohorts. The Phase 2 portion of the study is divided into
three parallel cohorts:
Cohort 1: Female TNBC Subjects Cohort 2: Female ER+ Subjects Cohort 3: Male ER+ BC or TNBC
Subjects
Inclusion Criteria
Each subject eligible to participate in this study must meet or have all the following
criteria:
1. Is 18 years of age or older.
2. Can provide written informed consent or have their legal representatives provide
written informed consent
3. Have documented histological or cytological evidence of invasive cancer of the breast,
defined by one of the following:
- ER+ breast cancer, defined as positive if ≥ 1% by IHC and HER2 normal, defined as
IHC 0-1+ or IHC 2+(and FISH<2), or FISH < 2.0
- TNBC, defined as ER-/PgR- if 0 % by IHC and HER2 normal, defined as IHC 0-1+ or
IHC 2+(and FISH<2), or FISH < 2.0
4. ECOG PS of 0 or 1 for Females, 0, 1, or 2 for Males.
5. Undergoing or willing to undergo gonadal suppression:
- Female subjects with ER+/HER2 normal tumors must be post-menopausal defined by
local practice. Ovarian suppression with a LHRH analogue to achieve cessation of
regular menses is allowed on study
- Male subjects must be undergoing or willing to undergo gonadal suppression whilst
on study drug and continue with the LHRH analogue for the duration of the study
6. Subjects must have adequate hematopoietic function as evidenced by:
- WBC ≥ 3,000/μl
- ANC ≥ 1,500/μl
- Platelet count ≥ 100,000/μl
- HGB ≥ 9 g/dl and not transfusion dependent
7. 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
8. Subjects must have adequate renal function as evidenced by a serum creatinine of ≤ 2.0
mg/dl.
9. Potassium (K+) ≥3.5 mEq/L
10. Women of child-bearing potential must have a negative serum or urine pregnancy test
within 72 hours of C1D1.
11. Women of child-bearing potential and male subjects with a female partner 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 i. Two acceptable forms of birth control include:
1. Condom (barrier method of contraception), and 2. One of the following:
1. Oral, injected or implanted hormonal contraception
2. Placement of an intrauterine device (IUD) or intrauterine system (ISU)
3. Additional barrier methods of contraception: Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
4. Vasectomy or surgical castration ≥ 6 months prior to Screening. 12. Able to swallow
study medication 13. Able to comply with study requirements
Exclusion Criteria
1. Received any investigational agent within 5 half-lives of the agent in question; if
the half-life is not known, ≤ 28 days of C1D1.
2. Received palliative radiotherapy ≤ 2 weeks of C1D1
3. Received any other therapeutic treatment for breast cancer ≤ 2 weeks of C1D1, except
for hormonal therapies.
4. Symptomatic CNS metastases.
5. History of another invasive malignancy ≤ 3 years of C1D1.
6. A QTcF interval >470 msec on the Screening ECG. If the ECG QTcF interval is >470 msec,
then the mean QTcF of a triplicate ECGs can be used and if the mean is <470 msec, the
subject may be enrolled.
7. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, ventricular
fibrillation, atrial fibrillation with rapid ventricular response, torsades de
pointes, second degree or third degree atrioventricular heart block without a
permanent pacemaker in place).
8. 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
9. Initiated a bone modifying agent (e.g. denosumab) ≤ 28 days of C1D1.
10. Any medical condition that could preclude their participation in the study, pose an
undue medical hazard, or which could interfere with the interpretation of the study
results.
11. A history of seizure ≤ 2 years of C1D1 or those who require prophylactic anti-seizure
medications.
12. A history of loss of consciousness or transient ischemic attack ≤ 12 months before
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.
