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: March 13, 2020
• Sponsor: Kyowa Kirin Co., Ltd.
• Information provided by (Responsible Party): Kyowa Kirin Co., Ltd.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Advanced or Recurrent Breast Cancer	Drug: Entinostat; Drug: Entinostat(Placebo); Drug: Exemestane	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Double-blinded, randomized trial
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Study of KHK2375 in Subjects With Advanced or Recurrent Breast Cancer
• Actual Study Start Date: September 22, 2017
• Actual Primary Completion Date: April 4, 2019
• Estimated Study Completion Date: November 2021

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: Entinostat; Given PO; Other Names: KHK2375; MS-275; SNDX-275; Drug: Exemestane; Given PO; Other Names: EXE001; Aromasin; FCE-24304
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.	Drug: Entinostat(Placebo); Given PO; Other Names: KHK2375; MS-275; SNDX-275; Drug: Exemestane; Given PO; Other Names: EXE001; Aromasin; FCE-24304

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.

Other Outcome Measures:

1. 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) ]
2. Frequency of subjects with treatment-emergent adverse events [ Time Frame: Assessed up to 28 days after study discontinuation ]

Eligibility Criteria

• Ages Eligible for Study: 20 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Japan

Aichi Cancer Center Hospital

Nagoya, Aichi, Japan

Nagoya City University Hospital

Nagoya, Aichi, Japan

Shikoku Cancer Center

Matsuyama, Ehime, Japan

Kitakyushu Municipal Medical Center

Kitakyushu, Fukuoka, Japan

Gunma Cancer Center

Ota, Gunma, Japan

Hokkaido Cancer Center

Sapporo, Hokkaido, Japan

Hokkaido University Hospital

Sapporo, Hokkaido, Japan

The Hospital of Hyogo College of Medicine

Nishinomiya, Hyogo, Japan

Tsukuba University Hospital

Tsukuba, Ibaraki, Japan

Tokai University Hospital

Isehara, Kanagawa, Japan

Kanagawa Cancer Center

Yokohama, Kanagawa, Japan

Nahanishi Clinic

Naha, Okinawa, Japan

Kindai University Hospital

Osakasayama, Osaka, Japan

Osaka University Hospital

Suita, Osaka, Japan

Saitama Medical University International Medical Center

Hidaka, Saitama, Japan

Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital

Bunkyo, Tokyo, Japan

National Cancer Center Hospital

Chuo, Tokyo, Japan

The Cancer Institute Hospital of JFCR

Koto, Tokyo, Japan

Toranomon Hospital

Minato, Tokyo, Japan

Showa University Hospital

Shinagawa, Tokyo, Japan

Chiba Cancer Center

Chiba, Japan

Kyushu Cancer Center

Fukuoka, Japan

Sagara Hospital

Kagoshima, Japan

Kumamoto University Hospital

Kumamoto, Japan

Kyoto University Hospital

Kyoto, Japan

Niigata Cancer Center Hospital

Niigata, Japan

Okayama University Hospital

Okayama, Japan

Osaka National Hospital

Osaka, Japan

Sponsors and Collaborators

Kyowa Kirin Co., Ltd.

More Information

• Responsible Party: Kyowa Kirin Co., Ltd.
• ClinicalTrials.gov Identifier: NCT03291886
• Other Study ID Numbers: 2375-002
• First Posted: September 25, 2017
• Last Update Posted: March 13, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Exemestane; Entinostat; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Histone Deacetylase Inhibitors