Abstract OT2-02-02: A randomized, open-label, multicenter, phase 1b/2 study of eribulin mesylate in combination with PEGylated recombinant human hyaluronidase in patients with human epidermal growth factor receptor 2-negative, high-hyaluronan metastatic breast cancer
Authors: Alvarez RH , Savulsky C , Almonte A , Xing D , Lokker N , Chondros D 
Published: March 2017

Abstract
Eribulin (ERI), a non-taxane microtubule inhibitor, is approved for treatment in patients (pts) with advanced or metastatic breast cancer (MBC) who have received ≥1 (European Union) or ≥2 (United States) prior chemotherapy regimens for metastatic disease, including an anthracycline and taxane in either the adjuvant or metastatic setting. In a phase 2 study, ERI has demonstrated single-agent activity in first line treatment of pts with human epidermal growth factor receptor 2-negative (HER2−) MBC. Hyaluronan (HA) is a major component of the tumor microenvironment, specifically within the stroma, and high levels of HA are associated with disease progression. In HA-High, triple-negative breast cancer (TNBC) xenografts, the anti-tumor effect of ERI was enhanced by addition of PEGylated recombinant human hyaluronidase (PEGPH20). PEGPH20 is an engineered enzyme under investigation for use in combination with anticancer therapies in pts with tumors that accumulate HA. PEGPH20 acts by temporarily degrading HA to reduce tumor interstitial pressure and decompress blood vessels, thus increasing access of anticancer agents and immune cells to tumor sites. This randomized, open-label, multicenter, study of ERI in combination with PEGPH20 vs ERI alone was designed to evaluate safety and tolerability and efficacy in pts with HER2−, HA-High, MBC previously treated with 0–1 systemic (cytotoxic or targeted) anticancer therapy.
The trial was activated in June 2016 and will enroll approximately 96 pts (aged ≥18 yrs; n=6–18 in phase 1b; n=84 randomized to obtain 80 evaluable pts in phase 2).Pts with measurable disease of ≥1 lesion ≥10 mm in long-axis diameter (nonlymph nodes) or ≥15 mm in short-axis diameter (lymph nodes) with ECOG PS of 0 or 1 will be included. Pts will be excluded for having had adjuvant chemotherapy within the past 6 months, hormonal/biological therapy within the past 3 wks, or radiation or small molecule targeted therapy within the past 2 wks. Pts will also be excluded if they were previously treated with ERI or any hyaluronidase agent.
Phase 1b includes at least 1 initial safety run-in cohort in which 6 pts (any HA level) will receive PEGPH20 3 μg/kg intravenous (IV) on days −1 and 7 of a 21-day cycle, each dose followed approximately 24 (±4) hours later with ERI 1.4 mg/m2 IV on days 1 and 8. Dose-limiting toxicity (DLT) will be assessed in the first cycle.The primary endpoint in phase 1b is the recommended phase 2 dose (RP2D) of the ERI and PEGPH20 combination, defined as the maximum dose at which ≤1 pt experiences a DLT.Alternatively, modified dose levels will be evaluated in additional cohorts.
In phase 2, HA-High pts will be stratified by TNBC vs other HER2− status and randomized to receive RP2D combination treatment or ERI alone. Pts with clinical benefit will remain on ERI or both study drugs until unacceptable toxicity or disease progression. The primary endpoint in phase 2 is objective response rate. Secondary endpoints include progression-free survival and overall survival. Exploratory endpoints include clinical benefit rate, disease control rate, and duration of response.
Citation Format: Alvarez RH, Savulsky C, Almonte A, Xing D, Lokker N, Chondros D. A randomized, open-label, multicenter, phase 1b/2 study of eribulin mesylate in combination with PEGylated recombinant human hyaluronidase in patients with human epidermal growth factor receptor 2-negative, high-hyaluronan metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-02-02.