Abstract B055: Phase 1b/2 study of rebastinib (DCC-2036) in combination with paclitaxel: Preliminary safety, efficacy, pharmacokinetics and pharmacodynamics in patients with advanced or metastatic solid tumors
Authors: Janku Filip , Birrer Michael , Richardson Debra , Chu Christina , Goel Sanjay , Su Ying , Matin Bahar , Kuida Keisuke , Ruiz-Soto Rodrigo , Hamilton Erika Paige 
Published: March 2020

Abstract
Background: Rebastinib is an orally administered, kinase inhibitor targeting the switch pocket of tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells, playing a role in angiogenesis. In addition, TIE2 is expressed in a subset of macrophages, TIE2 expressing macrophages (TEMs), which have pro-angiogenic, pro-metastatic, and immunosuppressive properties. Accumulating evidence suggests that chemotherapies, such as paclitaxel, increase the recruitment and activity of TEMs, leading to chemotherapy resistance. This study aims to investigate the efficacy of anti-TIE2 therapy against chemo-resistant advanced solid tumors. Methods: This is an open-label, Phase 1b/2, multicenter study with two parts. Part 1 evaluated two doses of rebastinib at 50 and 100 mg twice daily (BID) with paclitaxel administered weekly at 80 mg/m2 to determine the recommended phase 2 dose (RP2D) by enrolling at least 15 pts in each arm. The objective of Part 1 is to identify a recommended Phase 2 dose. Pts with locally advanced or metastatic solid tumors for which paclitaxel was considered appropriate treatment were enrolled. Part 2 has four disease-specific cohorts: triple-negative breast cancer, inflammatory breast cancer, platinum-resistant ovarian cancer and metastatic endometrial cancer to further evaluate the safety, tolerability and efficacy of the RP2D. This abstract focuses on data from Part 1. Results: A total of 43 pts were enrolled in Part 1 (24 pts at 50 mg BID and 19 pts at 100 mg BID) as of June 21, 2019. The median age was 61 years; 79% were female. Most frequent diagnoses were ovarian (11 pts), breast (8 pts) and endometrial cancer (7 pts). The median number of prior anti-cancer therapies was four (4). Median duration of treatment is 56 days. Treatment-emergent adverse events (TEAEs) were reported for 41 pts. Most TEAEs were previously observed in the rebastinib first-in-human study or were known AEs of paclitaxel. TEAEs &gt;10% include mostly Grade (Gr) 1 or 2 fatigue (30%), constipation (21%), dry mouth (21%), nausea and alopecia (19% each), anemia and UTI (16%), hypokalemia, hypomagnesemia, peripheral neuropathy, and dyspnea (14% each), diarrhea, stomatitis, vomiting, sepsis, dysgeusia, rash and ALT elevation (12% each). Twenty-four pts experienced at least one ≥Gr 3 TEAE. Six pts had ≥Gr 3 AEs related to rebastinib. No significant difference in TEAEs was observed between the two dose levels. The RP2D was determined for rebastinib at 100 mg BID in combination with weekly paclitaxel at 80 mg/m2. Exposure of rebastinib was dose-proportional. Plasma TIE2 and its ligand, ANG2, were induced in a dose-dependent manner. Evidence of observed preliminary clinical activity in heavily pre-treated patients will be presented. Conclusion: Preliminary results demonstrated that the combination of rebastinib and paclitaxel was generally well tolerated. This combination is currently under evaluation in four disease-specific cohorts in Part 2. Clinical trial information: NCT03601897.
Citation Format: Filip Janku, Michael Birrer, Debra Richardson, Christina Chu, Sanjay Goel, Ying Su, Bahar Matin, Keisuke Kuida, Rodrigo Ruiz-Soto, Erika Paige Hamilton. Phase 1b/2 study of rebastinib (DCC-2036) in combination with paclitaxel: Preliminary safety, efficacy, pharmacokinetics and pharmacodynamics in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B055. doi:10.1158/1535-7163.TARG-19-B055