Abstract P6-18-22: Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel (P) or eribulin (E) in patients with HER2-negative metastatic breast cancer (MBC)
Authors: Anampa JD , Xue X , Oh S-y , Kornblum N , Sadan S , Oktay MH , Condeelis J , Sparano JA 
Published: May 2019

BACKGROUND: TMEM (Tumor Microenvironment of Metastasis) are the portal for tumor cell intravasation into the circulation and subsequent metastasis (Harney et al Cancer Discov 2015). The potent Tie2 kinase inhibitor rebastinib inhibits intravasation at TMEM sites, reduces circulating tumor cell (CTC) burden, increases angiopoietin (Ang) 1/2 levels, prevents distant metastases, and improves survival in breast cancer animal models when added to either P or E (Harney et al MCT 2017), and circumvent chemotherapy-induced pro-metastatic changes in the tumor microenvironment mediated by TMEM (Karagiannis et al STM 2017). We sought to determine the safety of rebastinib combined with antitubulin therapy (P or E) in patients with HER2- MBC. We also hypothesized that addition of rebastinib would reduce CTC burden and increase Ang levels by blocking Ang-mediated stimulation of VEGF release from TMEM-associated macrophages.

METHODS: We aimed to determine the safety and recommended phase 2 dose (RP2D) of rebastinib (2 dose levels: 50 mg or 100 mg PO BID) in combination with P (80 mg/m2 x 12 weeks) or E (1.4 mg/m2 on day 1 & 8 q 21 days) using a standard 3+3 design (1 cycle = 21 days). Secondary objectives included evaluating the effect of the P/E + rebastinib combination on CTCs (TelomeScan) and Ang levels. Dose limiting toxicity (DLT) was defined as grade 3-4 febrile neutropenia, thrombocytopenia, and non-hematologic toxicity during the first 6 weeks of therapy. Eligibility included HER2- MBC, ECOG PS 0-1, CDK4/6 inhibitor progression if ER+. Patients with ≤ 2 prior non-taxane chemotherapy regimens received P+ rebastinib, whereas those with ≥ 2 chemo regimens (including a taxane) received E+ rebastinib.

RESULTS: Of 11 treated patients, 6 received rebastinib + P and 5 received rebastinib + E (2 non-evaluable due to rapid disease progression and non-compliance). Among 11 patients who received 60 treatment cycles, only 1 patient (treated with eribulin) had grade 3 events (anemia and neuropathy after week 6) potentially related to treatment. When combined with P, the RP2D of rebastinib was 100 mg PO BID, with DLT occurring in 0/6 patients. When combined with E, 0/3 evaluable patients had a DLT at 50 mg BID of rebastinib (accrual ongoing for 100mg BID). Best response included partial response/stable disease in 4(2PR/2SD) of 6 treated with P+ rebastinib, and 1(1PR) of 5 treated with E+ rebastinib. CTCs decreased during therapy (median decrease 99.7 %) and 4/8 patients converted from CTC+ to CTC-. Ang1 levels increased during therapy in 8 patients (0.2-7.0 fold), while Ang2 levels were also increased in 8 patients (0.2-1.4 fold).

CONCLUSIONS: When combined with P x 12 weeks, the RP2D of rebastinib is 100 mg PO BID. When combined with E, the RP2D of rebastinib is at least 50mg PO BID; however, the 100 mg PO BID dose level is still accruing patients. The P/E + rebastinib combinations are associated with antitumor activity and exhibit pharmacodynamic evidence indicating blockade of Tie2 (increased Ang) and TMEM function (reduced CTCs) We plan to further evaluate the P+ rebastinib combination as neoadjuvant therapy in the I-SPY program, and continue further evaluation of P/E + rebastinib combinations in MBC.

Citation Format: Anampa JD, Xue X, Oh S-y, Kornblum N, Sadan S, Oktay MH, Condeelis J, Sparano JA. Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel (P) or eribulin (E) in patients with HER2-negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-22.