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|Authors||E.P. Hamilton, S. Goel, R. Arend, C. Chu, D.L. Richardson, J.R. Diamond, V. John, F. Janku, C. Matthews, L. JeBailey, K. Kuida, H. Achour, R. Ruiz-Soto, J. Hays|
|Title||A phase Ib/II study of rebastinib and paclitaxel in advanced or metastatic platinum-resistant ovarian cancer|
|Journal||Annals of Oncology|
|Abstract Text||Background: Rebastinib is a switch control inhibitor of TIE2 kinase. TIE2 is expressed in endothelial cells and in some macrophages with pro-angiogenic, pro-metastatic and immunosuppressive properties associated with chemotherapy resistance. This is a 2-part open-label, phase Ib/II study with orally administered rebastinib in combination with weekly paclitaxel 80 mg/m2. In part 1, we observed antitumor activity across multiple tumor types (5 PRs in 24 pts at 50 mg BID and 3 PRs in 19 pts at 100 mg BID), including 3 PRs in platinum-resistant ovarian cancer (PROC). Part 2 has 5 cohorts: TNBC, inflammatory breast cancer, PROC, endometrial cancer and carcinosarcoma. Here, we present preliminary results from the PROC cohort. Methods: Part 2 is a Simon 2-stage design enrolling 18 pts into the first stage, and if ≥5 responses, an additional 15 pts in the second stage. Pts were treated with rebastinib in combination with paclitaxel 80 mg/m2 intravenous weekly (D1, D8, D15 of repeated 28-day cycles) and evaluated for safety (CTCAE v5.0) and efficacy (RECIST v1.1). Results: As of March 20, 2020, 20 pts were enrolled; the median age was 58 years. All received ≥ 1 prior regimen with paclitaxel/carboplatin; the median number of prior therapies was 5 (2, 7). Ten pts were initially treated with 100 mg BID rebastinib (reduced to 50 mg BID due to muscular weakness [4 pts in this cohort]) and 10 pts with 50 mg BID with a treatment median duration of 16 weeks (0.7, 31.9). In 17 evaluable pts, there were 5 PRs and 9 SDs (at 8 weeks) for an ORR of 29% and CBR of 82%. In addition, 8/13 (62%) pts had a CA-125 response. TEAEs (≥n=5) were mostly ≤ grade 2, including fatigue (n=8), nausea (n=8), diarrhea, dry mouth, peripheral sensory neuropathy, vomiting (n=6 each); abdominal pain, alopecia, constipation, peripheral edema and stomatitis (n=5 each). Serious AEs possibly related to rebastinib included grade 2, reversible muscular weakness (at 100 mg BID with no additional occurrences at rebastinib 50 mg BID), fatigue and constipation (n=1 each). Conclusions: The preliminary activity and safety of rebastinib at 50 mg BID in combination with weekly paclitaxel for heavily pretreated pts with PROC, all of whom received prior carboplatin/paclitaxel, is encouraging. Simon stage 2 enrollment is ongoing. Clinical trial identification: NCT03601897.|
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|Unknown unknown||ovarian cancer||not applicable||Paclitaxel + Rebastinib||Phase Ib/II||Actionable||In a Phase I/II trial, Rebastinib (DCC-2036) and Taxol (paclitaxel) combination therapy demonstrated acceptable safety, resulted in an objective response rate of 29% (5/17, 5 partial responses) and a clinical benefit rate of 82% in patients with advanced or metastatic platinum-resistant ovarian cancer, 62% (8/13) of patients had a CA-125 response (Annals of Oncology (2020) 31 (suppl_4): S629-S630; NCT03717415).||detail...|