Background:

Metastasis is the primary cause of death in breast cancer, yet no specific therapies are available that inhibit the metastatic process. TMEM (Tumor Microenvironment of Metastasis) are microanatomic structures formed by a Mena-expressing tumor cell, Tie2-expressing macrophage, and endothelial cell in direct content, which serve as the primary portal for tumor cell intravasation into the circulation and subsequent metastasis. High TMEM score in the primary tumor is associated with higher risk of recurrence in ER+, HER2- early breast cancer. Paclitaxel induces the formation of TMEM in the primary tumors of patients treated with neoadjuvant chemotherapy (NAC), and in the primary tumor and distant metastases in the PyMT rodent model and patient-derived xenograft (PDX) models. Intravasation of tumor cells is mediated by release of vascular endothelial growth factor (VEGF) that promotes focal vascular leakiness specifically at TMEM sites, and is derived from TMEM-associated Tie2HI/VEGFHI macrophages that release VEGF upon binding of the Tie2 receptor to angiopoietin, which is elaborated by TMEM-associated endothelial cells. The Tie2 inhibitor rebastinib inhibits intravasation at TMEM sites, reduces circulating tumor cell (CTC) burden, prevents distant metastases, and improves survival in breast cancer animal models when added to either paclitaxel or eribulin. We therefore hypothesize that the addition of a potent Tie2 inhibitor (rebastinib) to antitubulin therapy with paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC) will prevent hematogenous dissemination and distant metastasis by inhibiting TMEM function, reduce CTC burden, and improve clinical outcomes.

Methods:

Primary objective of this phase Ib study (NCT02824575) is to evaluate safety and tolerability of rebastinib (Tie2 inhibitor) in two dose levels (DL) (50mg or 100mg po BID) combined with paclitaxel IV 80mg/m2 (day 1, 8 and 15) or eribulin IV 1.4mg/m2 (day1 and 8) for four 21-day cycles.

Key eligibility includes histologically confirmed HER2 negative MBC or not amenable to curative surgery. Up to two prior non-taxane chemotherapy regimens are allowed for rebastinib plus paclitaxel arm, while at least two chemotherapy regimens (including a taxane) are required for eribulin plus rebastinib arm. ER positive patients must have failed at least two lines of endocrine therapy including an approved CDK4/6 inhibitor. Patients require ECOG PS 0 or 1 and normal organ and marrow function. Exclusion criteria include significant ocular disease (retinal neovascularization, macular edema or macular degeneration), significant history of cardiac disease or concomitant use drugs that prolong QTc interval.

Pharmacodynamic biomarkers to be measured during cycle 1(day1 and 15), cycle 2(day1 and 15) and cycle 3(day1) include CTCs, angiopoietin 1/2 levels and Tie-2 expressing monocytes. Tissue biopsy after two treatment cycles in 6 patients who have accessible tumors will be performed to evaluate TMEM score and function. With two DL of rebastinib, and 3-6 patients at each DL, it is anticipated that 6-12 patients will be required.

This trial has enrolled two patients assigned to paclitaxel arm combined with rebastinib 50mg BID.

Citation Format: Jesus D. Anampa, Xiaonan Xue, Maja oktay, John Condeelis, Joseph A. Sparano. Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT040. doi:10.1158/1538-7445.AM2017-CT040