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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03250676
Recruitment Status : Active, not recruiting
First Posted : August 16, 2017
Last Update Posted : January 18, 2020
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Eisai Inc. ( H3 Biomedicine Inc. )

Tracking Information
First Submitted Date  ICMJE August 11, 2017
First Posted Date  ICMJE August 16, 2017
Last Update Posted Date January 18, 2020
Actual Study Start Date  ICMJE August 17, 2017
Estimated Primary Completion Date July 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 26, 2018)
  • 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 ]
  • 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 ]
  • 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  ICMJE
 (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  ICMJE Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer
Official Title  ICMJE A Phase I-II 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 purpose of phase 1 is to determine safety, tolerability and pharmacokinetics (PK) of H3B-6545 in women with locally advanced or metastatic estrogen receptor-positive, human epidermal growth factor 2 (HER2)-negative breast cancer.

The purpose of phase 2 is to estimate the efficacy of H3B-6545 in terms of response rate, duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Neoplasms
  • Breast Cancer
  • Estrogen-receptor Positive Breast Cancer
  • Cancer, Breast
  • Breast Cancer Female
  • Breast Adenocarcinoma
  • Estrogen Receptor Positive Tumor
  • ER Positive
Intervention  ICMJE Drug: H3B-6545
Oral capsules by mouth once daily
Study Arms  ICMJE
  • Experimental: H3B-6545 Arm 1: Dose escalation
    Intervention: Drug: H3B-6545
  • Experimental: H3B-6545 Arm 2: Phase 2
    Intervention: Drug: H3B-6545
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 15, 2020)
127
Original Estimated Enrollment  ICMJE
 (submitted: August 11, 2017)
110
Estimated Study Completion Date  ICMJE January 31, 2022
Estimated Primary Completion Date July 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
  4. Must be willing to undergo a biopsy prior to treatment and on Cycle 2 Day 1.
  5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
  6. Adequate bone marrow and organ function.

Exclusion Criteria:

  1. Participant with bone-only disease (Phase I only). Note: Phase II subjects may have predominantly lytic bone only disease.
  2. Participant with inflammatory breast cancer.
  3. Participant has received more than one prior chemotherapy regimen for metastatic disease (Phase II only).
  4. Females of childbearing potential who are unable or unwilling to follow adequate contraceptive measures.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03250676
Other Study ID Numbers  ICMJE H3B-6545-A001-101
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  ICMJE Not Provided
Responsible Party Eisai Inc. ( H3 Biomedicine Inc. )
Study Sponsor  ICMJE H3 Biomedicine Inc.
Collaborators  ICMJE Eisai Inc.
Investigators  ICMJE Not Provided
PRS Account Eisai Inc.
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP