A Study of H3B-6545 in Combination With Palbociclib in Women With Advanced or Metastatic Estrogen Receptor-Positive Human Epidermal Growth Factor Receptor-2 (HER2)-Negative Breast Cancer

An Open-Label Multicenter Phase 1b Study of H3B-6545 in Combination With Palbociclib in Women With Advanced or Metastatic Estrogen Receptor-Positive HER2-Negative Breast Cancer

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Neoplasms; Receptors, Estrogen; Genes, Erbb-2
• Intervention / Treatment: Drug: Palbociclib (75, 100, 125 milligram [mg]); Drug: H3B-6545 (150, 300, 450 mg)

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Royal Marsden NHS Foundation Trust
  • London, United Kingdom
    • Sarah Cannon Research Institute UK - SCRI
  • Sutton, United Kingdom
    • Royal Marsden NHS Foundation Trust
• United States
  • Florida
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists South - SCRI - PPDS
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Cancer Institute
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC - SCRI - PPDS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Palbociclib + H3B-6545 (Dose Escalation and Dose Expansion); Participants will receive Palbociclib 75, 100, 125 milligram (mg) capsules or tablets, orally, once daily from Days 1 to 21 followed by 7 days off treatment in 28-day cycles along with H3B-6545 150, 300, 450 mg capsules or tablets, orally, once daily from Days 1 to 28 in 28-day cycles in dose escalation part. Based on MTD or RP2D determined for H3B-6545 in combination with palbociclib in dose escalation part, participants will continue to receive study treatment in dose expansion part until PD, development of unacceptable toxicity, or withdrawal of consent (up to 24 months).

Drug: Palbociclib (75, 100, 125 milligram [mg]); Palbociclib orally, once daily (QD).; Drug: H3B-6545 (150, 300, 450 mg); H3B-6545 orally, QD.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Cycle 1 (Cycle length = 28 Days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From first dose up to 28 days after the last dose of study drug (up to Month 48)
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.	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)
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.	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)
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.	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)
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.	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)
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.	Dose Escalation Part: Cycle 1 Days 8 and 21: 0-24 hours postdose
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.	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 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.	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 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.	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 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.	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 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.	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)
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.	From first dose of study drug up to Month 48
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.	From the date of first documented CR/PR until the PD or death, whichever occurs first (up to Month 48)
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.	From the first dose of study drug until disease progression or death, whichever occurs first (up to Month 48)
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.	From first dose of study drug until first documentation of PD or death, whichever occurs first (up to Month 48)
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.	From the date of first dose to the date of death from any cause (up to Month 48)

Collaborators and Investigators

• Sponsor: Eisai Inc.

Publications and helpful links

General Publications

• Furman C, Puyang X, Zhang Z, Wu ZJ, Banka D, Aithal KB, Albacker LA, Hao MH, Irwin S, Kim A, Montesion M, Moriarty AD, Murugesan K, Nguyen TV, Rimkunas V, Sahmoud T, Wick MJ, Yao S, Zhang X, Zeng H, Vaillancourt FH, Bolduc DM, Larsen N, Zheng GZ, Prajapati S, Zhu P, Korpal M. Covalent ERalpha Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer. Mol Cancer Ther. 2022 Jun 1;21(6):890-902. doi: 10.1158/1535-7163.MCT-21-0378.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2020
• Primary Completion (Actual): September 16, 2022
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: February 26, 2020
• First Submitted That Met QC Criteria: February 26, 2020
• First Posted (Actual): February 27, 2020

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 16, 2026
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Palbociclib; HER2-Negative Breast Cancer; H3B-6545; Metastatic Estrogen Receptor-Positive
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; palbociclib; H3B-6545
• Other Study ID Numbers: H3B-6545-G000-102; 2019-004622-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No