Abstract OT2-06-04: Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer
Authors: JD Anampa, X Xue, M Oktay, J Condeelis, JA Sparano
Journal: Cancer Research (2018)

Abstract 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, and in the primary tumor and distant metastases in the PyMT/PDX models. Tumor cell intravasation is mediated by release of 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 angiopoietin2 (ANG2), which is elaborated by TMEM-associated endothelial cells. Moreover, ANG2-stimulated release of IL-10 by tumor-associated macrophages suppresses T cell proliferation, increases the ratio of CD4+T cells to CD8+ T cells, and promotes the expansion of CD4+CD25highFOXP3+ 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 in patients with HER2 negative metastatic breast cancer (MBC) will prevent hematogenous dissemination and distant metastasis by inhibition of TMEM function, reduction in CTC burden, and inhibition of immune-system suppression resulting in improvement in breast clinical outcomes Methods: Primary objective of this phase Ib study (NCT02824575) is to evaluate safety and tolerability of rebastinib 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. ≤ 2 non-taxane chemotherapy regimens are allowed for rebastinib plus paclitaxel arm, while ≥ 2 chemotherapy regimens (including a taxane) are required for eribulin plus rebastinib arm. ≥ 2 endocrine regimens, including an approved CDK4/6 inhibitor, is required for ER+ disease. Patients require ECOG PS 0 or 1 and normal organ and marrow function. Exclusion criteria include significant ocular disease, significant history of cardiac disease or concomitant use drugs that prolong QTc interval. Pharmacodynamic biomarkers to be measured during cycle 1-3 include CTCs, ANG 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 three patients assigned paclitaxel arm (DL1) and one patient in eribulin arm(DL1). Citation Format: Anampa JD, Xue X, Oktay M, Condeelis J, Sparano JA. Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-06-04.