Clinical Trials /

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

NCT03250676

Description:

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).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: H3B-6545-A001-101
  • SECONDARY ID: BRE 287
  • NCT ID: NCT03250676

Conditions

  • Breast Neoplasms

Interventions

DrugSynonymsArms
H3B-6545Arm 1: ERα^WT

Purpose

Phase 1 of the study will be conducted to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of H3B-6545 in women with locally advanced or metastatic estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Phase 2 of the study will be conducted 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) in all participants and in participants with and without the estrogen receptor alpha (ERα) mutation.

Trial Arms

NameTypeDescriptionInterventions
Arm 1: ERα^WTExperimentalH3B-6545 capsules will be administered orally (PO) to all estrogen receptor alpha (ERα) wild type participants at their assigned dose, once daily (QD) in an open-label fashion. The starting dose of H3B-6545 will be 100 milligrams (mg) QD PO. Participants will be instructed to take the dose on an empty stomach (no food 2 hours before or 2 hours after dose) (with the exception of participants taking the fed dose of the food-effect cohort) at approximately the same time each morning.
  • H3B-6545
Arm 2: ERα^mutExperimentalH3B-6545 capsules will be administered orally (PO) to all ERα mutant participants at their assigned dose, once daily (QD) in an open-label fashion. The starting dose of H3B-6545 will be 100 milligrams (mg) QD PO. Participants will be instructed to take the dose on an empty stomach (no food 2 hours before or 2 hours after dose) (with the exception of participants taking the fed dose of the food-effect cohort) at approximately the same time each morning.
  • H3B-6545

Eligibility Criteria

        Inclusion Criteria:

          -  Participant has signed informed consent form (ICF) before any trial related activities
             and according to local guidelines.

          -  Only females are eligible. Menopausal status:

             i. Postmenopausal defined by:

               1. Prior bilateral oophorectomy;

               2. Age ≥60 years; or

               3. Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy,
                  tamoxifen, toremifen, or ovarian suppression) and follicle-stimulating hormone
                  (FSH) value >40 milli-international units per milliliter (mIU/mL) and an
                  estradiol value <40 picograms per milliliter (pg/mL) (140 picomoles per liter
                  [pmol/L]).

                  Or ii. Premenopausal or perimenopausal concurrently given a luteinizing
                  hormone-releasing hormone (LHRH) agonist starting at least 4 weeks before the
                  start of trial therapy and is planned to continue LHRH during the study.

          -  Participant has a histologically and/or cytologically confirmed diagnosis of
             estrogen-receptor (ER) positive breast cancer by local laboratory.

          -  Participant has human epidermal growth factor receptor 2 (HER2) negative breast cancer
             as defined by American Society of Clinical Oncology (ASCO)-College of American
             Pathologists guidelines.

          -  Participant must have progressed on the most recent therapy.

          -  Prior therapy for breast cancer in the advanced/metastatic setting must have included
             at least:

               1. two prior hormonal therapies;

               2. one prior hormonal therapy and one prior chemotherapy regimen; or

               3. one prior hormonal therapy and a Cyclin-dependent kinase (CDK)4/6 inhibitor.
                  Note: Participants may have received treatment for brain metastases, but must be
                  neurologically stable, completed radiotherapy and off corticosteroids for at
                  least one month prior to starting trial therapy.

          -  Participant must have at least one biopsiable lesion in the Phase 1 portion. In the
             Phase 2 part of the trial, participants must have either (a) at least one measurable
             lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or (b) at
             least one predominantly lytic bone lesion.

          -  Participant must be willing to undergo tumor biopsies prior to treatment and on Cycle
             2 Day 1. In the Phase 2 part of the trial, participants with bone-only disease, or
             participants for whom a biopsy is contra-indicated, may opt out of providing tumor
             biopsies. Note: A subset of participants in Phase 2 will be required to provide tumor
             tissue until tumor pairs have been collected from at least 15 ER˄WT and 15 ER˄mut
             (determined by sponsor-designated central laboratory test).

          -  Participant has an Eastern Cooperative Oncology Group (ECOG) performance status (PS)
             of 0 or 1.

          -  Participant has adequate bone marrow and organ function as defined by the following
             laboratory values:

               1. Absolute neutrophil count (ANC) ≥1.5 × 10˄9/Liter (L);

               2. Platelets ≥100 × 10˄9/L;

               3. Hemoglobin ≥9.0 grams per deciliter (g/dL);

               4. Potassium, sodium, calcium (corrected for serum albumin), magnesium, and
                  phosphorus within normal limits for the institution;

               5. International normalized ratio (INR) ≤1.5;

               6. Serum creatinine ≤1.5 × upper limit of normal (ULN);

               7. Serum albumin ≥3.5 g/dL (≥35 grams per liter (g/L));

               8. In the absence of liver metastases, alanine aminotransferase (AST) and aspartate
                  aminotransferase (ALT) should be below 3.0 × ULN. If the participant has liver
                  metastases, ALT and AST should be below 5.0 × ULN.

               9. Total serum bilirubin less than ULN.

          -  Willingness and ability to comply with study and follow-up procedures.

          -  Ability to understand the nature of this study and give written informed consent.

        Exclusion Criteria:

          -  Participant with bone-only disease (Phase 1 only). Note: Phase 2 participants may have
             predominantly lytic bone-only disease.

          -  Participant with inflammatory breast cancer.

          -  Participant has received more than one prior chemotherapy regimen for metastatic
             disease.

          -  Participant has had prior antineoplastic therapy within 14 days prior to starting
             study drug.

          -  Participant is currently receiving or has received systemic corticosteroids ≤2 weeks
             prior to starting study drug, or has not fully recovered from side effects of such
             treatment.

        Note: The following uses of corticosteroids are permitted: single doses, topical
        applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye
        drops, or local injections (e.g., intra-articular).

          -  Participant has received radiotherapy ≤4 weeks or limited field radiation for
             palliation ≤2 weeks prior to starting study drug, and who has not recovered to Grade 1
             or better from related side effects of such therapy (with the exception of alopecia)
             and/or for whom ≥30% of the bone marrow was irradiated.

          -  Major surgical procedures ≤14 days of beginning study drug, or minor surgical
             procedures ≤7 days, or has not recovered from major side effects. No waiting required
             following port-a-cath placement.

          -  Participant has active cardiac disease or a history of cardiac dysfunction including
             any of the following:

               1. History of angina pectoris, symptomatic pericarditis, or myocardial infarction
                  within 12 months prior to study entry;

               2. History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV);

               3. Documented cardiomyopathy;

               4. Participant has a left ventricular ejection fraction (LVEF) <50% as determined by
                  multiple gated acquisition (MUGA) scan or echocardiogram (ECHO);

               5. History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal
                  arrhythmias, or conduction abnormality in the previous 12 months;

               6. On screening, any of the following cardiac parameters: interval between P and R
                  (PR interval) >220 milliseconds (msec), interval between Q, R, and S (QRS)
                  interval >109 msec, or QT interval corrected for heart rate using Fridericia's
                  formula (QTcF) >450 msec;

               7. Systolic blood pressure (BP) not deemed clinically controlled by the
                  investigator.

          -  Participant has impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of H3B-6545 (e.g., ulcerative diseases,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
             resection).

          -  Participant has a known hypersensitivity to any of the excipients of H3B-6545.

          -  Participant has a known history of human immunodeficiency virus (HIV) infection or
             hepatitis C virus (HCV), or requires treatment with protease inhibitors (testing not
             mandatory).

          -  Participant has any other concurrent severe and/or uncontrolled medical condition that
             would, in the investigator's judgment, contraindicate participant participation in the
             clinical study (e.g., chronic pancreatitis, active hepatitis, etc.).

          -  Participant that received in the 7 days prior to the administration of study drug or
             is currently receiving any of the following medications:

               1. Known strong inducers or inhibitors of cytochrome (CYP)3A4 or P-glycoprotein
                  (P-gp);

               2. Medications that have a known risk to prolong the QT interval or induce Torsades
                  de Pointes;

               3. Proton-pump inhibitors and histamine H2-receptor antagonists;

               4. Medications that have a narrow therapeutic window and are predominantly
                  metabolized through CYP2C8, CYP2C9, CYP2C19, or CYP3A4;

               5. Herbal preparations/medications. These herbal medications include, but are not
                  limited to: St. John's wort, kava, ephedra (ma huang), gingko biloba,
                  dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.

          -  Any adverse events related to previous therapies for breast cancer that have not
             resolved to ≤Grade 1.

          -  Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a
             positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin
             [hCG]) test with a minimum sensitivity of 25 International units per liter [IU/L] or
             equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a
             negative screening pregnancy test was obtained more than 72 hours before the first
             dose of study drug.

          -  Females of childbearing potential who:

               1. Had unprotected sexual intercourse within 30 days before study entry and who do
                  not agree to use a highly effective method of contraception (e.g., total
                  abstinence, an intrauterine device, a double-barrier method [such as condom plus
                  diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or
                  have a vasectomized partner with confirmed azoospermia) throughout the entire
                  study period or for 28 days after study drug discontinuation.

               2. Are currently abstinent, and do not agree to use a double-barrier method (as
                  described above) or refrain from sexual activity during the study period or for
                  28 days after study drug discontinuation.

               3. Are using hormonal contraceptives but are not on a stable dose of the same
                  hormonal contraceptive product for at least 4 weeks before dosing and who do not
                  agree to use the same contraceptive during the study or for 28 days after study
                  drug discontinuation.

               4. All females will be considered to be of childbearing potential unless they are
                  postmenopausal (amenorrheic for at least 12 consecutive months, in the
                  appropriate age group, and without other known or suspected cause) or have been
                  sterilized surgically (i.e, bilateral tubal ligation, total hysterectomy, or
                  bilateral oophorectomy, all with surgery at least 1 month before dosing).

          -  Alcohol dependency within 6 months before study entry

          -  Participant has a concurrent malignancy or malignancy within 3 years of enrollment,
             with the exception of adequately treated basal or squamous cell carcinoma,
             non-melanomatous skin cancer, or curatively resected cervical cancer.

          -  Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with the protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Phase 1 and Phase 2: Number of participants with any treatment-emergent (TE) serious adverse event (SAE)
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Phase 1 and Phase 2: Number of participants with any non-serious TEAE
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Phase 1 and Phase 2: Number of participants with an abnormal, clinically significant clinical laboratory value
Time Frame:Up to 3 years
Safety Issue:
Description:Laboratory results will be summarized using Systeme International (SI) units, as appropriate. Clinical significance will be determined by the Investigator.
Measure:Phase 1 and Phase 2: Number of participants with an abnormal, clinically significant vital sign value
Time Frame:Up to 3 years
Safety Issue:
Description:Clinical significance will be determined by the Investigator.
Measure:Phase 1 and Phase 2: Number of participants with an abnormal, clinically significant 12-lead electrocardiogram (ECG) finding
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Area under the curve (AUC) represents the total drug exposure over a defined period of time after administration.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Racc is the rate and extent of accumulation of drug in the plasma.
Measure:Phase 1: ORR
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Phase 1 and Phase 2: Duration of response (DoR)
Time Frame:Up to 3 years
Safety Issue:
Description: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).
Measure:Phase 1 and Phase 2: Disease control rate (DCR)
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Phase 1 and Phase 2: Progression-free survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description: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).
Measure:Phase 1 and Phase 2: Overall survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description: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).
Measure:Phase 2: Relative bioavailability of H3B-6545 due to moderate-fat meal
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Phase 2: Change from Baseline in mean endometrial thickness
Time Frame:Baseline, Week 12, and after every 24 weeks up to 3 years
Safety Issue:
Description:Participants with an intact uterus will undergo an assessment of endometrial thickness using transvaginal ultrasound.
Measure:Phase 2: Change from Baseline in mean uterine volume
Time Frame:Baseline, Week 12, and after every 24 weeks up to 3 years
Safety Issue:
Description:Participants with an intact uterus will undergo an assessment of uterine volume using transvaginal ultrasound.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:CTX is a biomarker of bone resorption.
Measure:Phase 2: Mean AUC0-t under fasting condition
Time Frame:Cycle 1 Day 15
Safety Issue:
Description:AUC represents the total drug exposure over a defined period of time after administration.
Measure: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)
Safety Issue:
Description:AUC represents the total drug exposure over a defined period of time after administration.
Measure:Phase 2: Mean Cmax under fasting condition
Time Frame:Cycle 1 Day 15
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure:Phase 2: Mean Tmax under fasting condition
Time Frame:Cycle 1 Day 15
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure:Phase 2: Mean Racc under fasting condition
Time Frame:Cycle 1 Day 15
Safety Issue:
Description:Racc is the rate and extent of accumulation of drug in the plasma.
Measure: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)
Safety Issue:
Description:Racc is the rate and extent of accumulation of drug in the plasma.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:H3 Biomedicine Inc.

Trial Keywords

  • HER2
  • estrogen receptor alpha
  • H3B-6545
  • breast cancer

Last Updated

August 29, 2017