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

NCT03250676 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: H3B-6545-A001-1012018-000570-29
• Study Type: interventional
• Target: 151
• Locations: 3 countries
• Sites: 39

Brief Summary

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).

Conditions

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

Keywords

estrogen receptor; H3B-6545; breast cancer; Endocrine Therapy

Outcome Measures

Primary Outcomes (7)

• Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)

  DLT was graded as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. DLTs were defined as the following events that occurred in Cycle 1, for which a causal relationship with the study drug could not be ruled out: febrile neutropenia; Grade 4 neutropenia that was not resolved within 7 days; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia lasting greater than (\>) 7 days or associated with clinically significant bleeding; Grade 4 vomiting and diarrhea; Grade 3 vomiting and diarrhea lasting \>72 hours despite treatment; Grade 4 electrolyte abnormality or Grade 3 abnormality lasting \>24 hours; Grade 3 or 4 serum creatinine or bilirubin increase; Grade 4 biochemistry or Grade 3 lasting \>7 days; Grade 4 or Grade 3 or intolerable Grade 2 toxicities of any non-hematologic adverse event.

  Cycle 1 (Cycle length=28 days)

• Phase 1 and Phase 2: Objective Response Rate (ORR)

  ORR was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as defined by the Investigator based on radiologic criteria. ORR was defined as the percentage of participants who achieved a best overall response of confirmed partial response (PR) or complete response (CR). CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to less than (\<)10 millimeter (mm). PR was defined as at least a 30 percentage (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg dose was presented as enrolled participants in both the phases had similar demographics and disease characteristics.

  Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of progressive disease (PD) or death, whichever occurred first (up to 33 months)

• Phase 1 and Phase 2: Duration of Response (DoR)

  The DoR was assessed according to RECIST version 1.1. DoR was defined as the time from the date of the first documented CR/PR until the first documentation of disease progression or death, whichever comes first. CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.

  Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 33 months)

• Phase 1 and Phase 2: Disease Control Rate (DCR)

  The DCR was assessed according to RECIST version 1.1. DCR was defined as the percentage of participants who achieved best response of CR, PR, or stable disease (SD). CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.

  Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 33 months)

• Phase 1 and Phase 2: Clinical Benefit Rate (CBR)

  The CBR was assessed according to RECIST version 1.1. CBR defined as the percentage of participants with best overall response (BOR) of PR, CR, or durable SD (duration \>=23 weeks). It was calculated for participants whose BOR was SD. CR defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters on study. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.

  Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 33 months)

• Phase 1 and Phase 2: Progression-free Survival (PFS)

  PFS was defined as the time from the first dose date to the date of the first documentation of PD or death whichever occurred first. PD defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum diameters while on study. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.

  Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 33 months)

• Phase 1 and Phase 2: Overall Survival (OS)

  OS was defined as the time from first dose date to the date of death (event) or date last known alive (censored). As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.

  Phase 1 and Phase 2: From the first dose of study drug to date of death or last known alive (up to 63 months)

Secondary Outcomes (13)

• Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

  From start of the study up to 74 months

• Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545

  Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)

• Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545

  Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)

• Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545

  Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)

• Phase 1: Rac (Cmax): Accumulation Ratio of Cmax for H3B-6545

  Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)

Study Arms (2)

H3B-6545 Arm 1: Dose escalation

EXPERIMENTAL

Drug: H3B-6545

H3B-6545 Arm 2: Phase 2

EXPERIMENTAL

Drug: H3B-6545

Interventions

H3B-6545 DRUG

Oral capsules by mouth once daily

H3B-6545 Arm 1: Dose escalation; H3B-6545 Arm 2: Phase 2

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Eisai Inc.: lead

Study Sites (39)

Western Regional Medical Center, Inc., DBA Cancer Treatment Centers of America, Phoenix

Goodyear, Arizona, 85338, United States

Location

University of California Los Angeles

Los Angeles, California, 90404, United States

Location

University of California San Francisco

San Francisco, California, 94158, United States

Location

University of Colorado - Cancer Center

Aurora, Colorado, 80045, United States

Location

Holy Cross Hospital Inc

Fort Lauderdale, Florida, 33308, United States

Location

Florida Cancer Specialists South

Fort Myers, Florida, 33901, United States

Location

Florida Cancer Specialists and Research Institute

Sarasota, Florida, 34232, United States

Location

Florida Cancer Specialists North

St. Petersburg, Florida, 33705, United States

Location

Southeastern Regional Medical Center, Inc., DBA Cancer Treatment Centers of America, Atlanta

Newnan, Georgia, 30265, United States

Location

Carle Cancer Center

Urbana, Illinois, 61801, United States

Location

Midwestern Regional Medical Center, Inc., DBA Cancer Treatment Centers of Americal, Chicago

Zion, Illinois, 60099, United States

Location

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Saint Luke's Cancer Institute

Kansas City, Missouri, 64111, United States

Location

Research Medical Center

Kansas City, Missouri, 64132, United States

Location

Comprehensive Cancer Center of Nevada

Las Vegas, Nevada, 89169, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

Parkland Health and Hospital System

Dallas, Texas, 75235, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Tyler Oncology/Oncology PA

Tyler, Texas, 75701, United States

Location

Huntsman Cancer Institute at The University of Utah

Salt Lake City, Utah, 84112, United States

Location

Edog - Ico - Ppds

Angers, 49055, France

Location

Hopital Jean Minjoz

Besançon, 25030, France

Location

Centre Jean Perrin

Clermont-Ferrand, 63011, France

Location

Centre Oscar Lambret

Lille, 59000, France

Location

Hôpital Saint Louis

Paris, 75010, France

Location

Hôpital de la Pitié Salpétrière

Paris, 75013, France

Location

EDOG - Centre Eugene Marquis Centre Regional de Lutte Contre Le Cancer - PPDS

Rennes, 35042, France

Location

EDOG Institut de Cancerologie de l'Ouest - PPDS

Saint-Herblain, 44805, France

Location

Institut de Cancérologie Strasbourg Europe

Strasbourg, 67200, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

The Royal Marsden NHS Foundation Trust

Chelsea, London, SW3 6JJ, United Kingdom

Location

Velindre Cancer Centre

Cardiff, CF14 2TL, United Kingdom

Location

Barts Health NHS Trust

London, EC1A 7BE, United Kingdom

Location

Sarah Cannon Research Institute

London, W1G 6AD, United Kingdom

Location

Christie Hospital

Manchester, M20 4BX, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Furman C, Puyang X, Zhang Z, Wu ZJ, Banka D, Aithal KB, Albacker LA, Hao MH, Irwin S, Kim A, Montesion M, Moriarty AD, Murugesan K, Nguyen TV, Rimkunas V, Sahmoud T, Wick MJ, Yao S, Zhang X, Zeng H, Vaillancourt FH, Bolduc DM, Larsen N, Zheng GZ, Prajapati S, Zhu P, Korpal M. Covalent ERalpha Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer. Mol Cancer Ther. 2022 Jun 1;21(6):890-902. doi: 10.1158/1535-7163.MCT-21-0378.

  PMID: 35642432 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

H3B-6545

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Eisai Medical Information
• Organization: Eisai Inc.

esi_oncmedinfo@eisai.com

1-888-274-2378

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 11, 2017
• First Posted: August 16, 2017
• Study Start: August 23, 2017
• Primary Completion: October 26, 2023
• Study Completion: October 26, 2023
• Last Updated: February 25, 2025
• Results First Posted: February 25, 2025

Record last verified: 2024-03

Locations

US (23); FR (10); GB (6)