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

• ClinicalTrials.gov Identifier: NCT03250676
• Recruitment Status: Completed
• First Posted: August 16, 2017
• Last Update Posted: December 26, 2023
• Sponsor: Eisai Inc.
• Information provided by (Responsible Party): Eisai Inc.

Tracking Information

• First Submitted Date: August 11, 2017
• First Posted Date: August 16, 2017
• Last Update Posted Date: December 26, 2023
• Actual Study Start Date: August 17, 2017
• Actual Primary Completion Date: October 26, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 26, 2018)

• Number of Participants with Dose-limiting Toxicities (DLTs) [ Time Frame: Phase 1 Cycle 1 (28 days) ]
• Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Phase 1 and 2 continuously throughout the study until 28 days after treatment discontinuation (up to 36 months) ]

Original Primary Outcome Measures (submitted: August 11, 2017)

• Phase 1: Number of participants with dose-limiting toxicities (DLTs), as a function of the dose of H3B-6545 for determination of the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) [ Time Frame: Up to 28 days (Cycle 1) ]
  The MTD is the highest dose of a drug or product that doesn't cause unacceptable side effects. The Investigator will review all participants' safety and clinical data to jointly determine the MTD/RP2D of H3B-6545. During dose escalation if 2 out of 6 participants experience DLTs (side effects that prevent a dose increase) at a given dose level during Cycle 1 of the therapy, then the MTD has been exceeded and dose escalation will be stopped. The RP2D is determined based on the MTD.
• Phase 2: Objective Response Rate (ORR) [ Time Frame: Up to 3 years ]
  ORR is the proportion of participants achieving a best overall response (BOR) of confirmed partial response (PR) or complete response (CR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. It is determined by investigator review. The BOR is the best response recorded from the start of the treatment until disease progression/recurrence. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is defined as the disappearance of all target lesions.

Current Secondary Outcome Measures (submitted: September 7, 2020)

• Area under the Plasma Concentration-time Curve from Time 0 Through the Last Measurable Point (AUC0-t) of H3B-6545 [ Time Frame: Phase 1, Cycle 1 (28-day cycles): Days 1 and 15 pre-dose and at multiple time points (up to 24 hours) post-dose; or Phase 2 Cycle 1 (28-day cycles): Days 15 or 22 pre-dose and at multiple time points (up to 24 hours) post-dose ]
• Mean Maximum Observed Plasma Concentration (Cmax) of H3B-6545 [ Time Frame: Phase 1, Cycle 1 (28-day cycles): Days 1 and 15 (pre-dose and at multiple time points (up to 24 hours) post-dose; or Phase 2 Cycle 1 (28-day cycles): Days 15 or 22 pre-dose and at multiple time points (up to 24 hours) post-dose ]
• Time of Maximum Observed Plasma Concentration (tmax) of H3B-6545 [ Time Frame: Phase 1, Cycle 1 (28-day cycles): Days 1 and 15 pre-dose and at multiple time points (up to 24 hours) post-dose; or Phase 2 Cycle 1 (28-day cycles): Days 15 or 22 pre-dose and at multiple time points (up to 24 hours) post-dose ]
• Objective Response Rate (ORR) [ Time Frame: Phase 1 and 2 up to approximately 36 months ]
• Duration of Response (DoR) [ Time Frame: Phase 1 and 2 up to approximately 36 months ]
• Disease Control Rate (DCR) [ Time Frame: Phase 1 and 2 up to approximately 36 months ]
• Clinical Benefit Rate (CBR) [ Time Frame: Phase 1 and 2 up to approximately 36 months ]
• Progression-free survival (PFS) [ Time Frame: Phase 1 and 2 up to approximately 36 months ]
• Overall Survival (OS) [ Time Frame: Phase 1 and 2 up to approximately 36 months ]

Original Secondary Outcome Measures (submitted: August 11, 2017)

• Phase 1 and Phase 2: Number of participants with any treatment-emergent (TE) serious adverse event (SAE) [ Time Frame: Up to 3 years ]
  An SAE is any untoward medical occurrence that at any dose: results in death; is life threatening (i.e, the participant was at immediate risk of death from the adverse event [AE] as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment (baseline) or (1) reemerges during treatment, having been present at pretreatment (baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
• Phase 1 and Phase 2: Number of participants with any non-serious TEAE [ Time Frame: Up to 3 years ]
  An AE is any untoward medical occurrence in a participant or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with the medicinal product. A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment (baseline) or (1) reemerges during treatment, having been present at pretreatment (baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
• Phase 1 and Phase 2: Number of participants with an abnormal, clinically significant clinical laboratory value [ Time Frame: Up to 3 years ]
  Laboratory results will be summarized using Systeme International (SI) units, as appropriate. Clinical significance will be determined by the Investigator.
• Phase 1 and Phase 2: Number of participants with an abnormal, clinically significant vital sign value [ Time Frame: Up to 3 years ]
  Clinical significance will be determined by the Investigator.
• Phase 1 and Phase 2: Number of participants with an abnormal, clinically significant 12-lead electrocardiogram (ECG) finding [ Time Frame: Up to 3 years ]
  ECG assessments will be performed throughout the study, and abnormalities will be listed on a per-participant basis. Clinical significance will be determined by the Investigator.
• Phase 1: Mean area under the plasma concentration-time curve from time point 0 through the last measurable point (AUC0-t) [ Time Frame: Cycle 1: Days 1 and 15 (pre-dose; 0.5 hours [hr], 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose), and at pre-dose on Days 8 and 22 ]
  Area under the curve (AUC) represents the total drug exposure over a defined period of time after administration.
• Phase 1: Mean maximum observed plasma concentration (Cmax) [ Time Frame: Cycle 1: Days 1 and 15 (pre-dose; 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose), and at pre-dose on Days 8 and 22 ]
  Cmax is defined as the maximum observed concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered.
• Phase 1: Mean time of maximum observed plasma concentration (tmax) [ Time Frame: Cycle 1: Days 1 and 15 (pre-dose; 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose), and at pre-dose on Days 8 and 22 ]
  Tmax is defined as the time from dosing to reach the maximum observed concentration that a drug achieves in a specified compartment or test area of the body.
• Phase 1: Mean accumulation ratio (Racc) [ Time Frame: Cycle 1: Days 1 and 15 (pre-dose; 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose), and at pre-dose on Days 8 and 22 ]
  Racc is the rate and extent of accumulation of drug in the plasma.
• Phase 1: ORR [ Time Frame: Up to 3 years ]
  ORR is the proportion of participants achieving a BOR of confirmed PR or CR per RECIST 1.1. It is determined by investigator review. The BOR is the best response recorded from the start of the treatment until disease progression/recurrence. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is defined as the disappearance of all target lesions.
• Phase 1 and Phase 2: Duration of response (DoR) [ Time Frame: Up to 3 years ]
  DoR is the time from the date of first documented CR/PR until the first documentation of confirmed disease progression as determined by the investigator or death, whichever comes first. As per RECIST 1.1, PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and CR is defined as the disappearance of all target lesions. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions; taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
• Phase 1 and Phase 2: Disease control rate (DCR) [ Time Frame: Up to 3 years ]
  DCR is the proportion of participants achieving a best response of CR, PR, or stable disease (SD). As per RECIST 1.1, PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is defined as the disappearance of all target lesions, and SD is defined as the persistence of one or more non-target lesions and/or the persistence of tumor marker level above the normal limits.
• Phase 1 and Phase 2: Progression-free survival (PFS) [ Time Frame: Up to 3 years ]
  PFS is the time from the first dose date to the date of the first documentation of confirmed disease progression as determined by the investigator or death (whichever occurs first). Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions; taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
• Phase 1 and Phase 2: Overall survival (OS) [ Time Frame: Up to 3 years ]
  OS is the time from the first dose date to the date of death (event) or the date on which the participant was last known to be alive (censored).
• Phase 2: Relative bioavailability of H3B-6545 due to moderate-fat meal [ Time Frame: Up to 3 years ]
  Bioavailability of a drug is the proportion of the drug which enters the circulation when introduced into the body and thus is able to have an active effect.
• Phase 2: Change from Baseline in mean endometrial thickness [ Time Frame: Baseline, Week 12, and after every 24 weeks up to 3 years ]
  Participants with an intact uterus will undergo an assessment of endometrial thickness using transvaginal ultrasound.
• Phase 2: Change from Baseline in mean uterine volume [ Time Frame: Baseline, Week 12, and after every 24 weeks up to 3 years ]
  Participants with an intact uterus will undergo an assessment of uterine volume using transvaginal ultrasound.
• Phase 2: Mean concentration of bone-specific alkaline phosphatase (BSAP) in serum [ Time Frame: Screening, Cycle 1 Day 1, Cycle 2 Day 15, and Cycle 4 Day 1 ]
  Serum BSAP is a glycoprotein localized in the plasma membrane of osteoblasts. It is an indicator of the metabolic status of osteoblasts in human serum.
• Phase 2: Mean concentration of amino-terminal propeptide of type 1 collagen (PINP) in serum [ Time Frame: Screening, Cycle 1 Day 1, Cycle 2 Day 15, and Cycle 4 Day 1 ]
  PINP is a clinical indicator of bone turnover and the extent of metastatic spread in osseous metastatic breast cancer. Its assessment will monitor bone formation in participants.
• Phase 2: Mean concentration of C-terminal cross-linking telopeptide of type 1 collagen (CTX) in serum [ Time Frame: Screening, Cycle 1 Day 1, Cycle 2 Day 15, and Cycle 4 Day 1 ]
  CTX is a biomarker of bone resorption.
• Phase 2: Mean AUC0-t under fasting condition [ Time Frame: Cycle 1 Day 15 ]
  AUC represents the total drug exposure over a defined period of time after administration.
• Phase 2: Mean AUC0-t under fed condition [ Time Frame: Cycle 1: Days 15 and 22 (pre-dose; 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose) ]
  AUC represents the total drug exposure over a defined period of time after administration.
• Phase 2: Mean Cmax under fasting condition [ Time Frame: Cycle 1 Day 15 ]
  Cmax is defined as the maximum observed concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered.
• Phase 2: Mean Cmax under fed condition [ Time Frame: Cycle 1: Days 15 and 22 (pre-dose; 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose) ]
  Cmax is defined as the maximum observed concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered.
• Phase 2: Mean Tmax under fasting condition [ Time Frame: Cycle 1 Day 15 ]
  Tmax is defined as the time from dosing to reach the maximum observed concentration a drug achieves in a specified compartment or test area of the body.
• Phase 2: Mean Tmax under fed condition [ Time Frame: Cycle 1: Days 15 and 22 (pre-dose; 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose) ]
  Tmax is defined as the time from dosing to reach the maximum observed concentration a drug achieves in a specified compartment or test area of the body.
• Phase 2: Mean Racc under fasting condition [ Time Frame: Cycle 1 Day 15 ]
  Racc is the rate and extent of accumulation of drug in the plasma.
• Phase 2: Mean Racc under fed condition [ Time Frame: Cycle 1: Days 15 and 22 (pre-dose; 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, and 24 hr post-dose) ]
  Racc is the rate and extent of accumulation of drug in the plasma.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer
• Official Title: A Phase 1-2 Multicenter, Open Label Trial of H3B-6545, a Covalent Antagonist of Estrogen Receptor Alpha, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer

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).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Breast Neoplasms
• Breast Cancer
• Estrogen-receptor Positive Breast Cancer
• Cancer, Breast
• Breast Cancer Female
• Breast Adenocarcinoma
• Estrogen Receptor Positive Tumor
• ER Positive

Intervention

Drug: H3B-6545

Oral capsules by mouth once daily

Study Arms

• Experimental: H3B-6545 Arm 1: Dose escalation
  Intervention: Drug: H3B-6545
• Experimental: H3B-6545 Arm 2: Phase 2
  Intervention: Drug: H3B-6545

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 22, 2023): 206
• Original Estimated Enrollment (submitted: August 11, 2017): 110
• Actual Study Completion Date: October 26, 2023
• Actual Primary Completion Date: October 26, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, United Kingdom, United States

Administrative Information

• NCT Number: NCT03250676
• Other Study ID Numbers: H3B-6545-A001-101; 2018-000570-29 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Eisai Inc.
• Original Responsible Party: H3 Biomedicine Inc.
• Current Study Sponsor: Eisai Inc.
• Original Study Sponsor: H3 Biomedicine Inc.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Eisai Inc.
• Verification Date: March 2023