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)

Study Overview
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Brief Summary
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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.

Detailed Description
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Phase 1b will occur in two parts: Part 1: Run-in safety cohort(s) (dose levels 1, 0, and -1, as necessary) of 6 participants each will be conducted until the RP2D is determined. The purpose of the run-in safety cohort(s) is to study the safety of the 2-drug combination and determine a RP2D. Dose limiting toxicity (DLT) will be assessed in the first cycle to determine the RP2D of eribulin mesylate in combination with PEGPH20. Part 2 (Phase 1b Expansion Part): A total of 12 additional participants will be enrolled at the RP2D determined in Part 1 (using Phase 1b criteria, i.e., participants previously treated with up to 2 lines of systemic anticancer therapy) in order to assess the safety profile of the combination and identify any potential safety signals and the incidence of thromboembolic events in this population (RP2D determined dosing). In Phase 2, 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 milligrams per square meters (mg/m^2).

Official Title
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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)

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Eribulin mesylate
* Drug: Eribulin mesylate
* Drug: Eribulin mesylate
* Other: Biologic: PEGylated recombinant human hyaluronidase (PEGPH20)
* Other: Biologic: PEGylated recombinant human hyaluronidase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Metastatic Her-2- breast cancer Up to 2 prior lines of cytotoxic or targeted anti-cancer therapy for metastatic disease Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Exclusion Criteria Less than 6 months since prior neoadjuvant/adjuvant chemotherapy 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 Previous history or current evidence of deep vein thrombosis (DVT), hereditary thrombophilic syndromes, pulmonary embolism (PE), cerebral vascular accident (CVA), transient ischemic attack (TIA), atrial fibrillation (AF), or active carotid artery disease requiring treatment Treatment with chemotherapy, hormonal, or biological therapy within the previous 3 weeks, radiation or small molecule targeted therapy within the previous 2 weeks preceding informed consent Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eribulin mesylate plus PEGPH20 (Phase 1b)<br>Recommended Phase 2 dose (RP2D) will be determined from the below dose levels: Dose level 1: PEGPH20 (3.0 microgram per kilogram (mcg/kg)) followed by eribulin mesylate (1.4 milligrams per square meter (mg/m^2)) or Dose level 0: PEGPH20 (1.6 mcg/kg) followed by eribulin mesylate (1.4 mg/m^2) or Dose level -1: PEGPH20 (1.6 mcg/kg) followed by eribulin mesylate (1.1 mg/m^2) Dose level 1 can be selected as the RP2D if no more than 1 out of 6 participants has a DLT; DLT was only observed from the first treatment cycle; 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. Upon determination of the RP2D, study Phase 1b Expansion Part will proceed to confirm the RP2D, and thereafter Phase 2 part will proceed. | Drug: Eribulin mesylate<br>* Eribulin mesylate will be administered at 1.4 mg/m^2 or 1.1 mg/m^2 as intravenous (IV) infusion on Day 1 and 8 of 21-day cycle<br>* Other names: E7389;Other: Biologic: PEGylated recombinant human hyaluronidase (PEGPH20)<br>* PEGPH20 will be administered at 3.0 mcg/kg or 1.6 mcg/kg as IV infusion on Day -1 and 7 of 21-day cycle<br>|
| Experimental: Eribulin mesylate plus PEGPH20 (Phase 2)<br>Participants will receive eribulin mesylate and PEGPH20 at the established RP2D level achieved in the Phase 1b. | Drug: Eribulin mesylate<br>* Eribulin mesylate will be administered at 1.4 mg/m^2 or 1.1 mg/m^2, depending on RP2D, as IV infusion on Day 1 and 8 of each 21-day cycle<br>* Other names: E7389;Other: Biologic: PEGylated recombinant human hyaluronidase<br>* PEGPH20 will be administered at 3.0 mcg/kg or 1.6 mcg/kg, depending on RP2D, as IV infusion on Day -1 and 7 of each 21-day cycle<br>|
| Experimental: Eribulin mesylate (Phase 2)<br>Participants will receive eribulin mesylate at 1.4 mg/m^2. | Drug: Eribulin mesylate<br>* Eribulin mesylate will be administered at 1.4 mg/m^2 as IV infusion on Day 1 and 8 of 21-day cycle<br>* Other names: E7389;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Recommended Phase 2 Dose (RP2D) of Eribulin Mesylate in Combination With PEGPH20 | The RP2D was the maximum tolerated dose (MTD) or less. The MTD was determined as the dose level (1, 0) at which less than or equal to (<=) 1 of 6 evaluable participants experienced dose limiting toxicity (DLT) within the first 21 days of treatment (end of Cycle 1). Upon determination of RP2D in Cycle 1 of Phase 1b, RP2D was to be confirmed in Phase 1b-expansion Part. | Up to Cycle 28 (Cycle Length= 21 days) | 
| Phase 1b: Recommended Phase 2 Dose (RP2D) of PEGPH20 in Combination With Eribulin Mesylate | The RP2D was the MTD or less. The MTD was determined as the dose level (1, 0) at which <=1 of 6 evaluable participants experienced DLT within the first 21 days of treatment (end of Cycle 1). Upon determination of RP2D in Cycle 1 of Phase 1b, RP2D was to be confirmed in Phase 1b-expansion Part. | Up to Cycle 28 (Cycle Length= 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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E7389, PEGylated Recombinant Human Hyaluronidase, Eribulin Mesylate, PEGPH20, Human Epidermal Growth Factor Receptor 2-Negative, High-Hyaluronan