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

Phase 1

Completed

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

Interventions: Drug: H3B-6545

Registration Number: NCT03250676

Lead Sponsor: Eisai Inc.

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 151

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
H3B-6545 Arm 2: Phase 2	H3B-6545	-
H3B-6545 Arm 1: Dose escalation	H3B-6545	-

Primary Outcome Measures

Name	Time	Method
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)	Cycle 1 (Cycle length=28 days)	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.
Phase 1 and Phase 2: Objective Response Rate (ORR)	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)	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: Duration of Response (DoR)	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)	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: Disease Control Rate (DCR)	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)	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: Clinical Benefit Rate (CBR)	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)	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: Progression-free Survival (PFS)	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)	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: Overall Survival (OS)	Phase 1 and Phase 2: From the first dose of study drug to date of death or last known alive (up to 63 months)	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.

Secondary Outcome Measures

Name	Time	Method
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	TEAE was defined per NCI CTCAE version 4.03 as an adverse event (AE) with an onset that occurred after receiving study drug. An AE was defined as any untoward medical occurrence in a participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A serious adverse event (SAE) was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. Pooled data from phase 1 and phase 2 was presented for 450 mg arm as enrolled participants in both the phases had similar demographics and disease characteristics with no major changes in inclusion/exclusion criteria as defined in the protocol.
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)	AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 time to last measurable point for H3B-6545.
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)	Cmax was defined as the maximum plasma concentration for H3B-6545.
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)	Tmax was defined as the time to reach maximum observed plasma concentration for H3B-6545.
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)	Accumulation ratio of Cmax was calculated as Cmax at Cycle 1 Day 15/Cmax at Cycle 1 Day 1.
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	Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)	Rac (AUC0-24h) was calculated as AUC(0-24h) at Cycle 1 Day 15/AUC(0-24h) at Cycle 1 Day 1.
Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using AUC(0-24h)	Cycle 1 Days 15 and 22: predose and up to 24 hours postdose (Cycle length = 28 days)	Relative bioavailability based on food effect was calculated by taking ratio of AUC(0-24h) under fed condition divided by AUC(0-24h) under fasting condition. Data for the fasted and fed cohorts was collected on both Day 15 and Day 22 and was averaged.
Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using Cmax	Cycle 1 Days 15 and 22: predose and up to 24 hours postdose (Cycle length = 28 days)	Relative bioavailability based on food effect was calculated by taking ratio of Cmax under fed condition divided by Cmax under fasting condition. Data for the fasted and fed cohorts was collected on both Day 15 and Day 22 and was averaged.
Phase 2: Mean Change From Baseline in Endometrial Thickness Due to H3B-6545	Baseline, Week 12, Week 36 and Week 60	Participants with an intact uterus underwent transvaginal ultrasound to examine the effect of H3B-6545 on endometrial thickness. Baseline was defined as the last non-missing value before the first dose of study drug (Day 1). Mean change from baseline was calculated as post-baseline visit value minus baseline value.
Phase 2: Mean Change From Baseline in Uterine Volume Due to H3B-6545	Baseline, Week 12 and Week 36	Participants with an intact uterus underwent transvaginal ultrasound to examine the effect of H3B-6545 on uterine volume. Baseline was defined as the last non-missing value before the first dose of study drug (Day 1). Mean change from baseline was calculated as post-baseline visit value minus baseline value.
Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase	Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days)	Blood samples were collected at indicated timepoint for evaluation of bone turn-over marker BSAP. Baseline is defined as the last non-missing value before the first dose of study drug (Day1). Change from baseline was calculated as post-baseline visit value minus baseline value. Pooled data from phase 1 and phase 2 was presented for 450 mg arm as enrolled participants in both the phases had similar demographics and disease characteristics with no major changes in inclusion/exclusion criteria as defined in the protocol.
Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP)	Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days)	Blood samples were collected at indicated timepoint for evaluation of Bone turn-over marker PINP. Baseline is defined as the last non-missing value before the first dose of study drug (Day 1). Change from baseline was calculated as post-baseline visit value minus baseline value. Pooled data from phase 1 and phase 2 was presented for 450 mg arm as enrolled participants in both the phases had similar demographics and disease characteristics with no major changes in inclusion/exclusion criteria as defined in the protocol.
Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX)	Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days)	Blood samples were collected at indicated timepoint for evaluation of Bone turn-over marker CTX. Baseline is defined as the last non-missing value before the first dose of study drug (Day 1). Change from baseline was calculated as post-baseline visit value minus baseline value. Pooled data from phase 1 and phase 2 was presented for 450 mg arm as enrolled participants in both the phases had similar demographics and disease characteristics with no major changes in inclusion/exclusion criteria as defined in the protocol.

Trial Locations

Locations (38): Carle Cancer Center
🇺🇸
Urbana, Illinois, United States
Parkland Health and Hospital System
🇺🇸
Dallas, Texas, United States
University of California Los Angeles
🇺🇸
Los Angeles, California, United States
Western Regional Medical Center, Inc., DBA Cancer Treatment Centers of America, Phoenix
🇺🇸
Goodyear, Arizona, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Edog - Ico - Ppds
🇫🇷
Angers, France
Southeastern Regional Medical Center, Inc., DBA Cancer Treatment Centers of America, Atlanta
🇺🇸
Newnan, Georgia, United States
Hopital Jean Minjoz
🇫🇷
Besançon, France
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Tyler Oncology/Oncology PA
🇺🇸
Tyler, Texas, United States
Christie Hospital
🇬🇧
Manchester, United Kingdom
Florida Cancer Specialists South
🇺🇸
Fort Myers, Florida, United States
EDOG - Centre Eugene Marquis Centre Regional de Lutte Contre Le Cancer - PPDS
🇫🇷
Rennes, France
Institut Gustave Roussy
🇫🇷
Villejuif Cedex, France
Saint Luke's Cancer Institute
🇺🇸
Kansas City, Missouri, United States
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
🇺🇸
Baltimore, Maryland, United States
UT Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Centre Jean Perrin
🇫🇷
Clermont-Ferrand, France
Institut de Cancérologie Strasbourg Europe
🇫🇷
Strasbourg, France
The Royal Marsden NHS Foundation Trust
🇬🇧
Sutton, United Kingdom
Hôpital Saint Louis
🇫🇷
Paris, France
Barts Health NHS Trust
🇬🇧
London, United Kingdom
Hôpital de la Pitié Salpétrière
🇫🇷
Paris, France
Sarah Cannon Research Institute
🇬🇧
London, United Kingdom
Centre Oscar Lambret
🇫🇷
Lille, France
EDOG Institut de Cancerologie de l'Ouest - PPDS
🇫🇷
St. Herblain, France
Velindre Cancer Centre
🇬🇧
Cardiff, United Kingdom
University of California San Francisco
🇺🇸
San Francisco, California, United States
Comprehensive Cancer Center of Nevada
🇺🇸
Las Vegas, Nevada, United States
Tennessee Oncology
🇺🇸
Nashville, Tennessee, United States
Holy Cross Hospital Inc
🇺🇸
Fort Lauderdale, Florida, United States
Florida Cancer Specialists and Research Institute
🇺🇸
Sarasota, Florida, United States
Florida Cancer Specialists North
🇺🇸
Saint Petersburg, Florida, United States
Research Medical Center
🇺🇸
Kansas City, Missouri, United States
Midwestern Regional Medical Center, Inc., DBA Cancer Treatment Centers of Americal, Chicago
🇺🇸
Zion, Illinois, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Huntsman Cancer Institute at The University of Utah
🇺🇸
Salt Lake City, Utah, United States
University of Colorado - Cancer Center
🇺🇸
Aurora, Colorado, United States