An open label, multicenter, phase 1b/2 study of rebastinib (DCC-2036) in combination with carboplatin to assess safety, tolerability, and pharmacokinetics in patients with advanced or metastatic solid tumors.

Abstract

TPS2666 Background: Rebastinib is a potent, orally administered, kinase switch control inhibitor selectively targeting the tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells and has critical roles in angiogenesis. In addition, TIE2 is highly expressed in a subset of macrophages, TIE2-expressing macrophages (TEMs), which are known to have proangiogenic, pro-metastatic, and immunosuppressive properties. Accumulating evidence suggests that chemotherapies, such as carboplatin, increase the recruitment and activity of pro-tumoral TEMs, leading to chemotherapy resistance. Taken together, investigation of rebastinib in combination with a chemotherapy such as carboplatin, one of the most commonly used agents across different tumor types, is warranted in advanced solid tumors. Methods: This study is an open-label, Phase 1b/2, multicenter study in patients with advanced or metastatic solid tumors. The study has two parts: the first part is the 3+3 dose escalation phase designed to evaluate the safety, tolerability and pharmacokinetics of 50 mg and 100 mg rebastinib twice daily in combination with carboplatin of AUC 5 or 6 administered once every three weeks to determine the recommended phase 2 dose (RP2D). Patients who have exhausted all therapies and for whom carboplatin is considered appropriate treatment will be enrolled. The second part is the dose expansion phase with three cohorts: previously treated breast cancer, recurrent, platinum-sensitive ovarian cancer, and malignant mesothelioma to evaluate the safety, tolerability, and efficacy of the RP2D. A Simon’s two-stage design will be used in the second part and initially up to 18 patients will be enrolled into each cohort. If more than 4 responses are observed, then the cohort will be expanded up to 33 patients. This trial is expected to enroll up to 117 patients in total, with approximately 18 patients in the first part and up to 99 patients in the second part. The study is currently open only in the US. Clinical trial information: NCT03717415.