Background: Recurrent endometrial cancer (EC) has a poor prognosis with few therapeutic options. Targeting angiogenesis through VEGF inhibition has demonstrated real but limited efficacy. Simultaneous inhibition of angiogenesis and putative resistance mechanisms may provide more durable therapeutic responses. MET/HGF (hepatocyte growth factor) paracrine signaling has been implicated in more aggressive tumour biology, angiogenesis and resistance to VEGF targeting in EC. XL-184 (cabozantinib) is an orally bioavailable, multi-targeted inhibitor with activity against MET and VEGFR2 in addition to TIE2, RET, AXL and KIT. Methods: This phase II, multicenter single arm trial has a planned enrollment of 36 pts utilizing a Simon 2-stage design to evaluate co-primary endpoints of response rate and 12 week progression-free-survival (PFS) in pts with serous, endometrioid or mixed histology EC (experimental cohort). Eligible pts must have radiographic progression after 1 line of chemotherapy for metastatic disease, or progression within 12 months of adjuvant chemotherapy; prior radio- and hormonal therapy is allowed. Stage I has a planned accrual of 18 pts, study will proceed to stage II with observation of > 2 partial responses (PR) and > 6 12-wk PFS. Pts are also accrued to an exploratory cohort (maximum 30 pts) of rare histology EC (clear cell, carcinosarcoma). XL-184 is administered at a starting dose of 60mg orally once daily on a continuous 28 day cycle. Adverse event (AE) reporting is as per CTCAE v4.0. Pts undergo first CT evaluation after 1 cycle, those with SD or PD and ≤ grade 1 toxicity are eligible for dose escalation. Response assessment is completed every 2 cycles (starting with cycle 3) and per RECIST 1.1. Correlative studies will explore associations between tumour response and baseline mutational and met amplification status. To date 14 (experimental) and 6 (exploratory) pts have been enrolled. Median age is 64 (range 51-80). All pts have received chemotherapy and 70% prior radiation. 44 cycles have been completed (median 2 range 1-5). Once the final pts have been accrued to the experimental arm, a decision to proceed to stage II will be made. Clinical trial information: NCT01935934.