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

Sponsor
Kyowa Kirin Co., Ltd. (Industry)
Overall Status
Completed
CT.gov ID
NCT03291886
Collaborator
(none)
133
Enrollment
28
Locations
2
Arms
42.1
Actual Duration (Months)
4.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

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
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
133 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Double-blinded, randomized trialDouble-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 :
Sep 22, 2017
Actual Primary Completion Date :
Apr 4, 2019
Actual Study Completion Date :
Mar 26, 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) [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) [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 [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 [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 [Assessed up to 28 days after study discontinuation]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    20 Years and Older
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    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

    1. Eastern Cooperative Oncology Group(ECOG) performance status (PS) of 0 or 1 at enrollment

    2. Measurable or nonmeasurable lesions per RECIST version 1.1 criteria

    3. 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

    1. 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

    2. 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

    1. Two or more prior chemotherapy regimens for advanced or recurrent breast cancer

    2. Chemotherapy within 21 days before enrollment

    3. Treatment with bisphosphonates or anti-RANKL antibody that is scheduled to be started within 7 days before the first dose of investigational product

    4. History of or current central nervous system metastasis, or current leptomeningeal or periosteal disease

    5. 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

    6. Ongoing treatment with any other anticancer therapy or investigational product (Except for treatment with exemestane or radiotherapy as described in exclusion criterion 1)

    7. Prior treatment with histone deacetylase inhibitor (e.g. valproate, vorinostat)

    8. Known allergy to imidazoles, exemestane, or entinostat

    9. Any medical or psychiatric condition that could affect compliance with the protocol, ability to give consent, or assessment of anticipated toxicities

    10. Uncontrolled complications (e.g., active infections)

    11. Positive for either hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus antibody

    12. Any other conditions unsuitable for the study in the opinion of the investigator or subinvestigator

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Aichi Cancer Center Hospital Nagoya Aichi Japan
    2 Nagoya City University Hospital Nagoya Aichi Japan
    3 Shikoku Cancer Center Matsuyama Ehime Japan
    4 Kitakyushu Municipal Medical Center Kitakyushu Fukuoka Japan
    5 Gunma Cancer Center Ota Gunma Japan
    6 Hokkaido Cancer Center Sapporo Hokkaido Japan
    7 Hokkaido University Hospital Sapporo Hokkaido Japan
    8 The Hospital of Hyogo College of Medicine Nishinomiya Hyogo Japan
    9 Tsukuba University Hospital Tsukuba Ibaraki Japan
    10 Tokai University Hospital Isehara Kanagawa Japan
    11 Kanagawa Cancer Center Yokohama Kanagawa Japan
    12 Nahanishi Clinic Naha Okinawa Japan
    13 Kindai University Hospital Osakasayama Osaka Japan
    14 Osaka University Hospital Suita Osaka Japan
    15 Saitama Medical University International Medical Center Hidaka Saitama Japan
    16 Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital Bunkyo Tokyo Japan
    17 National Cancer Center Hospital Chuo Tokyo Japan
    18 The Cancer Institute Hospital of JFCR Koto Tokyo Japan
    19 Toranomon Hospital Minato Tokyo Japan
    20 Showa University Hospital Shinagawa Tokyo Japan
    21 Chiba Cancer Center Chiba Japan
    22 Kyushu Cancer Center Fukuoka Japan
    23 Sagara Hospital Kagoshima Japan
    24 Kumamoto University Hospital Kumamoto Japan
    25 Kyoto University Hospital Kyoto Japan
    26 Niigata Cancer Center Hospital Niigata Japan
    27 Okayama University Hospital Okayama Japan
    28 Osaka National Hospital Osaka Japan

    Sponsors and Collaborators

    • Kyowa Kirin Co., Ltd.

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Kyowa Kirin Co., Ltd.
    ClinicalTrials.gov Identifier:
    NCT03291886
    Other Study ID Numbers:
    • 2375-002
    First Posted:
    Sep 25, 2017
    Last Update Posted:
    Jun 21, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    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
    Recurrence
    Exemestane
    Entinostat

    Study Results

    No Results Posted as of Jun 21, 2022