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

Study of KHK2375 in Subjects With Advanced or Recurrent Breast Cancer

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.

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