Breast Neoplasms, Genes, Erbb-2, Receptors, Estrogen
Conditions
Keywords
H3B-6545, Palbociclib, Metastatic Estrogen Receptor-Positive, HER2-Negative Breast Cancer
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of H3B-6545 and palbociclib when administered in combination in order to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of this combination in women with advanced or metastatic estrogen receptor-positive (ER+) HER2- breast cancer.
Interventions
DRUGPalbociclib (75, 100, 125 milligram [mg])
Palbociclib orally, once daily (QD).
DRUGH3B-6545 (150, 300, 450 mg)
H3B-6545 orally, QD.
Sponsors
Eisai Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. ER+ HER2- locally advanced, recurrent, or metastatic breast cancer, as per local laboratory 2. Prior therapy in the advanced/metastatic setting 3. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 4. Has adequate bone marrow and organ function
Exclusion criteria
1. Uncontrolled significant active infections 2. Major surgery or other locoregional treatment within 4 weeks before the 1st dose of study drug 3. Inability to take oral medication or presence of malabsorption 4. Active cardiac disease or a history of cardiac dysfunction 5. Evidence of ongoing Alcohol or Drug Abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of H3B-6545 and Palbociclib | Cycle 1 (Cycle length = 28 Days) | The MTD was defined as the highest dose at which no more than 1 of 6 participants experienced a Dose-Limiting Toxicity (DLT) in the dose cohort. DLT was graded as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From first dose up to 28 days after the last dose of study drug (up to Month 48) | TEAE was defined as an adverse event (AE) with an onset that had occurred after receiving study drug. An AE was defined as any untoward medical occurrence in a participants or clinical investigation 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. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| AUC(0-t): Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Point for Palbociclib and H3B-6545 | Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Cmax: Maximum Observed Plasma Concentration for Palbociclib and H3B-6545 | Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Tmax: Time to Reach the Cmax for Palbociclib and H3B-6545 | Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| C24: Plasma Concentration at 24 Hour Post-dose for Palbociclib and H3B-6545 | Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Ratio of Pharmacokinetic (PK) Cmax Parameter Estimates Between Day 21 (Palbociclib) and Day 8 (Palbociclib) | Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose | Ratio of palbociclib Cmax Day 21/Day 8, is the ratio of palbociclib exposure on Day 21 and palbociclib exposure on Day 8. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Ratio of PK AUC24 Parameter Estimates Between Day 21 (Palbociclib) and Day 8 (Palbociclib) | Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | Ratio of palbociclib AUC24 Day 21/Day 8, is the ratio of palbociclib exposure on Day 21 and palbociclib exposure on Day 8. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Ratio of PK C24 Parameter Estimates Between Day 21 (Palbociclib) and Day 8 (Palbociclib) | Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | Ratio of palbociclib C24 Day 21/Day 8, is the ratio of palbociclib exposure on Day 21 and palbociclib exposure on Day 8. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Ratio of PK Cmax Parameter Estimates Between Day 21 (H3B-6545) and Day 28 (H3B-6545) | Dose Escalation Part: Cycle 1 Days 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | Ratio of palbociclib Cmax Day 21/Day 28, is the ratio of H3B-6545 exposure on Day 21 and H3B-6545 exposure on Day 28. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Ratio of PK AUC24 Parameter Estimates Between Day 21 (H3B-6545) and Day 28 (H3B-6545) | Dose Escalation Part: Cycle 1 Days 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | Ratio of H3B-6545 AUC24 Day 21/Day 28, is the ratio of H3B-6545 exposure on Day 21 and H3B-6545 exposure on Day 28. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Ratio of PK C24 Parameter Estimates Between Day 21 (H3B-6545) and Day 28 (H3B-6545) | Dose Escalation Part: Cycle 1 Days 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days) | Ratio of H3B-6545 C24 Day 21/Day 28, is the ratio of H3B-6545 exposure on Day 21 and H3B-6545 exposure on Day 28. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Objective Response Rate (ORR) | From first dose of study drug up to Month 48 | ORR is defined as the percentage of participants achieving a best overall response (BOR) of confirmed partial response (PR) or complete response (CR). The ORR will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Duration of Response (DoR) | From the date of first documented CR/PR until the PD or death, whichever occurs first (up to Month 48) | DoR is defined as the time from the date of the first documented CR/PR until the first documentation of disease progression (PD) or death, whichever comes first. The DoR will be assessed according to RECIST version 1.1. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Clinical Benefit Rate (CBR) | From the first dose of study drug until disease progression or death, whichever occurs first (up to Month 48) | CBR is defined as the percentage of participants with BOR of PR, CR, or durable stable disease (SD) (duration of SD greater than or equal to 23 weeks). Duration of SD is defined as the time from the date of first dose to the date of the first documentation of disease progression or death, whichever occurs first. It will be calculated for participants whose BOR is SD. The CBR will be assessed according to RECIST version 1.1. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Progression-free Survival (PFS) | From first dose of study drug until first documentation of PD or death, whichever occurs first (up to Month 48) | PFS is defined as the time from the first dose date to the date of the first documentation of PD or death (whichever occurs first). Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
| Overall Survival (OS) | From the date of first dose to the date of death from any cause (up to Month 48) | OS is defined as the time from first dose date to the date of death from any cause. Analysis is not final for this outcome measure, and complete data will be posted at study completion date. |
Countries
United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 8 investigative sites in the United States and the United Kingdom from 1 April 2020 to 16 September 2022.
Pre-assignment details
This study was planned to be conducted in two parts: Dose Escalation and Dose Expansion. In the Dose Escalation part, a total of 31 participants were enrolled and received the study treatment. However, no participants were enrolled in the Dose Expansion part. In this result summary, data has been reported for dose escalation part only and up to primary completion date (16 September 2022). This study is ongoing and will be updated with final results after study completion.
Participants by arm
| Arm | Count |
|---|---|
| H3B-6545 300 mg + Palbociclib 100 mg Participants received palbociclib 100 milligram (mg) capsule, orally, once daily (QD) from Days 1 to 21 followed by H3B-6545 300 mg capsule, orally, QD from Days 9 to 28 in Cycle1. In all 28 days subsequent cycles, palbociclib was administered on Days 1 to 21, and H3B-6545 was administered on Days 1 to 28 until disease progression, development of unacceptable toxicity, or withdrawal of consent. | 7 |
| H3B-6545 300 mg + Palbociclib 125 mg Participants received palbociclib 125 mg capsule, orally, QD from Days 1 to 21 followed by H3B-6545 300 mg capsule, orally, QD from Days 9 to 28 in Cycle1. In all 28 days subsequent cycles, palbociclib was administered on Days 1 to 21, and H3B-6545 was administered on Days 1 to 28 until disease progression, development of unacceptable toxicity, or withdrawal of consent. | 8 |
| H3B-6545 450 mg + Palbociclib 125 mg Participants received palbociclib 125 mg capsule, orally, QD from Days 1 to 21 followed by H3B-6545 450 mg capsule, orally, QD from Days 9 to 28 in Cycle1. In all 28 days subsequent cycles, palbociclib was administered on Days 1 to 21, and H3B-6545 was administered on Days 1 to 28 until disease progression, development of unacceptable toxicity, or withdrawal of consent. | 8 |
| H3B-6545 450 mg + Palbociclib 100 Participants received palbociclib 100 mg capsule, orally, QD from Days 1 to 21 followed by H3B-6545 450 mg capsule, orally, QD from Days 9 to 28 in Cycle1. In all 28 days subsequent cycles, palbociclib was administered on Days 1 to 21, and H3B-6545 was administered on Days 1 to 28 until disease progression, development of unacceptable toxicity, or withdrawal of consent. | 8 |
| Total | 31 |
Baseline characteristics
| Characteristic | H3B-6545 300 mg + Palbociclib 100 mg | H3B-6545 300 mg + Palbociclib 125 mg | H3B-6545 450 mg + Palbociclib 125 mg | H3B-6545 450 mg + Palbociclib 100 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.4 Years STANDARD_DEVIATION 7.76 | 51.9 Years STANDARD_DEVIATION 15.61 | 56.0 Years STANDARD_DEVIATION 4.96 | 59.1 Years STANDARD_DEVIATION 14.53 | 57.2 Years STANDARD_DEVIATION 11.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 8 Participants | 8 Participants | 6 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 6 Participants | 8 Participants | 8 Participants | 5 Participants | 27 Participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 8 Participants | 8 Participants | 31 Participants |
| Sex: Female, Male Male | 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 |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 7 | 3 / 8 | 4 / 8 | 0 / 8 |
| other Total, other adverse events | 7 / 7 | 7 / 8 | 8 / 8 | 8 / 8 |
| serious Total, serious adverse events | 2 / 7 | 2 / 8 | 3 / 8 | 3 / 8 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of H3B-6545 and Palbociclib
The MTD was defined as the highest dose at which no more than 1 of 6 participants experienced a Dose-Limiting Toxicity (DLT) in the dose cohort. DLT was graded as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 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: The Dose Evaluable Set (DES) included all participants who were evaluated for DLTs in dose escalation part.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants | Maximum Tolerated Dose (MTD) of H3B-6545 and Palbociclib | Palbociclib | 125 milligram |
| All Participants | Maximum Tolerated Dose (MTD) of H3B-6545 and Palbociclib | H3B-6545 | 300 milligram |
Secondary
AUC(0-t): Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Point for Palbociclib and H3B-6545
Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days)
Secondary
C24: Plasma Concentration at 24 Hour Post-dose for Palbociclib and H3B-6545
Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days)
Secondary
Clinical Benefit Rate (CBR)
CBR is defined as the percentage of participants with BOR of PR, CR, or durable stable disease (SD) (duration of SD greater than or equal to 23 weeks). Duration of SD is defined as the time from the date of first dose to the date of the first documentation of disease progression or death, whichever occurs first. It will be calculated for participants whose BOR is SD. The CBR will be assessed according to RECIST version 1.1. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: From the first dose of study drug until disease progression or death, whichever occurs first (up to Month 48)
Secondary
Cmax: Maximum Observed Plasma Concentration for Palbociclib and H3B-6545
Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days)
Secondary
Duration of Response (DoR)
DoR is defined as the time from the date of the first documented CR/PR until the first documentation of disease progression (PD) or death, whichever comes first. The DoR will be assessed according to RECIST version 1.1. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: From the date of first documented CR/PR until the PD or death, whichever occurs first (up to Month 48)
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
TEAE was defined as an adverse event (AE) with an onset that had occurred after receiving study drug. An AE was defined as any untoward medical occurrence in a participants or clinical investigation 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. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: From first dose up to 28 days after the last dose of study drug (up to Month 48)
Secondary
Objective Response Rate (ORR)
ORR is defined as the percentage of participants achieving a best overall response (BOR) of confirmed partial response (PR) or complete response (CR). The ORR will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: From first dose of study drug up to Month 48
Secondary
Overall Survival (OS)
OS is defined as the time from first dose date to the date of death from any cause. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: From the date of first dose to the date of death from any cause (up to Month 48)
Secondary
Progression-free Survival (PFS)
PFS is defined as the time from the first dose date to the date of the first documentation of PD or death (whichever occurs first). Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: From first dose of study drug until first documentation of PD or death, whichever occurs first (up to Month 48)
Secondary
Ratio of Pharmacokinetic (PK) Cmax Parameter Estimates Between Day 21 (Palbociclib) and Day 8 (Palbociclib)
Ratio of palbociclib Cmax Day 21/Day 8, is the ratio of palbociclib exposure on Day 21 and palbociclib exposure on Day 8. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose
Secondary
Ratio of PK AUC24 Parameter Estimates Between Day 21 (H3B-6545) and Day 28 (H3B-6545)
Ratio of H3B-6545 AUC24 Day 21/Day 28, is the ratio of H3B-6545 exposure on Day 21 and H3B-6545 exposure on Day 28. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days)
Secondary
Ratio of PK AUC24 Parameter Estimates Between Day 21 (Palbociclib) and Day 8 (Palbociclib)
Ratio of palbociclib AUC24 Day 21/Day 8, is the ratio of palbociclib exposure on Day 21 and palbociclib exposure on Day 8. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days)
Secondary
Ratio of PK C24 Parameter Estimates Between Day 21 (H3B-6545) and Day 28 (H3B-6545)
Ratio of H3B-6545 C24 Day 21/Day 28, is the ratio of H3B-6545 exposure on Day 21 and H3B-6545 exposure on Day 28. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days)
Secondary
Ratio of PK C24 Parameter Estimates Between Day 21 (Palbociclib) and Day 8 (Palbociclib)
Ratio of palbociclib C24 Day 21/Day 8, is the ratio of palbociclib exposure on Day 21 and palbociclib exposure on Day 8. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days)
Secondary
Ratio of PK Cmax Parameter Estimates Between Day 21 (H3B-6545) and Day 28 (H3B-6545)
Ratio of palbociclib Cmax Day 21/Day 28, is the ratio of H3B-6545 exposure on Day 21 and H3B-6545 exposure on Day 28. Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days)
Secondary
Tmax: Time to Reach the Cmax for Palbociclib and H3B-6545
Analysis is not final for this outcome measure, and complete data will be posted at study completion date.
Time frame: Dose Escalation Part: Cycle 1 Days 8, 21 and 28: 0-24 hours postdose; Dose Expansion Part: Cycle 1 Day 21: 0-24 hours postdose (Each Cycle length=28 days)