Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer

Study Overview
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Brief Summary
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The primary purpose of phase 1 portion of this study is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of H3B-6545 in women with locally advanced or metastatic estrogen receptor (ER)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer. The primary purpose of phase 2 portion of this study is to estimate the efficacy of H3B-6545 in terms of best overall response rate, duration of response (DoR), clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in all participants with ER-positive, HER2-negative breast cancer and in those with and without ER alpha mutation (including a clonal estrogen receptor 1 gene [ESR1] Y537S mutation).

Official Title
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A Phase 1-2 Multicenter, Open Label Trial of H3B-6545, a Covalent Antagonist of Estrogen Receptor Alpha, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer

Conditions
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ER Positive, Breast Neoplasms, Breast Cancer, Estrogen-receptor Positive Breast Cancer, Cancer, Breast, Breast Cancer Female, Breast Adenocarcinoma, Estrogen Receptor Positive Tumor

Intervention / Treatment
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* Drug: H3B-6545


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre- or post-menopausal women. ER-positive, HER2-negative breast cancer that is advanced or metastatic. Progressed on prior therapy. Multiple prior lines of therapy allowed in Phase 1 and 2. Participants under amendment 6 (or subsequent amendments) must have received prior cyclin-dependent kinase (CDK4/6) inhibitor therapy. Up to one prior chemotherapy in the metastatic setting is allowed. A recent archival tumor tissue obtained within 6 months prior to enrollment or a fresh tumor biopsy must be provided. A second biopsy after initiating trial therapy is not required. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Adequate bone marrow and organ function. Participants under amendment 6 (or subsequent amendments) must have measurable disease at baseline as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Participants under amendment 6 (or subsequent amendments) must have ESR1 Y537S mutation in absence of ESR1 D538G mutation as per the results of a central laboratory from a Nucleic Acids Whole Blood sample. Exclusion Criteria: Participants must have at least one measurable lesion. Participant with inflammatory breast cancer. Participant has received more than one prior chemotherapy regimen for metastatic disease (Phase 2 only). Females of childbearing potential who are unable or unwilling to follow adequate contraceptive measures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: H3B-6545 Arm 1: Dose escalation<br> | Drug: H3B-6545<br>* Oral capsules by mouth once daily<br>|
| Experimental: H3B-6545 Arm 2: Phase 2<br> | Drug: H3B-6545<br>* Oral capsules by mouth once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose-limiting Toxicities (DLTs) |  | Phase 1 Cycle 1 (28 days) | 
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Phase 1 and 2 continuously throughout the study until 28 days after treatment discontinuation (up to 36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the Plasma Concentration-time Curve from Time 0 Through the Last Measurable Point (AUC0-t) of H3B-6545 |  | Phase 1, Cycle 1 (28-day cycles): Days 1 and 15 pre-dose and at multiple time points (up to 24 hours) post-dose; or Phase 2 Cycle 1 (28-day cycles): Days 15 or 22 pre-dose and at multiple time points (up to 24 hours) post-dose | 
| Mean Maximum Observed Plasma Concentration (Cmax) of H3B-6545 |  | Phase 1, Cycle 1 (28-day cycles): Days 1 and 15 (pre-dose and at multiple time points (up to 24 hours) post-dose; or Phase 2 Cycle 1 (28-day cycles): Days 15 or 22 pre-dose and at multiple time points (up to 24 hours) post-dose | 
| Time of Maximum Observed Plasma Concentration (tmax) of H3B-6545 |  | Phase 1, Cycle 1 (28-day cycles): Days 1 and 15 pre-dose and at multiple time points (up to 24 hours) post-dose; or Phase 2 Cycle 1 (28-day cycles): Days 15 or 22 pre-dose and at multiple time points (up to 24 hours) post-dose | 
| Objective Response Rate (ORR) |  | Phase 1 and 2 up to approximately 36 months | 
| Duration of Response (DoR) |  | Phase 1 and 2 up to approximately 36 months | 
| Disease Control Rate (DCR) |  | Phase 1 and 2 up to approximately 36 months | 
| Clinical Benefit Rate (CBR) |  | Phase 1 and 2 up to approximately 36 months | 
| Progression-free survival (PFS) |  | Phase 1 and 2 up to approximately 36 months | 
| Overall Survival (OS) |  | Phase 1 and 2 up to approximately 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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estrogen receptor, H3B-6545, breast cancer, Endocrine Therapy