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Study of Eribulin Mesylate in Combination With PEGylated Recombinant Human Hyaluronidase (PEGPH20) Versus Eribulin Mesylate Alone in Subjects With Human Epidermal Growth Factor Receptor 2 (HER2)-Negative, High-Hyaluronan (HA) Metastatic Breast Cancer (MBC)

NCT02753595

Description:

The primary objective for the study is as follows: For the Phase 1b - to determine safety tolerability and recommended Phase 2 dose (RP2D) of eribulin mesylate in combination with PEGylated recombinant human hyaluronidase (PEGPH20) in participants with Human Epidermal Growth Factor Receptor (HER2)-negative metastatic breast cancer (MBC) previously treated with up to two lines of systemic anticancer therapy in the metastatic setting. For the Phase 2 - to evaluate objective response rate (ORR) of eribulin mesylate in combination with PEGPH20 in participants with HER2-negative, High-Hyaluronan (HA)-high, MBC previously treated with up to 2 lines of systemic anticancer therapy in the metastatic setting.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title:Study of Eribulin Mesylate in Combination With PEGylated Recombinant Human Hyaluronidase (PEGPH20) Versus Eribulin Mesylate Alone in Subjects With Human Epidermal Growth Factor Receptor 2 (HER2)-Negative, High-Hyaluronan (HA) Metastatic Breast Cancer (MBC)
  • Official Title:A Randomized, Open-label, Multicenter, Phase 1b/2 Study of Eribulin Mesylate in Combination With PEGylated Recombinant Human Hyaluronidase (PEGPH20) Versus Eribulin Mesylate Alone in Subjects With Human Epidermal Growth Factor Receptor 2 (HER2)-Negative, High-Hyaluronan (HA) Metastatic Breast Cancer (MBC)

Clinical Trial IDs

  • ORG STUDY ID: E7389-M000-219
  • NCT ID: NCT02753595

Trial Conditions

  • Metastatic Breast Cancer

Trial Interventions

DrugSynonymsArms
Eribulin mesylateE7389Eribulin mesylate plus PEGPH20 (Phase 1b)
Eribulin mesylateE7389Eribulin mesylate plus PEGPH20 (Phase 2)
Eribulin mesylateE7389Eribulin mesylate (Phase 2)

Trial Purpose

The primary objective for the study is as follows:

For the Phase 1b - to determine safety tolerability and recommended Phase 2 dose (RP2D) of eribulin mesylate in combination with PEGylated recombinant human hyaluronidase (PEGPH20) in participants with Human Epidermal Growth Factor Receptor (HER2)-negative metastatic breast cancer (MBC) previously treated with 0 to 1 line of systemic anticancer therapy in the metastatic setting.

For the Phase 2 - to evaluate objective response rate (ORR) of eribulin mesylate in combination with PEGPH20 in participants with HER2-negative, High-Hyaluronan (HA)-high, MBC previously treated with 0 to 1 line of systemic anticancer therapy in the metastatic setting.

Detailed Description

The Phase 1b part will have dose limiting toxicity (DLT) assessed in the first cycle to determine the RP2D of eribulin mesylate in combination with PEGPH20. In the Phase 2 part, participants will be stratified by triple negative breast cancer (TNBC) status and randomized 1:1 to receive eribulin mesylate and PEGPH20 at the established RP2D level or eribulin mesylate alone at 1.4 milligram per square meter (mg/m2).

Trial Arms

NameTypeDescriptionInterventions
Eribulin mesylate plus PEGPH20 (Phase 1b)ExperimentalRecommended Phase 2 dose (RP2D) will be assessed in the below dose levels: RP2D level 1: PEGPH20 (3.0 microgram per killogram (μg/kg)) plus eribulin mesylate (1.4 milligrams per square meter (mg/m2)) or RP2D level 0: PEGPH20 (1.6 μg/kg) plus eribulin mesylate (1.4 mg/m2) or RP2D level -1: PEGPH20 (1.6 μg/kg) plus eribulin mesylate (1.1 mg/m2) Dose level 1 can be selected as the RP2D if no more than 1 out of 6 participants has a DLT; otherwise, Dose level 0 will be assessed in a second cohort of 6 subjects and will be selected as the RP2D if no more than 1 subject has a DLT. Otherwise, Dose level - 1 will be assessed in a third cohort of 6 subjects. If no more than 1 of 6 subjects in this third cohort has a DLT, the Phase 2 part will proceed with dose level -1 as the RP2D. Otherwise, alternative doses will be explored prior to the start of Phase 2.
  • Eribulin mesylate
    Eribulin mesylate plus PEGPH20 (Phase 2)ExperimentalParticipants will receive eribulin mesylate and PEGPH20 at the established RP2D level achieved in the Phase 1b.
      • Eribulin mesylate
      Eribulin mesylate (Phase 2)ExperimentalParticipants will receive eribulin mesylate at 1.4 mg/m2.
          • Eribulin mesylate

        Eligibility Criteria

        Inclusion Criteria

        1. Histological adenocarcinoma of the breast.

        2. Females or males, aged ≥18 years at the time of signing the informed consent form (ICF).

        3. Human epidermal growth factor receptor 2-negative (defined as immunohistochemistry (IHC) <2 or fluorescence in situ hybridization (FISH) negative) breast cancer previously treated with 0 to 1 line of systemic anticancer therapy (cytotoxic or targeted anticancer agents) in the metastatic setting. Hormonal therapy and bone metastases treatment (eg, bisphosphonates, denosumab, etc.) are not considered forms of systemic anticancer therapy.

        4. Archived tissue sample or new biopsy sample:

        Metastatic breast cancer tissue with High-Hyaluronan (HA)-high levels based on available tumor tissue in formaldehyde fixed-paraffin embedded (FFPE) block or minimum of 5 (10 preferred) unstained core biopsy slides that meet specific tissue sample requirements. Fine needle aspirates (FNA) or brushing biopsies will not be acceptable.

        (NOTE: HA status is not a requirement for enrollment in Phase 1b).

        5. Phase 2 participants must be determined to be HA-high based on a clinical trial assay from a central laboratory (details in a separate Laboratory Manual). Tumor samples must meet the requirements noted in the previous criteria (see Study Laboratory Manual).

        6. Presence of measureable disease meeting the following criteria:

        1. At least 1 lesion of ≥10 mm in long axis diameter for non-lymph nodes or ≥15 mm in short axis diameter for lymph nodes that is serially measurable according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) using computerized tomography (CT) or magnetic resonance imaging (MRI).

        2. Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show evidence of subsequent progressive disease (substantial size increase of ≥20%) to be deemed a target lesion.

        7. Life expectancy of ≥3 months.

        8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

        9. Adequate renal function as evidenced by serum creatinine ≤1.5 milligram/deciliter (mg/dL) or calculated creatinine clearance ≥50 mL/minute according to the Cockcroft and Gault formula.

        10. Adequate bone marrow function, defined as:

        1. Absolute neutrophil count (ANC) ≥1.5 × 10^9/liter (L) and

        2. Hemoglobin (Hgb) ≥9.0 gram/deciliter (g/dL); can be corrected by growth factor or transfusion and

        3. Platelet count ≥100 × 10^9/L.

        11. Adequate liver function, defined as:

        1. Total bilirubin ≤1.5 × upper limit of normal (ULN), except for unconjugated hyperbilirubinemia or Gilbert's syndrome.

        2. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3 × ULN (≤5 × ULN if participant has liver metastases). If ALP is >3 × ULN (in the absence of liver metastases) or >5 × ULN (in the presence of liver metastases) and participants are also known to have bone metastases, the liver specific ALP must be separated from the total and used to assess the liver function instead of the total ALP.

        12. Willing and able to comply with all aspects of the treatment protocol.

        13. Provide written informed consent.

        Exclusion Criteria

        1. Previous treatment with eribulin mesylate or any hyaluronidase agent.

        2. Less than 6 months since prior neoadjuvant/adjuvant chemotherapy.

        3. Intolerant of dexamethasone as determined by the investigator.

        4. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.

        5. Previous history or current evidence of deep vein thrombosis (DVT), hereditary thrombophilic syndromes, pulmonary embolism (PE), cerebral vascular attack (CVA), transient ischemic attack (TIA), or active carotid artery disease requiring treatment.

        6. Current enrollment in another interventional clinical study or used any investigational drug or device within the past 28 days preceding informed consent.

        7. Treatment with hormonal or biological therapy within the previous 3 weeks, radiation or small molecule targeted therapy within the previous 2 weeks.

        8. Known central nervous system (CNS) disease, except for those participants with treated brain metastasis who are stable for at least 1 month, having no evidence of progression or hemorrhage after treatment and no ongoing requirement for corticosteroids, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period.

        9. Known history of human immunodeficiency virus (HIV) positive.

        10. Known active hepatitis B (eg, HBsAg reactive) or hepatitis C (eg, Hepatitis C virus (HCV) ribonucleic acid (RNA) detected).

        11. Existing anticancer treatment-related toxicities of Grades ≥2 (except for alopecia and Grade 2 sensory neuropathy) according to Common Terminology Criteria for Adverse Events (CTCAE v4.03).

        12. Other active malignancy (except definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within past 24 months.

        13. Significant cardiovascular impairment: History of (a) congestive heart failure greater than New York Heart Association (NYHA) Class II, (b) unstable angina, (c) myocardial infarction (d) stroke or (e) cardiac arrhythmia associated with hemodynamic instability within 6 months of the first dose of study drug.

        14. Clinically significant electrocardiogram (ECG) abnormality, including a marked Baseline prolonged QT/QTc (QT interval/corrected QT interval), eg, a repeated demonstration of a corrected QT (QTc) interval >500 millisecond (ms)).

        15. Pulmonary lymphangitic spread.

        16. Scheduled for major surgery during the study.

        17. 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 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.

        18. Females of childbearing potential who:

        - Do not agree to use a highly effective method of contraception (eg, total abstinence if it is their preferred and usual lifestyle, an intrauterine device, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) within 30 days before study entry and throughout the entire study period or for 28 days after study drug discontinuation.

        - Are currently totally abstinent (as their preferred and usual lifestyle), and who do not agree to continue to be totally abstinent during the study period or for 28 days after study drug discontinuation.

        - 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.

        - (NOTE: 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 [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]).

        19. Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (ie, not of childbearing potential or using effective contraception throughout the study period or for 28 days after study drug discontinuation). No sperm donation is allowed during the study period or for 28 days after study drug discontinuation.

        20. Known intolerance to the study drugs or any of the excipients.

        21. Known allergy to hyaluronidase.

        22. History of concomitant medical conditions or infectious diseases that, in the opinion of the investigator, would compromise the participant's ability to safely complete the study.

        23. The investigator's belief that the participant is medically unfit to receive eribulin mesylate and PEGPH20 or unsuitable for any other reason.

        Maximum Eligible Age:N/A
        Minimum Eligible Age:18 Years
        Eligible Gender:Both
        Healthy Volunteers:No

        Primary Outcome Measures

        Measure:Recommended Phase 2 dose (RP2D) of eribulin mesylate in combination with PEGylated recombinant human hyaluronidase (PEGPH20) - Phase 1b
        Time Frame:up to 21 days (Cycle 1)
        Safety Issue:No
        Description:

        Secondary Outcome Measures

        Measure:Progression-free survival (PFS) - Phase 2
        Time Frame:Up to approximately 30 months
        Safety Issue:No
        Description:
        Measure:Overall survival (OS) - Phase 2
        Time Frame:Up to approximately 30 months
        Safety Issue:No
        Description:

        Trial Keywords

        • PEGylated Recombinant Human Hyaluronidase
        • Eribulin Mesylate
        • E7389
        • PEGPH20
        • Human Epidermal Growth Factor Receptor 2-Negative
        • High-Hyaluronan