Phase 2 Study of KHK2375 in Subjects With Advanced or Recurrent Breast Cancer

• ClinicalTrials.gov Identifier: NCT03291886
• Recruitment Status: Active, not recruiting
• First Posted: September 25, 2017
• Last Update Posted: February 11, 2019
• Sponsor: Kyowa Kirin Co., Ltd.
• Information provided by (Responsible Party): Kyowa Kirin Co., Ltd.

Tracking Information

• First Submitted Date: September 14, 2017
• First Posted Date: September 25, 2017
• Last Update Posted Date: February 11, 2019
• Actual Study Start Date: September 22, 2017
• Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 21, 2017)

Progression Free Survival(PFS) defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) [ Time Frame: Approximately 29 months ]

PFS is defined as the number of days from the date of randomization to the date of first documented progressive disease (PD) or the date of death from any cause, whichever comes first (date of first documented PD or death － date of randomization + 1). The date of first documented PD is the date when PD is first documented at overall response assessment or the date when overall response other than complete response (CR) and not evaluable (NE) is documented after first CR. Subjects who receive post-study treatment before the documentation of PD and subjects with no documented PD or death will be censored at the last date they were confirmed to have no PD. Subjects whose overall response from the date of randomization onward is only NE or who have never undergone assessment of antitumor effect, and whose death has not been documented will be censored at the date of randomization.

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT03291886 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: September 21, 2017)

• Overall survival (OS) [ Time Frame: Up to 50 months ]
  OS is defined as the number of days from the date of randomization to death from any cause (date of death － date of randomization + 1). Subjects without documented death at the time of data cutoff will be censored at the last date they were confirmed to be alive.
• Antitumor effect [ Time Frame: Up to 50 months ]
  The best overall response is defined as the best response recorded from the start of treatment until progression or recurrence according to the categories ordered as CR > partial response(PR) > stable disease (SD) > PD > NE or CR > Non-CR/non-PD > PD > NE. A best overall response of CR or PR will be regarded as objective response. A best overall response of CR, PR, or SD for at least 6 months will be regarded as clinical benefit.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: September 21, 2017)

• Plasma concentration of KHK2375 [ Time Frame: Day 1 of Cycle 1, Day 15 of Cycle 1 , and Day 1 of Cycle 2 (each cycle is 28 days) ]
• Frequency of subjects with treatment-emergent adverse events [ Time Frame: Assessed up to 28 days after study discontinuation ]

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Phase 2 Study of KHK2375 in Subjects With Advanced or Recurrent Breast Cancer
• Official Title: Study of KHK2375 in Subjects With Advanced or Recurrent Breast Cancer
• Brief Summary: The primary objective of this study is to investigate the effect of 5 mg KHK2375 on progression free survival (PFS) when administered orally at weekly intervals in combination with exemestane in a placebo-controlled, double-blind comparative study in subjects with advanced or recurrent hormone receptor-positive breast cancer. The secondary objectives are to investigate the effect of on overall survival (OS) and the antitumor effect and to evaluate the pharmacokinetics and safety.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Double-blinded, randomized trial

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Advanced or Recurrent Breast Cancer

Intervention

• Drug: Entinostat
  Given PO
  Other Names:

  • KHK2375
  • MS-275
  • SNDX-275
• Drug: Entinostat(Placebo)
  Given PO
  Other Names:

  • KHK2375
  • MS-275
  • SNDX-275
• Drug: Exemestane
  Given PO
  Other Names:

  • EXE001
  • Aromasin
  • FCE-24304

Study Arms

• Experimental: Arm A (exemestane, Entinostat)

  5 mg KHK2375 will be administered to subjects once weekly. EXE001 will be administered at a dose of 25 mg once daily orally.

  Pre/perimenopausal female patients also receive luteinizing hormone-releasing hormone (LH-RH) agonist.

  Interventions:

  • Drug: Entinostat
  • Drug: Exemestane
• Placebo Comparator: Arm B (exemestane, Entinostat(placebo))

  KHK2375 Placebo will be administered to subjects once weekly. EXE001 will be administered at a dose of 25 mg once daily orally.

  Pre/perimenopausal female patients also receive luteinizing hormone-releasing hormone (LH-RH) agonist.

  Interventions:

  • Drug: Entinostat(Placebo)
  • Drug: Exemestane

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: September 21, 2017): 124
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2021
• Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Personally submitted voluntary written informed consent to participate in the study
2. Age ≥ 20 years at the time of consent
3. Histologically or cytologically confirmed breast cancer positive for estrogen receptor (ER) and/or progesterone receptor (PgR)
4. Human epidermal growth factor 2 (HER2)-negative
5. Stage III/locally advanced or metastatic carcinoma of the breast where local therapy with curative intent is impossible

6. Pre/Peri- and postmenopausal women

   • Postmenopausal status is defined either by:

     1. Age ≥ 55 years and ≥ 1 year of amenorrhea
     2. Age < 55 years and ≥ 1 year of amenorrhea, with blood estradiol (E2) < 20 pg/mL
     3. Age < 55 years with hysterectomy, with ovaries and E2 < 20 pg/mL
   • Surgical menopause with bilateral oophorectomy Pre/perimenopausal women may be enrolled only if they agree to receive an luteinizing hormone-releasing hormone (LH-RH) agonist
7. Eastern Cooperative Oncology Group(ECOG) performance status (PS) of 0 or 1 at enrollment
8. Measurable or nonmeasurable lesions per RECIST version 1.1 criteria

9. Subjects meeting either of the following criteria:

   • History of treatment with a nonsteroidal aromatase inhibitor (AI) for advanced or recurrent breast cancer, and development of progressive disease (PD) after the most recent prior treatment
   • No history of treatment with endocrine therapy for advanced or recurrent breast cancer that has recurred during or within 12 months after postoperative adjuvant therapy with an nonsteroidal AI
10. An adverse event for which a causal relationship to prior treatment cannot be denied (except alopecia) is Grade ≤ 1 in severity or has returned to the baseline level, i.e., the level before the start of the prior treatment

11. The latest laboratory values obtained prior to enrollment must meet all of the following requirements:

    • Hemoglobin concentration: ≥ 9.0 g/dL
    • Platelet count: ≥ 100000/μL
    • Neutrophil count: ≥ 1500/μL
    • Serum creatinine: ≤ 2.0 mg/dL
    • Total bilirubin in serum: < 1.5 × institutional upper limit of normal (≤ 3 mg/dL for subjects with Gilbert's syndrome)
    • Aspartate transaminase(AST) and Alanine transaminase(ALT): ≤ 3.0 × institutional upper limit of normal

Exclusion Criteria:

1. Endocrine therapy (except for LH-RH agonist), treatment with everolimus, treatment with a cyclin-dependent kinase inhibitor, or radiation therapy within 14 days before enrollment

   Subjects with prior treatment with exemestane may be enrolled if they meet either of the following criteria:

   • Start of treatment with exemestane for advanced or recurrent breast cancer within 28 days before enrollment
   • Recurrence-free period >12 months after completion of treatment with exemestane as postoperative adjuvant therapy. For painful bone lesions or impending fractures, radiation therapy may be used concomitantly if there is a measurable or nonmeasurable lesion that is suitable for efficacy evaluation in a region other than the radiation field
2. Two or more prior chemotherapy regimens for advanced or recurrent breast cancer
3. Chemotherapy within 21 days before enrollment
4. Treatment with bisphosphonates or anti-RANKL antibody that is scheduled to be started within 7 days before the first dose of investigational product
5. History of or current central nervous system metastasis, or current leptomeningeal or periosteal disease
6. History of cancer other than breast cancer within 5 years, or concurrent cancer other than breast cancer (except for basal cell carcinoma of skin, squamous cell carcinoma of skin, and intraepithelial carcinoma of uterine cervix).Subjects continuing to receive treatment for cancer other than breast cancer are ineligible for enrollment
7. Ongoing treatment with any other anticancer therapy or investigational product (Except for treatment with exemestane or radiotherapy as described in exclusion criterion 1)
8. Prior treatment with histone deacetylase inhibitor (e.g. valproate, vorinostat)
9. Known allergy to imidazoles, exemestane, or entinostat
10. Any medical or psychiatric condition that could affect compliance with the protocol, ability to give consent, or assessment of anticipated toxicities
11. Uncontrolled complications (e.g., active infections)
12. Positive for either hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus antibody
13. Any other conditions unsuitable for the study in the opinion of the investigator or subinvestigator

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 20 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan

Administrative Information

• NCT Number: NCT03291886
• Other Study ID Numbers: 2375-002
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Kyowa Kirin Co., Ltd.
• Study Sponsor: Kyowa Kirin Co., Ltd.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Kyowa Kirin Co., Ltd.
• Verification Date: February 2019