Clinical trial NCT02580448: CYP17 Lyase and Androgen Receptor Inhibitor Treatment With Seviteronel Trial (INO-VT-464-006; NCT02580448)
Official title: A Phase 1/2 Open-Label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of Seviteronel in Subjects With Advanced Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cancer of the Breast
Breast Cancer
Advanced Breast Cancer
Metastatic Breast Cancer
Male Breast Cancer
Triple Negative Breast Cancer
ER+ Breast Cancer
Keywords: Breast Cancer
Breast
Advanced Breast Cancer
Metastatic Breast Cancer
CYP17
Male Breast Cancer
Triple Negative Cancer
ER+ Breast Cancer
Lead sponsor: Innocrin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2015-10-20
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Eligibility criteria: 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.

Primary outcomes:
measure: Estimate efficacy of seviteronel as measured by clinical benefit rate at 16 weeks (CBR16) for female subjects with TNBC.
timeFrame: Duration of Study
measure: Estimate efficacy of seviteronel as measured by clinical benefit rate at 24 weeks (CBR24) for female subjects with ER+ BC.
timeFrame: Duration of Study
measure: Estimate efficacy of seviteronel as measured by CBR16 for all male BC subjects.
timeFrame: Duration of Study
Secondary outcomes:
measure: Describe the pharmacokinetics of seviteronel
timeFrame: At least monthly over the first eight 28-day cycles
measure: Estimate efficacy of seviteronel as measured by the overall response rate (ORR) based on RECIST 1.1
timeFrame: At least monthly over the first eight 28-day cycles
measure: Estimate efficacy of seviteronel as measured by progression-free survival (PFS)
timeFrame: At least monthly over the first eight 28-day cycles
measure: Describe the safety profile of seviteronel
timeFrame: Duration of the study
measure: Compare the safety profile of seviteronel with or without concurrent glucocorticoid administration
timeFrame: Duration of the study
measure: Compare the CBR16 with or without concurrent glucocorticoid administration for female subjects with TNBC
timeFrame: Duration of the study
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Wallace Tumor Institute- University of Alabama
state: Alabama
city: Huntsville
country: United States
facility: Clearview Cancer Institute
state: Alabama
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Lakewood
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists- North
state: Florida
city: Augusta
country: United States
facility: Georgia Cancer Center at Augusta University
state: Georgia
city: Kansas City
country: United States
facility: SCRI - HCA Midwest Division
state: Kansas
city: Louisville
country: United States
facility: University of Louisville Hospital / James Brown Cancer Center
state: Kentucky
city: Silver Spring
country: United States
facility: Maryland Oncology Hematology
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Masonic Cancer Center
state: Minnesota
city: Omaha
country: United States
facility: Cancer Network/Oncology Associates PC
state: Nebraska
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: East Setauket
country: United States
facility: North Shore Hematology Oncology Associates
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center - Oncology Research
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Cincinnati
country: United States
facility: Oncology Hematology Care, Inc
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
city: Charleston
country: United States
facility: Charleston Hematology and Oncology Associates
state: South Carolina
city: Knoxville
country: United States
facility: Precision Cancer Research/Brig Center for Cancer Care and Survivorship, LLC
state: Tennessee
city: Nashville
country: United States
facility: SCRI Tenessee Oncology Nashville
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Centers
state: Texas
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders (Fort Worth)
state: Texas
city: Fort Worth
country: United States
facility: US Oncology
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
Study officials:
affiliation: Sponsor GmbH
name: Victoria Brown, BS
role: STUDY_CHAIR
References: