Clinical trial NCT03291886: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Advanced or Recurrent Breast Cancer
Lead sponsor: Kyowa Kirin Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2017-09-25
Enrollment: 133
Sex: FEMALE
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blinded, randomized trial
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Progression Free Survival(PFS) defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1)
timeFrame: Approximately 29 months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Up to 50 months
measure: Antitumor effect
timeFrame: Up to 50 months
Other outcomes:
measure: Plasma concentration of KHK2375
timeFrame: Day 1 of Cycle 1, Day 15 of Cycle 1 , and Day 1 of Cycle 2 (each cycle is 28 days)
measure: Frequency of subjects with treatment-emergent adverse events
timeFrame: Assessed up to 28 days after study discontinuation
Locations:
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
state: Aichi
city: Nagoya
country: Japan
facility: Nagoya City University Hospital
state: Aichi
city: Matsuyama
country: Japan
facility: Shikoku Cancer Center
state: Ehime
city: Kitakyushu
country: Japan
facility: Kitakyushu Municipal Medical Center
state: Fukuoka
city: Ota
country: Japan
facility: Gunma Cancer Center
state: Gunma
city: Sapporo
country: Japan
facility: Hokkaido Cancer Center
state: Hokkaido
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Nishinomiya
country: Japan
facility: The Hospital of Hyogo College of Medicine
state: Hyogo
city: Tsukuba
country: Japan
facility: Tsukuba University Hospital
state: Ibaraki
city: Isehara
country: Japan
facility: Tokai University Hospital
state: Kanagawa
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center
state: Kanagawa
city: Naha
country: Japan
facility: Nahanishi Clinic
state: Okinawa
city: Osakasayama
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Suita
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Hidaka
country: Japan
facility: Saitama Medical University International Medical Center
state: Saitama
city: Bunkyo
country: Japan
facility: Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital
state: Tokyo
city: Chuo
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Koto
country: Japan
facility: The Cancer Institute Hospital of JFCR
state: Tokyo
city: Minato
country: Japan
facility: Toranomon Hospital
state: Tokyo
city: Shinagawa
country: Japan
facility: Showa University Hospital
state: Tokyo
city: Chiba
country: Japan
facility: Chiba Cancer Center
city: Fukuoka
country: Japan
facility: Kyushu Cancer Center
city: Kagoshima
country: Japan
facility: Sagara Hospital
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Niigata
country: Japan
facility: Niigata Cancer Center Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Osaka National Hospital
Study officials:
References:
citation: Iwata H, Nakamura R, Masuda N, Yamashita T, Yamamoto Y, Kobayashi K, Tsurutani J, Iwasa T, Yonemori K, Tamura K, Aruga T, Tokunaga E, Kaneko K, Lee MJ, Yuno A, Kawabata A, Seike T, Kaneda A, Nishimura Y, Trepel JB, Saji S. Efficacy and exploratory biomarker analysis of entinostat plus exemestane in advanced or recurrent breast cancer: phase II randomized controlled trial. Jpn J Clin Oncol. 2023 Jan 6;53(1):4-15. doi: 10.1093/jjco/hyac166.