Related Experiment Video
Updated: Jun 16, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Phase I study of H3B-6545 in patients with estrogen receptor-positive breast cancer
K Yonemori1, T Shimoi1, K Yamamoto1
1Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Background:
This phase I study (NCT04568902) evaluated a novel selective estrogen receptor (ER)-α covalent antagonist (H3B-6545) at doses of 300-450 mg in Japanese women with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced/metastatic breast cancer (mBC).
Patients And Methods:
This study consisted of three parts. In the dose-escalation (DE) part, two dose levels [300 and 450 mg once daily (QD)] were evaluated. The next two parts (antihistamine prophylactic administration and randomization) evaluated oral antihistamines for rash occurrence. Primary endpoints were dose-limiting toxicities (DLTs) and safety; secondary endpoints included objective response rate [ORR; i.e. complete response (CR) + partial response (PR)] and clinical benefit rate [CBR; i.e. CR + PR + stable disease (SD) for ≥23 weeks].
Results:
Thirty-three patients were enrolled to receive H3B-6545 (300 mg, n = 3; 450 mg with antihistamine, n = 15; 450 mg without antihistamine, n = 15). Median age was 57 years. The median number of prior therapies for mBC was three including fulvestrant (78.8%) and cyclin-dependent kinase 4/6 inhibitors (72.7%). In the DE part, no DLTs were observed with H3B-6545 300 mg. One DLT (grade 3 QT interval prolonged) occurred among six patients with H3B-6545 450 mg. Overall, the most common adverse event (AE) was sinus bradycardia (93.9%); the most common grade 3 AE was anemia (15.2%). No grade 4/5 AEs were reported. Rash maculopapular or rash occurred in 10 of 15 patients (66.7%) given H3B-6545 450 mg QD with prophylactic antihistamines and in 4 of 15 patients (26.7%) not given prophylactic antihistamines. Overall, 1 patient had a PR and 19 had SD; the ORR was 3.0% and the CBR was 33.3%. Of 12 patients with mutant ESR1, the CBR was 66.7% with 1 PR.
Conclusions:
H3B-6545 at 450 mg QD was tolerated and showed preliminary antitumor effects in Japanese patients with ER-positive, HER2-negative mBC, particularly for those with ESR1 mutations.
Insights
H3B-6545, a novel estrogen receptor-alpha antagonist, showed preliminary antitumor effects in Japanese women with advanced ER-positive, HER2-negative breast cancer. The 450 mg dose was tolerated, especially in patients with ESR1 mutations.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Phase I study NCT04568902 evaluated H3B-6545, a novel selective estrogen receptor (ER)-α covalent antagonist.
- Investigated in Japanese women with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced/metastatic breast cancer (mBC).
Purpose of the Study:
- Evaluate safety and tolerability of H3B-6545 at 300-450 mg doses.
- Assess preliminary antitumor activity, including objective response rate (ORR) and clinical benefit rate (CBR).
- Investigate the effect of prophylactic antihistamines on rash occurrence.
Main Methods:
- Dose-escalation study with two dose levels (300 mg and 450 mg once daily).
- Included evaluation of oral antihistamines for rash prevention.
- Primary endpoints: dose-limiting toxicities (DLTs) and safety. Secondary endpoints: ORR and CBR.
Main Results:
- 33 patients enrolled; 450 mg dose evaluated with and without antihistamines.
- Most common adverse event: sinus bradycardia (93.9%). Grade 3 anemia occurred in 15.2%. No grade 4/5 AEs.
- Overall ORR was 3.0% and CBR was 33.3%. In patients with ESR1 mutations, CBR was 66.7%.
Conclusions:
- H3B-6545 at 450 mg once daily was tolerated in Japanese patients with ER-positive, HER2-negative mBC.
- Demonstrated preliminary antitumor effects, particularly in patients with ESR1 mutations.
- Antihistamine prophylaxis reduced the incidence of rash.
