臨床研究等提出・公開システム

A Phase 1 study of H3B-6545 in Japanese women with estrogen receptor-positive, HER2 negative breast cancer

A Phase 1 study of H3B-6545 in Japanese women with estrogen receptor-positive, HER2 negative breast cancer

33

All subjects were Japanese women, with a median age of 57.0 years (range: 28 to 80). The majority of subjects (25/33 subjects, 75.8%) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 at baseline.

A total of 37 subjects were screened, of whom 4 were screen failures and 33 were assigned to study treatment. All 33 subjects received at least 1 dose of study drug. Of these, 3 subjects in the Dose Escalation Part received 300 mg once daily (QD). A total of 30 subjects received 450 mg QD, either with prophylactic antihistamine (6 subjects in the Antihistamine Prophylactic Administration Part and 9 subjects in the Randomization Part) or without prophylactic antihistamine (6 subjects in the Dose Escalation Part and 9 subjects in the Randomization Part). The dose limiting toxicity (DLT) Analysis Set included 9 subjects receiving the study treatment at doses of 300 or 450 mg QD to evaluate DLT in the Dose Escalation Part. The Safety Analysis Set included 33 subjects who received the study treatment and was identical to PK Analysis Set.

All subjects experienced at least 1 treatment-emergent adverse event (TEAE) and at least 1 treatment-related TEAE. Grade 3 or higher TEAEs occurred in 16 of 33 subjects (48.5%), all of whom received 450 mg QD; no subjects treated with 300 mg QD had Grade 3 or higher events. TEAEs occurring in 2 or more subjects treated with 300 mg QD included rash maculo-papular and anemia (3 subjects each, 100%), sinus bradycardia, pruritus, diarrhea, and hypoalbuminemia (2 subjects each, 66.7%). Among subjects treated with 450 mg QD, common TEAEs (>=30%) were sinus bradycardia (96.7%), electrocardiogram QT prolonged (60.0%), anemia (56.7%), alanine aminotransferase increased and aspartate aminotransferase increased (46.7% each), white blood cell count decreased (43.3%), rash maculo-papular (40.0%), fatigue (36.7%), and neutrophil count decreased (33.3%). No Grade 3 or higher TEAEs were reported in subjects treated with 300 mg QD. Among subjects treated with 450 mg QD, no Grade 4 TEAEs were reported; the most common Grade 3 TEAE in subjects treated with 450 mg QD was anemia (5 subjects, 16.7%), followed by electrocardiogram QT prolonged and rash maculo-papular (4 subjects each, 13.3%). No fatal TEAEs were reported. Serious TEAEs occurred in 4 subjects treated with 450 mg QD and included atrial flutter, nausea, intracranial tumor hemorrhage, and rash maculo-papular, with each event occurring in 1 subject. Nausea and rash maculo-papular were considered related to study treatment.

No DLTs were observed among initial 3 subjects treated with 300 mg QD, whereas 1 of 6 subjects treated with 450 mg QD had a nonhematologic DLT (Grade 3 electrocardiogram QT prolonged) in the Dose Escalation Part.

Following single and multiple doses administered on Cycle 1 Day 1 and Cycle 1 Day 15, respectively, at 300 mg QD and 450 mg QD, systemic exposure to H3B-6545 (Cmax and AUC) increased with dose. The geometric mean accumulation ratios (Rac) for Cmax and AUC(0-24h) were below 1.4 at both the 300 mg and 450 mg dose levels, indicating only slight accumulation of H3B-6545 following multiple once-daily administrations.

DLT observed during the Dose Escalation Part indicated that H3B-6545 was tolerated up to 450 mg QD. TEAEs during the study were generally manageable with dose modification of H3B-6545. No new safety signals or any major concerns for H3B-6545 were identified. Systemic exposure to H3B-6545 (Cmax and AUC) increased with dose from 300 mg to 450 mg. Accumulation of H3B-6545 was observed following multiple dosing; however, the extent of accumulation was slight.

July. 27, 2026

June. 01, 2022

https://pubmed.ncbi.nlm.nih.gov/35642432/

Yes

https://www.eisai.com/company/business/research/clinical/index.html

Eisai Co., Ltd.

4-6-10 Koishikawa, Bunkyo-ku, Tokyo

eisai-chiken_hotline@hhc.eisai.co.jp

Eisai Co., Ltd.

4-6-10 Koishikawa, Bunkyo-ku, Tokyo

+81-3-3817-5252

eisai-chiken_hotline@hhc.eisai.co.jp

completed

Oct. 16, 2020

Interventional

open label

treatment purpose

1

1. Subject has a histologically and/or cytologically confirmed diagnosis of ER-positive, HER2-negative breast cancer.
Note: Status of ER and HER2 should be diagnosed by method approved by regulatory authority
2. Only females, age >=20 years at the time of informed consent.
3. Prior therapy for breast cancer in the adjuvant and/or advanced/metastatic setting must have included a minimum of:
a) two prior hormonal therapies, or
b) one prior hormonal therapy and one prior chemotherapy regimen, or
c) one prior hormonal therapy and a CDK4/6 inhibitor.
4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
5. Subject has adequate bone marrow and organ function.
6. Subjects who are expected to survive for 3 months or longer after starting administration of the investigational drug.
7. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

1. Subject with inflammatory breast cancer.
2. Subject is currently receiving or has received systemic corticosteroids =<2 weeks prior to starting study drug, or has not fully recovered from side effects of such treatment.
3. Subject has active cardiac disease or a history of cardiac dysfunction, including any of the following:
a. History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry.
b. History of documented congestive heart failure (New York Heart Association functional classification II to IV).
c. Documented cardiomyopathy.
d. Subject has a left ventricular ejection fraction (LVEF) <50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO).
e. History of any cardiac arrhythmias, eg, ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months.
f. Heart Rate <60 bpm on the screening.
g. On screening, any of the following cardiac parameters: PR interval >220 msec, QRS interval >109 msec, or QTcF >450 msec.
h. Systolic blood pressure (BP) not deemed clinically controlled by the investigator.
4. Subject has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug.
5. Known to be human immunodeficiency virus (HIV) positive.
6. Active viral hepatitis (B or C) as demonstrated by positive serology. Subjects with chronic HBV infection is on antiviral therapy is eligible.
7. Any adverse event related to previous therapies for breast cancer that has not resolved to =<Grade 1 (with exception of the alopecia).
8. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [beta-hCG] or human chorionic gonadotropin [hCG] test).
9. Women of childbearing potential who don't agree that both the subject and her partner will use a medically effective method for contraception (as below) throughout the entire study period or for 28 days after study drug discontinuation.
If a subject is on oral contraceptives, they should also be using some additional method.
10. Alcohol dependency within 6 months before study entry.
11. Subject has a concurrent malignancy or malignancy within 3 years of enrollment, with the exception of adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer.
12. Diagnosed with meningeal carcinomatosis.
13. Subjects with brain or subdural metastases.
14. Subject has a known intolerability to any oral antihistamine drug (only for Antihistamine Prophylactic Administration Part and Randomization Part).
15. Subject needs to receive systemic or topical usage of either antihistamine or corticosteroid during Cycle 1 (only for Randomization Part).
16. Subject has initiated to receive drugs may cause rash 7 days prior to starting study drug.

Female

estrogen receptor-positive, HER2 negative breast cancer

investigational material(s)
Generic name etc : H3B-6545
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Dose escalation Part: Starting dose of 450 mg or less arally, once per day.
Antihistamine Prophylactic Administration Part: H3B-6545 450 mg, once per day.
Non-sedating systemic antihistamine prophylactic administration from Day 1 until Day 28 of Cycle 1
Randomization Part: Participants will be randomized in 1:1 ratio to receive H3B-6545 450 mg, once daily in 28 days cycle either with non-sedating systemic antihistamine prophylactic administration from Day 1 until Day 28 of Cycle 1 OR without antihistamine.

safety
DLT, AE

efficacy
pharmacokinetics
pharmacodynamics
pharmacogenomics
PK

Sept. 14, 2020