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

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

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

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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
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Exemestane

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




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 ]


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03291886


Locations
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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.

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Responsible Party: Kyowa Kirin Co., Ltd.
ClinicalTrials.gov Identifier: NCT03291886     History of Changes
Other Study ID Numbers: 2375-002
First Posted: September 25, 2017    Key Record Dates
Last Update Posted: February 11, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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