Breast Adenocarcinoma, Breast Cancer, Breast Cancer Female, Breast Neoplasms, Cancer, Breast, ER Positive, Estrogen-receptor Positive Breast Cancer, Estrogen Receptor Positive Tumor
Conditions
Keywords
estrogen receptor, H3B-6545, breast cancer, Endocrine Therapy
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).
Interventions
DRUGH3B-6545
Oral capsules by mouth once daily
Sponsors
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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: 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 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. |
| 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: (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. |
Countries
France, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 39 investigative sites in the United States, France, and the United Kingdom from 23 Aug 2017 to 26 Oct 2023. This study was conducted in two parts: dose escalation and dose expansion.
Pre-assignment details
In the dose escalation part, a total of 47 participants were enrolled and received the study treatment and 104 participants were enrolled in the dose expansion part and received the study treatment. A food-effect sub-study was conducted during the dose expansion phase, where a total of 18 participants (9 participants in each intervention sequence) received H3B-6545 under fed and fasted conditions in a cross-over manner and aided in evaluation of pharmacokinetic (PK) data.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg Participants received H3B-6545 100 mg capsule, orally, QD in each 28-days treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or study discontinuation. | 6 |
| Phase 1: Dose Escalation: H3B-6545 200 mg Participants received H3B-6545 200 mg capsule, orally, QD in each 28-days treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or study discontinuation. | 12 |
| Phase 1: Dose Escalation: H3B-6545 300 mg Participants received H3B-6545 300 mg capsule, orally, QD in each 28-days treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or study discontinuation. | 11 |
| Phase 1: Dose Escalation: H3B-6545 450 mg Participants received H3B-6545 450 mg capsule, orally, QD in each 28-days treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or study discontinuation. | 11 |
| Phase 1: Dose Escalation: H3B-6545 600 mg Participants received H3B-6545 600 mg capsule, orally, QD in each 28-days treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or study discontinuation. | 7 |
| Phase 2: Dose Expansion: H3B-6545 450 mg Participants received H3B-6545 450 mg capsule, orally, QD in each 28-days treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent or study discontinuation. | 104 |
| Total | 151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 2 | 9 |
| Overall Study | Disease progression | 4 | 12 | 9 | 7 | 4 | 88 |
| Overall Study | Other | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 2 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 | 1 | 2 |
| Overall Study | Withdrawal of consent | 0 | 0 | 2 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 2: Dose Expansion: H3B-6545 450 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 4 Participants | 4 Participants | 3 Participants | 4 Participants | 43 Participants | 61 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 8 Participants | 7 Participants | 8 Participants | 3 Participants | 61 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 10 Participants | 11 Participants | 11 Participants | 7 Participants | 98 Participants | 143 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 12 Participants | 14 Participants |
| Race (NIH/OMB) White | 6 Participants | 9 Participants | 10 Participants | 11 Participants | 7 Participants | 84 Participants | 127 Participants |
| Sex: Female, Male Female | 6 Participants | 12 Participants | 11 Participants | 11 Participants | 7 Participants | 104 Participants | 151 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 10 / 12 | 11 / 11 | 83 / 115 | 7 / 7 |
| other Total, other adverse events | 6 / 6 | 12 / 12 | 11 / 11 | 114 / 115 | 7 / 7 |
| serious Total, serious adverse events | 2 / 6 | 1 / 12 | 2 / 11 | 30 / 115 | 1 / 7 |
Outcome results
Primary
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)
Population: Response-evaluable set included those participants who received at least 1 dose of study drug and had measurable disease at baseline and at least 1 post-baseline evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) | 83.3 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) | 27.3 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) | 20.0 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) | 41.5 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and Phase 2: Clinical Benefit Rate (CBR) | 40.0 percentage of participants |
Primary
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)
Population: Response-evaluable set included those participants who received at least 1 dose of study drug and had measurable disease at baseline and at least 1 post-baseline evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and Phase 2: Disease Control Rate (DCR) | 100.0 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and Phase 2: Disease Control Rate (DCR) | 54.5 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and Phase 2: Disease Control Rate (DCR) | 30.0 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and Phase 2: Disease Control Rate (DCR) | 61.7 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and Phase 2: Disease Control Rate (DCR) | 40.0 percentage of participants |
Primary
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)
Population: Response-evaluable set included those participants who received at least 1 dose of study drug and had measurable disease at baseline and at least 1 post-baseline evaluation. Here, Overall number of participants analyzed signifies participants who had CR or/and PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and Phase 2: Duration of Response (DoR) | 7.95 months |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and Phase 2: Duration of Response (DoR) | 6.05 months |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and Phase 2: Duration of Response (DoR) | 9.23 months |
Primary
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)
Population: Response-evaluable set included those participants who received at least 1 dose of study drug and had measurable disease at baseline and at least 1 post-baseline evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and Phase 2: Objective Response Rate (ORR) | 16.7 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and Phase 2: Objective Response Rate (ORR) | 9.1 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and Phase 2: Objective Response Rate (ORR) | 0 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and Phase 2: Objective Response Rate (ORR) | 20.2 percentage of participants |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and Phase 2: Objective Response Rate (ORR) | 0 percentage of participants |
Primary
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)
Population: Full analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and Phase 2: Overall Survival (OS) | 12.37 months |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and Phase 2: Overall Survival (OS) | 11.25 months |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and Phase 2: Overall Survival (OS) | 13.50 months |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and Phase 2: Overall Survival (OS) | 21.52 months |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and Phase 2: Overall Survival (OS) | 5.32 months |
Primary
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)
Population: Full analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and Phase 2: Progression-free Survival (PFS) | 9.28 months |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and Phase 2: Progression-free Survival (PFS) | 3.38 months |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and Phase 2: Progression-free Survival (PFS) | 1.84 months |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and Phase 2: Progression-free Survival (PFS) | 4.60 months |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and Phase 2: Progression-free Survival (PFS) | 2.76 months |
Primary
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)
Population: Dose evaluable set included all participants who were evaluated for DLTs in dose escalation part.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 2 Participants |
Secondary
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)
Population: Bone turnover markers-evaluable set included participants who had baseline/screening assessments of bone turnover markers and at least 1 additional assessment at 6 and/or 12 weeks after starting trial therapy. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure and n signifies participants who were evaluable for specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 2 Day 15 | -32.750 micrograms per liter (mcg/L) | Standard Deviation 61.6786 |
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 4 Day 1 | -35.500 micrograms per liter (mcg/L) | Standard Deviation 67.9828 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 4 Day 1 | -13.967 micrograms per liter (mcg/L) | Standard Deviation 43.6322 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 2 Day 15 | -14.139 micrograms per liter (mcg/L) | Standard Deviation 40.4722 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Off-Treatment | -3.560 micrograms per liter (mcg/L) | — |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 4 Day 1 | -94.000 micrograms per liter (mcg/L) | — |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 2 Day 15 | 53.568 micrograms per liter (mcg/L) | Standard Deviation 104.0942 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 4 Day 1 | 3.555 micrograms per liter (mcg/L) | Standard Deviation 119.9087 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 2 Day 15 | 26.242 micrograms per liter (mcg/L) | Standard Deviation 154.4307 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Off-Treatment | -22.920 micrograms per liter (mcg/L) | Standard Deviation 71.8744 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 2 Day 15 | 38.750 micrograms per liter (mcg/L) | Standard Deviation 60.3179 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP) | Cycle 4 Day 1 | 10.170 micrograms per liter (mcg/L) | — |
Secondary
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)
Population: Bone turnover markers-evaluable set included participants who had baseline/screening assessments of bone turnover markers and at least 1 additional assessment at 6 and/or 12 weeks after starting trial therapy. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure and n signifies participants who were evaluable for specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase | Cycle 2 Day 15 | -5.543 units per liter (U/L) | Standard Deviation 14.769 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase | Cycle 4 Day 1 | -0.390 units per liter (U/L) | — |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase | Cycle 2 Day 15 | 2.327 units per liter (U/L) | Standard Deviation 4.5368 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase | Cycle 2 Day 15 | 5.912 units per liter (U/L) | Standard Deviation 40.7469 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase | Off-Treatment | -4.469 units per liter (U/L) | Standard Deviation 37.2991 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase | Cycle 4 Day 1 | 0.381 units per liter (U/L) | Standard Deviation 33.6782 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase | Cycle 2 Day 15 | -5.683 units per liter (U/L) | Standard Deviation 5.4399 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase | Cycle 4 Day 1 | -0.900 units per liter (U/L) | — |
Secondary
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)
Population: Bone turnover markers-evaluable set included participants who had baseline/screening assessments of bone turnover markers and at least 1 additional assessment at 6 and/or 12 weeks after starting trial therapy. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure and n signifies participants who were evaluable for specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 2 Day 15 | 0.034 nanograms per millilitre (ng/mL) | Standard Deviation 0.1648 |
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 4 Day 1 | 0.028 nanograms per millilitre (ng/mL) | Standard Deviation 0.2529 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 4 Day 1 | -0.008 nanograms per millilitre (ng/mL) | Standard Deviation 0.1743 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 2 Day 15 | 0.024 nanograms per millilitre (ng/mL) | Standard Deviation 0.1038 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Off-Treatment | -0.184 nanograms per millilitre (ng/mL) | — |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 4 Day 1 | -0.549 nanograms per millilitre (ng/mL) | — |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 2 Day 15 | -0.270 nanograms per millilitre (ng/mL) | Standard Deviation 0.3861 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 4 Day 1 | 0.021 nanograms per millilitre (ng/mL) | Standard Deviation 0.3562 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 2 Day 15 | 0.047 nanograms per millilitre (ng/mL) | Standard Deviation 0.433 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Off-Treatment | -0.148 nanograms per millilitre (ng/mL) | Standard Deviation 0.3735 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 2 Day 15 | -0.036 nanograms per millilitre (ng/mL) | Standard Deviation 0.1976 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX) | Cycle 4 Day 1 | 0.009 nanograms per millilitre (ng/mL) | — |
Secondary
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
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 6 Participants |
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 12 Participants |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 11 Participants |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 30 Participants |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 115 Participants |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 7 Participants |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
Secondary
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)
Population: PK analysis set included all participants who had received at least 1 dose of study drug H3B-6545 and had sufficient PK data to derive at least 1 PK parameter. Here, number analyzed signifies participants who were evaluable for specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 1 | 1680 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 85.4 |
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 15 | 2590 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 57.4 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 1 | 3310 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 66.5 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 15 | 5200 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 70.6 |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 1 | 8520 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 49 |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 15 | 10700 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 50.3 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 15 | 14100 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 53.2 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 1 | 16200 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 43.2 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 1 | 12600 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 512 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545 | Cycle 1 Day 15 | 14900 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 99.5 |
Secondary
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)
Population: PK analysis set included all participants who had received at least 1 dose of study drug H3B-6545 and had sufficient PK data to derive at least 1 PK parameter. Here, number analyzed signifies participants who were evaluable for specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 1 | 178 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 85.3 |
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 15 | 287 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31.3 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 1 | 391 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 55.7 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 15 | 605 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 56 |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 1 | 879 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 62.5 |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 15 | 1200 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 38.2 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 15 | 1410 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 53.5 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 1 | 1500 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 53.1 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 1 | 1490 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 167 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545 | Cycle 1 Day 15 | 1310 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 129 |
Secondary
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)
Population: PK analysis set included all participants who had received at least 1 dose of study drug H3B-6545 and had sufficient PK data to derive at least 1 PK parameter. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | 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 | 1.52 ratio | Geometric Coefficient of Variation 58.3 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | 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 | 1.55 ratio | Geometric Coefficient of Variation 77.8 |
| Phase 1: Dose Escalation: H3B-6545 300 mg | 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 | 1.23 ratio | Geometric Coefficient of Variation 26.1 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | 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 | 0.917 ratio | Geometric Coefficient of Variation 48.5 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | 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 | 0.646 ratio | Geometric Coefficient of Variation 37.5 |
Secondary
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.
Time frame: Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days)
Population: PK analysis set included all participants who had received at least 1 dose of study drug H3B-6545 and had sufficient PK data to derive at least 1 PK parameter. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1: Rac (Cmax): Accumulation Ratio of Cmax for H3B-6545 | 1.61 ratio | Geometric Coefficient of Variation 69.3 |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1: Rac (Cmax): Accumulation Ratio of Cmax for H3B-6545 | 1.52 ratio | Geometric Coefficient of Variation 80.6 |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1: Rac (Cmax): Accumulation Ratio of Cmax for H3B-6545 | 1.37 ratio | Geometric Coefficient of Variation 35.8 |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1: Rac (Cmax): Accumulation Ratio of Cmax for H3B-6545 | 1.05 ratio | Geometric Coefficient of Variation 42.1 |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1: Rac (Cmax): Accumulation Ratio of Cmax for H3B-6545 | 0.598 ratio | Geometric Coefficient of Variation 98 |
Secondary
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)
Population: PK analysis set included all participants who had received at least 1 dose of study drug H3B-6545 and had sufficient PK data to derive at least 1 PK parameter. Here, number analyzed signifies participants who were evaluable for specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 1 | 3.05 hours |
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 15 | 2.00 hours |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 1 | 3.00 hours |
| Phase 1: Dose Escalation: H3B-6545 200 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 15 | 2.17 hours |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 1 | 3.97 hours |
| Phase 1: Dose Escalation: H3B-6545 300 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 15 | 4.00 hours |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 15 | 4.00 hours |
| Phase 1: Dose Escalation: H3B-6545 450 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 1 | 4.00 hours |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 1 | 4.00 hours |
| Phase 1: Dose Escalation: H3B-6545 600 mg | Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545 | Cycle 1 Day 15 | 5.00 hours |
Secondary
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
Population: Endometrium safety evaluable set included all participants with intact uteri at baseline, who received at least 1 dose of study drug and had ultrasound assessments at screening/baseline and three months after starting trial therapy. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure and Number analyzed signifies participants who were evaluable for specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 2: Mean Change From Baseline in Endometrial Thickness Due to H3B-6545 | At Week 12 | 4.079 millimeter | Standard Deviation 4.9659 |
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 2: Mean Change From Baseline in Endometrial Thickness Due to H3B-6545 | At Week 36 | 5.400 millimeter | Standard Deviation 6.9931 |
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 2: Mean Change From Baseline in Endometrial Thickness Due to H3B-6545 | At Week 60 | -0.050 millimeter | Standard Deviation 0.0707 |
Secondary
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
Population: Endometrium safety evaluable set included all participants with intact uteri at baseline, who received at least 1 dose of study drug and had ultrasound assessments at screening/baseline and three months after starting trial therapy. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure and Number analyzed signifies participants who were evaluable for specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 2: Mean Change From Baseline in Uterine Volume Due to H3B-6545 | At Week 12 | 66.822 milliliter | Standard Deviation 63.7151 |
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 2: Mean Change From Baseline in Uterine Volume Due to H3B-6545 | At Week 36 | 41.083 milliliter | Standard Deviation 60.632 |
Secondary
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)
Population: Food-effect analysis set included all participants who were assigned to the food-effect cohort and had sufficient PK data to derive at least 1 PK parameter. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using AUC(0-24h) | 1.53 ratio |
Secondary
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)
Population: Food-effect analysis set included all participants who were assigned to the food-effect cohort and had sufficient PK data to derive at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Phase 1: Dose Escalation: H3B-6545 100 mg | Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using Cmax | 1.51 ratio |