An open-label, multicenter, phase Ib/II study of rebastinib in combination with paclitaxel in a dose-expansion cohort to assess safety and preliminary efficacy in patients with advanced or metastatic endometrial cancer.

Abstract

6085 Background: Rebastinib is a switch control inhibitor targeting tunica interna endothelial cell kinase (TIE2). TIE2 is primarily expressed in endothelial cells playing a role in angiogenesis. TIE2 is also expressed in a subset of macrophages with pro-metastatic and immunosuppressive properties and linked to chemo-resistance. This study is a 2-part open-label, phase Ib/II, multicenter study of rebastinib orally administered, in combination with paclitaxel. In Part 1, we observed encouraging antitumor activity of rebastinib with 5 PRs in 24 patients (pts) at 50 mg BID and 3 PRs in 19 pts at 100 mg BID from a heavily pretreated heterogeneous patient population. Here we summarize preliminary results from the endometrial cancer (EC) cohort of Part 2. Methods: Part 2 of this study has four disease-specific cohorts (TNBC, inflammatory breast cancer, ovarian cancer and EC). Pts were evaluated for safety (CTCAE v5.0) and efficacy (RECIST v1.1). According to the Simon 2-stage design of this study, for each cohort, 15 additional pts will be enrolled if more than 4 PRs are observed. Results: As of Jan 21, 2020, 19 EC pts were enrolled with a median age of 66 years. All pts received at least one prior line of paclitaxel and 12 (63%) pts received >3 prior anti-cancer therapies. Sixteen pts were treated with rebastinib starting dose 100 mg BID (reduced to 50 mg BID due to a higher frequency of muscular weakness) and 3 pts with 50 mg BID, in combination with 80 mg/m2 weekly paclitaxel with a median duration of treatment 85 days (6, 225). In 15 evaluable pts, there were 5 PRs (4 confirmed) and 6 SD8 weeks for an ORR of 33% and clinical benefit rate of 73%. Treatment-emergent AEs (>20%) were mostly ≤ grade 2: constipation, fatigue (each n=9); alopecia, peripheral edema (each n=8); dysgeusia, peripheral sensory neuropathy, arthralgia (each n=6); diarrhea, hypomagnesaemia, vomiting, dry mouth (each n=5); anemia, decreased appetite, dyspnea, nausea, and muscular weakness (each n=4). Serious AEs possibly related or related to rebastinib included muscular weakness (n=2, at 100 mg BID), head discomfort (n=1) and increase troponin (n=1) which resolved after dose interruption. Conclusions: Preliminary activity of rebastinib in combination with paclitaxel was encouraging in heavily pretreated EC pts, all of whom received prior paclitaxel. The safety profile of rebastinib at 50 mg BID was generally well tolerated. The EC cohort is enrolling at 50 mg BID in stage 2 of the study. Clinical trial information: NCT03601897.