Clinical trial NCT03250676: Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2017-08-16
Enrollment: 151
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).


Eligibility criteria: Inclusion Criteria:

1. Pre- or post-menopausal women.
2. ER-positive, HER2-negative breast cancer that is advanced or metastatic.
3. 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.
4. 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.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
6. Adequate bone marrow and organ function.
7. 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.
8. 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:

1. Participants must have at least one measurable lesion.
2. Participant with inflammatory breast cancer.
3. Participant has received more than one prior chemotherapy regimen for metastatic disease (Phase 2 only).
4. Females of childbearing potential who are unable or unwilling to follow adequate contraceptive measures.

Primary outcomes:
measure: Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1 (Cycle length=28 days)
measure: Phase 1 and Phase 2: Objective Response Rate (ORR)
timeFrame: 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)
measure: Phase 1 and Phase 2: Duration of Response (DoR)
timeFrame: 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)
measure: Phase 1 and Phase 2: Disease Control Rate (DCR)
timeFrame: 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)
measure: Phase 1 and Phase 2: Clinical Benefit Rate (CBR)
timeFrame: 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)
measure: Phase 1 and Phase 2: Progression-free Survival (PFS)
timeFrame: 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)
measure: Phase 1 and Phase 2: Overall Survival (OS)
timeFrame: 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:
measure: Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From start of the study up to 74 months
measure: Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545
timeFrame: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)
measure: Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545
timeFrame: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)
measure: Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545
timeFrame: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)
measure: Phase 1: Rac (Cmax): Accumulation Ratio of Cmax for H3B-6545
timeFrame: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)
measure: Phase 1: Rac (AUC0-24h): Accumulation Ratio of Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC0-24h) for H3B-6545
timeFrame: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)
measure: Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using AUC(0-24h)
timeFrame: Cycle 1 Days 15 and 22: predose and up to 24 hours postdose (Cycle length = 28 days)
measure: Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using Cmax
timeFrame: Cycle 1 Days 15 and 22: predose and up to 24 hours postdose (Cycle length = 28 days)
measure: Phase 2: Mean Change From Baseline in Endometrial Thickness Due to H3B-6545
timeFrame: Baseline, Week 12, Week 36 and Week 60
measure: Phase 2: Mean Change From Baseline in Uterine Volume Due to H3B-6545
timeFrame: Baseline, Week 12 and Week 36
measure: Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase
timeFrame: Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days)
measure: Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP)
timeFrame: Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days)
measure: Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX)
timeFrame: Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days)
Other outcomes:
Locations:
city: Goodyear
country: United States
facility: Western Regional Medical Center, Inc., DBA Cancer Treatment Centers of America, Phoenix
state: Arizona
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado - Cancer Center
state: Colorado
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital Inc
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists South
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists North
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists and Research Institute
state: Florida
city: Newnan
country: United States
facility: Southeastern Regional Medical Center, Inc., DBA Cancer Treatment Centers of America, Atlanta
state: Georgia
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Zion
country: United States
facility: Midwestern Regional Medical Center, Inc., DBA Cancer Treatment Centers of Americal, Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Kansas City
country: United States
facility: Saint Luke's Cancer Institute
state: Missouri
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Center of Nevada
state: Nevada
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Dallas
country: United States
facility: Parkland Health and Hospital System
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Tyler
country: United States
facility: Tyler Oncology/Oncology PA
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute at The University of Utah
state: Utah
city: Angers
country: France
facility: Edog - Ico - Ppds
city: Besançon
country: France
facility: Hopital Jean Minjoz
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Lille
country: France
facility: Centre Oscar Lambret
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hôpital de la Pitié Salpétrière
city: Rennes
country: France
facility: EDOG - Centre Eugene Marquis Centre Regional de Lutte Contre Le Cancer - PPDS
city: St. Herblain
country: France
facility: EDOG Institut de Cancerologie de l'Ouest - PPDS
city: Strasbourg
country: France
facility: Institut de Cancérologie Strasbourg Europe
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy
city: Chelsea
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
state: London
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
References:
citation: 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.