CYP17 Lyase and Androgen Receptor Inhibitor Treatment With Seviteronel Trial (INO-VT-464-006; NCT02580448) (CLARITY-01)

A Phase 1/2 Open-Label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of Seviteronel in Subjects With Advanced Breast Cancer

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Advanced Breast Cancer; Metastatic Breast Cancer; Triple Negative Breast Cancer; Male Breast Cancer; ER+ Breast Cancer; Cancer of the Breast
• Intervention / Treatment: Drug: Seviteronel

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

• Study Type: Interventional
• Enrollment (Anticipated): 175
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • Wallace Tumor Institute- University of Alabama
    • Huntsville, Alabama, United States, 35805
      • Clearview Cancer Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
    • Lakewood, Colorado, United States, 80228
      • Rocky Mountain Cancer Centers
  • Florida
    • Fort Myers, Florida, United States, 33916
      • Florida Cancer Specialists
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists- North
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Cancer Center at Augusta University
  • Kansas
    • Kansas City, Kansas, United States, 61432
      • SCRI - HCA Midwest Division
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Hospital / James Brown Cancer Center
  • Maryland
    • Silver Spring, Maryland, United States, 20902
      • Maryland Oncology Hematology
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Nebraska Cancer Specialists
    • Omaha, Nebraska, United States, 68118
      • Cancer Network/Oncology Associates PC
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center
  • New York
    • East Setauket, New York, United States, 11733
      • North Shore Hematology Oncology Associates
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Presbyterian Medical Center - Oncology Research
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care, Inc
    • Columbus, Ohio, United States, 43202
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Stephenson Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • OHSU Knight Cancer Institute
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Charleston Hematology and Oncology Associates
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • Precision Cancer Research/Brig Center for Cancer Care and Survivorship, LLC
    • Nashville, Tennessee, United States, 37203
      • SCRI Tenessee Oncology Nashville
  • Texas
    • Dallas, Texas, United States, 75390
      • The University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75230
      • Mary Crowley Cancer Research Centers
    • Fort Worth, Texas, United States, 76104
      • The Center for Cancer and Blood Disorders (Fort Worth)
    • Fort Worth, Texas, United States, 76177
      • US Oncology
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Female Triple Negative Breast Cancer Patients; TNBC Patients - Enrollment is complete in this cohort	Drug: Seviteronel; Seviteronel given daily with evening meal in 28 day cycles
Experimental: Female Estrogen Receptor (+) Breast Cancer Patients; Female ER(+) BC Patients - Enrollment is complete in this cohort	Drug: Seviteronel; Seviteronel given daily with evening meal in 28 day cycles
Experimental: Male Breast Cancer Patients; Locally advanced or metastatic males with BC	Drug: Seviteronel; Seviteronel given daily with evening meal in 28 day cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Estimate efficacy of seviteronel as measured by clinical benefit rate at 16 weeks (CBR16) for female subjects with TNBC.	Duration of Study
Estimate efficacy of seviteronel as measured by clinical benefit rate at 24 weeks (CBR24) for female subjects with ER+ BC.	Duration of Study
Estimate efficacy of seviteronel as measured by CBR16 for all male BC subjects.	Duration of Study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Describe the pharmacokinetics of seviteronel	Area under the curve concentration verses time curve and Peak Plasma Concentration	At least monthly over the first eight 28-day cycles
Estimate efficacy of seviteronel as measured by the overall response rate (ORR) based on RECIST 1.1		At least monthly over the first eight 28-day cycles
Estimate efficacy of seviteronel as measured by progression-free survival (PFS)		At least monthly over the first eight 28-day cycles
Describe the safety profile of seviteronel		Duration of the study
Compare the safety profile of seviteronel with or without concurrent glucocorticoid administration		Duration of the study
Compare the CBR16 with or without concurrent glucocorticoid administration for female subjects with TNBC		Duration of the study

Collaborators and Investigators

• Sponsor: Innocrin Pharmaceutical
• Investigators: Study Chair: Victoria Brown, BS, Sponsor GmbH

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2015
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): January 1, 2019

Study Registration Dates

• First Submitted: October 7, 2015
• First Submitted That Met QC Criteria: October 16, 2015
• First Posted (Estimate): October 20, 2015

Study Record Updates

• Last Update Posted (Actual): February 1, 2019
• Last Update Submitted That Met QC Criteria: January 31, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Breast Cancer; Advanced Breast Cancer; Metastatic Breast Cancer; Breast; Male Breast Cancer; CYP17; Triple Negative Cancer; ER+ Breast Cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Breast Neoplasms, Male; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Cytochrome P-450 Enzyme Inhibitors; Seviteronel
• Other Study ID Numbers: INO-VT-464-CL-006