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

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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

Accumulation ratio of Cmax was calculated as Cmax at Cycle 1 Day 15/Cmax at Cycle 1 Day 1.

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

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.

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.

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.

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.

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.

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.

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.