CYP17 Lyase and Androgen Receptor Inhibitor Treatment With Seviteronel Trial (INO-VT-464-006; NCT02580448)

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:

• Is 18 years of age or older.
• Can provide written informed consent or have their legal representatives provide written informed consent
• 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
• ECOG PS of 0 or 1 for Females, 0, 1, or 2 for Males.
• 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
• 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
• 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
• Subjects must have adequate renal function as evidenced by a serum creatinine of ≤ 2.0 mg/dl.
• Potassium (K+) ≥3.5 mEq/L
• Women of child-bearing potential must have a negative serum or urine pregnancy test within 72 hours of C1D1.
• 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:

• Condom (barrier method of contraception), and 2. One of the following:

• Oral, injected or implanted hormonal contraception
• Placement of an intrauterine device (IUD) or intrauterine system (ISU)
• Additional barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
• Vasectomy or surgical castration ≥ 6 months prior to Screening. 12. Able to swallow study medication 13. Able to comply with study requirements

Exclusion criteria

• Received any investigational agent within 5 half-lives of the agent in question; if the half-life is not known, ≤ 28 days of C1D1.
• Received palliative radiotherapy ≤ 2 weeks of C1D1
• Received any other therapeutic treatment for breast cancer ≤ 2 weeks of C1D1, except for hormonal therapies.
• Symptomatic CNS metastases.
• History of another invasive malignancy ≤ 3 years of C1D1.
• 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.
• 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).
• 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
• Initiated a bone modifying agent (e.g. denosumab) ≤ 28 days of C1D1.
• 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.
• A history of seizure ≤ 2 years of C1D1 or those who require prophylactic anti-seizure medications.
• A history of loss of consciousness or transient ischemic attack ≤ 12 months before C1D1.
• Known active HIV, Hepatitis B, or Hepatitis C infections.
• Known or suspected hypersensitivity to seviteronel, or any components of the formulation.
• Any other condition which in the opinion of the investigator would preclude participation in the study.