UMIN-CTR Clinical Trial

Public title

A multicenter randomized phase II clinical trial with neo -adjuvant chemotherapy containing eribulin mesylate for triple negative primary breast cancer patients
(Neo-Entrance study)

Acronym

A multicenter randomized phase II clinical trial with neo -adjuvant chemotherapy containing eribulin mesylate for triple negative primary breast cancer patients
(Neo-Entrance study)

Scientific Title

A multicenter randomized phase II clinical trial with neo -adjuvant chemotherapy containing eribulin mesylate for triple negative primary breast cancer patients
(Neo-Entrance study)

Scientific Title:Acronym

A multicenter randomized phase II clinical trial with neo -adjuvant chemotherapy containing eribulin mesylate for triple negative primary breast cancer patients
(Neo-Entrance study)

Region

Japan

Condition

Patients with operable primary triple-negative breast cancer without prior treatment

Classification by specialty

Hematology and clinical oncology

Breast surgery

Classification by malignancy

Malignancy

Genomic information

YES

Narrative objectives1

To evaluate the efficacy and safety of neo -adjuvant chemotherapy based on eribulin mesylate for primary triple negative breast cancer

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Explanatory

Developmental phase

Phase II

Primary outcomes

Pathological complete response evaluated by the Central Decision Institution [CpCRypN0 (ypT0-TisypN0)]

Key secondary outcomes

- SpCR, SpCR and pN0 rate
- CpCR rate
- QpCR, QpCR and pN0 rate
- Clinical response rate (response rate of eribulin-based, anthracycline treatments and overall response rete)
- Breast-conserving surgery rate
- The rate of patients with axillary lymph nodes negative at the time of surgery which have been diagnosed as node positive before NAC.
- Disease-free Survival (DFS), Invasive Disease-free survival (IDFS), overall survival (OS)
(DFS, IDFS, and OS will be examined in an observational study after the completion of the investigator initiated clinical trial)
- Influence of an eribulin combination regimen on the effects of the second half of the regimen (anthracycline)
- Influence (e.g., neutrophil counts) of blood toxicity on Days 8 and 15 in Cycle 1 of the eribulin combination regimen on the therapeutic effects of eribulin and the effects of the second half of the regimen (anthracycline)
- Influence (e.g., neutrophil counts) of blood toxicity on Days 8 and 15 in Cycle 1 of the paclitaxel combination regimen on the therapeutic effects of paclitaxel and the effects of the second half of the regimen (anthracycline)
- Safety in each treatment groups (adverse events, completion rates, and dose intensity)

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Active

Stratification

YES

Dynamic allocation

YES

Institution consideration

Blocking

Concealment

Central registration

No. of arms

4

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Group A-1
Patient "with age <65 years and HRD positive" or "with BRCA mutation"

1)Combination therapy (paclitaxel + carboplatin) 4 cycles ,2)FEC or AC therapy (4 cycles) ,3) surgery

Combination therapy
Cycles 1-4: paclitaxel at mg/m² once every week (day 1, day 8, day 15) + carboplatin AUC6 (once every three weeks (day 1)

FEC or AC therapy
Cycles 5-8: FEC therapy (5-fluorouracil: 500 mg/m², epirubicin: 100 mg/m², cyclophosphamide: 500 mg/m²) once every three weeks, or AC therapy (doxorubicin: 60 mg/m², cyclophosphamide: 600 mg/m²) once every three weeks
(No change during the FEC and AC therapies)

Interventions/Control_2

Group A-2
Patient "with age <65 years and HRD positive" or "with BRCA mutation"

1)Combination therapy (eribulin + carboplatin)(4 cycles) ,2) FEC or AC therapy (4 cycles) ,3) surgery

Combination therapy
Cycles 1-4: eribulin at 1.4 mg/m² (administered once weekly for two consecutive weeks and washout in Week 3 (day 1, day 8)) + carboplatin AUC6 (once every three weeks, day 1)

FEC or AC therapy
Cycles 5-8: FEC therapy (5-fluorouracil: 500 mg/m², epirubicin: 100 mg/m², cyclophosphamide: 500 mg/m2) once every three weeks, or AC therapy (doxorubicin: 60 mg/m², cyclophosphamide: 600 mg/m²) once every three weeks
(No change during FEC and AC therapies)

Interventions/Control_3

Group B-1
Patient "with age <65 years and HRD negative" or "with age >=65 years(without BRCA mutation)"

1)Combination therapy (eribulin + cyclophosphamide)(6 cycles) ,2) surgery
However, the antitumor effects are examined at Cycles 4 and 6 to determine whether to continue combination therapy or convert to FEC or AC therapy or surgery.

Combination therapy
Eribulin at 1.4 mg/m² (administered once weekly for two consecutive weeks and washout in Week 3 (day 1,day 8)) + cyclophosphamide at 600 mg/m² (once every three weeks, day 1)

FEC or AC therapy
FEC therapy (5-fluorouracil: 500 mg/m², epirubicin: 100 mg/m², cyclophosphamide: 500 mg/m²) once every three weeks, or AC therapy (doxorubicin: 60 mg/m², cyclophosphamide: 600 mg/m²) once every three weeks)
(No change during the FEC and AC therapies)

Interventions/Control_4

Group B-2
Patient "with age <65 years and HRD negative" or "with age >=65 years(without BRCA mutation)"

1)Combination therapy (eribulin + capecitabine) (6 cycles) ,2) surgery
However, the antitumor effects are examined at Cycles 4 and 6 to determine whether to continue combination therapy or convert to FEC or AC therapy or surgery.

Combination therapy
Cycles 1-6: eribulin at 1.4 mg/m² (administered once weekly for two consecutive weeks and washout in Week 3 (day 1,day 8)) + capecitabine at 2,000 mg/m²/day (continuously administered twice daily on Days 1-14 and washout on Days 15-21)

FEC or AC therapy
FEC therapy (5-fulorouracil: 500 mg/m², epirubicin: 100 mg/m², cyclophosphamide: 500 mg/m2) once every three weeks, or AC therapy (doxorubicin: 60 mg/m², cyclophosphamide: 600 mg/m²) once every three weeks)
(No change during the FEC and AC therapies)

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

70

years-old

>=

Gender

Female

Key inclusion criteria

First key inclusion criteria
(1) Age at the time of informed consent and has signed an informed consent form is between 20 and 70years
(2) Primary breast cancer which is diagnosed as invasive breast cancer by needle or Vacuum-assisted breast biopsy (exclude apocrine or medullary carcinoma).
(3) Resectable primary breast cancer (cT1c-cT3, cN0-cN1, and cM0)with a tumor size<=70mm in diameter.
(4) Triple-negative (ER<1%, PgR<1%, and HER2-negative) is confirmed in primary lesion, Ki67 labelling index of>=10%.
(5) No previous therapy for breast cancer.
(6) Pt is considered as suitable indication for primary systemic therapy.
(7) Pt who evaluable primary disease using contrast-enhanced MRI or PET/CT
(8) Pt with evaluable primary disease using mammary ultrasonography
(9) Written informed consent

Secondary inclusion criteria
Pt who has been determined to be eligible for the primary registration and meet all of the following conditions:
(1) ECOG performance status (PS) 0-1
(2) By the pathological central review, invasive breast cancer, triple-negative breast cancer (ER <1%, PgR <1%, HER2 negative), and Ki67 labelling index of >=10% have been confirmed.
(3) HRD test result is confirmed when age <65 years at consent acquisition (not required if BRCA mutations are known).
(4) Clinical examination values at screening meet the criteria, with normal organ functions maintained.
(5) Pt with HRD negative and the creatinine clearance >=50 mL/min when age >=65 years at consent acquisition.
(6) No clinically significant arrhythmia by ECG (QTc: <=480 msec).
(7) No interstitial pneumonia or lung fibrosis diagnosed by chest CT or X-ray.
(8) Non-pregnancy is confirmed using a pregnancy test.
(9) Pt with possibility of pregnancy must agree to take contraception.
(10) HBs antigen, HBc antibody, and HBs antibody tests are all negative. In cases negative for HBs antigen and positive for HBc antibody and/or HBs antibody, HBV-DNA levels have to been below the detection limit.

Key exclusion criteria

(1) Bilateral invasive breast cancer whether metachronous,concurrent or bilateral DCIS. Contralateral DCIS after mastectomy (Bt), skin-sparing mastectomy (SSM), nipple-sparing mastectomy (NSM), or equivalent are permitted.
(2) Pt with multiple cancers other than breast cancer
(3) Pt with axillary lymph node dissection before pre-operative chemotherapy
(4) Pt with incisional or excisional biopsies for primary lesion or axillary lymph node
(5) Participation in another clinical trial within 28 days after the second registration
(6) Pt with peripheral neuropathy >= NCI CTCAE v.4.03 Grade 2
(7) Pt with cardiopulmonary dysfunctions within six months before the second registration
(8) Pt with myocardial infarction within 12 months before the second registration
(9) Pt with severe uncontrolled systemic diseases
(10) Pt who undergone major surgery or serious trauma within 28 days before the second registration, or who will have a major surgery during this trial.
(11) Pt with severe infectious disease requiring intravenous administration of antibiotics, antiviral agents, or anti-fungal agents at the second registration
(12) Pt with dental caries and/or oral infections requiring treatment
(13) Pt with diagnosed of active liver disease or sclerosing cholangitis caused by autoimmune liver disorders
(14) Pt with HIV infection
(15) Lactating Pt
(16)Other diseases that are considered to affect consent acquisition or protocol compliance by an investigator or sub-investigator.
(17) Pt with hypersensitive to the study drug or additives and with DPD deficiency
(18) Pt with difficulty of the oral ingestion, dysfunction of the upper gastrointestinal tract and malabsorption syndrome ( only in case HRD negative or age>=65 years at consent acquisition)
(19) Pt determined to be ineligible by an investigator.

Target sample size

200

Name of lead principal investigator

1st name	1)Masakazu 2) Norikazu
Middle name
Last name	1)Toi 2) Masuda

Organization

1) Kyoto University Graduate School of Medicine
2) National Hospital Organization Osaka National Hospital

Division name

1)Breast Surgery, 2) Department of surgery,Breast oncology

Zip code

606-8507

Address

1)54 Syogoin Kawahara-cho, Sakyu-ku, Kyoto , Japan

TEL

075-751-3660

Email

office@jbcrg.jp

Name of contact person

1st name	Jun
Middle name
Last name	Fukase

Organization

Japan Breast Cancer Research Group (JBCRG)

Division name

Head office

Zip code

103-0016

Address

9-4-3F, Nihonbashikoamicho, Chuo-ku, Tokyo, Japan

TEL

03-6264-8873

Homepage URL

https://www.jbcrg.jp/

Email

office@jbcrg.jp

Institute

Japan Breast Cancer Research Group)

Institute

Department

Personal name

Organization

Eisai Co., Ltd.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Japan

Co-sponsor

Name of secondary funder(s)

Organization

N/A

Address

N/A

Tel

N/A

Email

N/A

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

独立行政法人国立病院機構北海道がんセンター（北海道）
新潟県立がんセンター新潟病院（新潟県）
公立大学法人　福島県立医科大学附属病院（福島県）　
筑波大学附属病院 （茨城県）
埼玉医科大学国際医療センター（埼玉県）
埼玉県立がんセンター（埼玉県）
千葉県がんセンター（千葉県）
がん・感染症センター 都立駒込病院 （東京都）
国家公務員共済組合連合会 虎の門病院 （東京都）
公益財団法人 がん研究会有明病院 （東京都）
杏林大学医学部付属病院 （東京都）
地方独立行政法人神奈川県立病院機構 神奈川県立がんセンター（神奈川県）
京都大学医学部附属病院 （京都府）
独立行政法人 国立病院機構大阪医療センター（大阪府）
地方独立行政法人大阪府立病院機構 大阪府立成人病センター（大阪府）
地方独立行政法人広島市立病院機構 広島市立広島市民病院 （広島県）
広島大学病院 （広島県）
独立行政法人国立病院機構四国がんセンター（愛媛県）
熊本大学医学部附属病院（熊本県）
神戸市立医療センター中央市民病院（兵庫県）

Date of disclosure of the study information

2016

Year

09

Month

15

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

100

Results

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

No longer recruiting

Date of protocol fixation

2016

Year

06

Month

10

Day

Date of IRB

2016

Year

06

Month

10

Day

Anticipated trial start date

2017

Year

03

Month

09

Day

Last follow-up date

2024

Year

12

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2016

Year

07

Month

14

Day

Last modified on

2022

Year

01

Month

20

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000026361