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|Authors||F. Janku, A.W. Tolcher, L. Rosen, C. Taglienti, K. Kuida, H. Achour, R. Ruiz-Soto, P. Munster|
|Title||A phase I study of rebastinib and carboplatin in patients with metastatic solid tumours|
|Journal||Annals of Oncology|
|Abstract Text||Background: Rebastinib is a switch control inhibitor of TIE2 kinase. TIE2 is expressed in endothelial cells and in a subset of macrophages with pro-angiogenic, pro-metastatic and immunosuppressive properties associated with chemotherapy resistance. This study aims to investigate the safety and preliminary efficacy of rebastinib and carboplatin in pts with solid tumors. Methods: This is an open-label, phase Ib/II, study in which rebastinib 50 and 100 mg BID was evaluated with carboplatin AUC5/6 Q3W using 3 + 3 dose escalation rules to determine the RP2D. Dose escalation included pts with metastatic solid tumors for which carboplatin was considered appropriate treatment. Results: As of March 27, 2020, 22 pts were enrolled in 3 dose-escalating cohorts: rebastinib 50 mg BID + AUC5 (n=3), rebastinib 100 mg BID + AUC5 (n=14), and rebastinib 100 mg BID + AUC6 (n=5). The median age was 61 yrs. Most frequent diagnoses were breast cancer (n=5); neuroendocrine carcinoma (n=3); pancreatic adenocarcinoma, NSCLC, ovarian, and cholangiocarcinoma (n=2 each). The median number of prior anti-cancer therapies was 4 (1, 12). Median duration of treatment was 8.4 weeks (0.9, 22.6). Treatment-emergent adverse events >10% were mostly Grade 1 or 2: thrombocytopenia (36%); constipation (32%); fatigue and nausea (27% each); anemia (18%); ALT/AST increased, dry mouth, neutropenia, peripheral neuropathy, and vision blurred (13% each). One pt had a serious adverse event possibly related to rebastinib (Grade 2 retinal vascular disorder). 2 DLTs out of 12 evaluable pts were reported at 100 mg BID with AUC5. Preliminary clinical activity included 1 PR (4.8%), 10 SD (48%) and a CBR of 52% at 6 weeks. Rebastinib exposure was dose proportional; PK and PD to be presented. Rebastinib 100 mg BID and carboplatin AUC5 was initially selected as the RP2D. An increased frequency of reversible muscular weakness in the dose expansion cohorts was observed and the RP2D was adjusted to rebastinib 50 mg BID. Conclusions: The preliminary safety of rebastinib in combination with carboplatin AUC5 is acceptable. The dose expansion cohorts in TNBC, platinum-sensitive ovarian cancer, and mesothelioma are currently enrolling at rebastinib 50 mg BID with carboplatin AUC5. Clinical trial identification: NCT03717415.|
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|Unknown unknown||Advanced Solid Tumor||not applicable||Carboplatin + Rebastinib||Phase Ib/II||Actionable||In a Phase I/II trial, Rebastinib (DCC-2036) and Paraplatin (carboplatin) combination therapy demonstrated acceptable safety, resulted in a partial response in 4.8% (1/21) and stable disease in 48% (10/21) of patients with advanced solid tumors (Annals of Oncology (2020) 31 (suppl_4): S481-S482; NCT03717415).||detail...|