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

Eisai Inc.151 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

151

Conditions

Breast Neoplasms Breast Cancer Estrogen-receptor Positive Breast Cancer Cancer, Breast

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (39)

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

Goodyear, Arizona, United States

University of California Los Angeles

Los Angeles, California, United States

University of California San Francisco

San Francisco, California, United States

University of Colorado - Cancer Center

Aurora, Colorado, United States

Holy Cross Hospital Inc

Fort Lauderdale, Florida, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

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

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.

Time frame: 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

AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 time to last measurable point for H3B-6545.

Time frame: 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

Cmax was defined as the maximum plasma concentration for H3B-6545.

Time frame: 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

Tmax was defined as the time to reach maximum observed plasma concentration for H3B-6545.

Time frame: 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

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

Rac (AUC0-24h) was calculated as AUC(0-24h) at Cycle 1 Day 15/AUC(0-24h) at Cycle 1 Day 1.

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

Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using AUC(0-24h)

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.

Time frame: Cycle 1 Days 15 and 22: predose and up to 24 hours postdose (Cycle length = 28 days)

Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using Cmax

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.

Time frame: Cycle 1 Days 15 and 22: predose and up to 24 hours postdose (Cycle length = 28 days)

Phase 2: Mean Change From Baseline in Endometrial Thickness Due to H3B-6545

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.

Time frame: Baseline, Week 12, Week 36 and Week 60

Phase 2: Mean Change From Baseline in Uterine Volume Due to H3B-6545

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.

Time frame: Baseline, Week 12 and Week 36

Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase

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.

Time frame: Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days)

Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP)

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.

Time frame: Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days)

Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX)

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.

Time frame: Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days)

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

Overview

Conditions

Interventions

Eligibility

Locations (39)

Outcomes

Primary Outcomes

Secondary Outcomes