Background: Collecting duct carcinoma (CDC) of the kidney is a rare and aggressive neoplasm without any approved treatment. The anti-VEGF drugs can produce definite efficacy on renal clear cell carcinoma, but limited for advanced CDC. Gemcitabine plus cisplatin (GC) has showed some activity in patients with advanced CDC. This study was designed to evaluate the efficacy and safety of sorafenib combined with GC as first line treatment in patients with advanced CDC. Methods: This study is a prospective multicenter, single-arm phase II trial. Patients with metastatic, or unresectable CDC by central pathological confirmation and ≥ 1 measurable lesion per RECIST criteria, ECOG PS ≤ 2, and adequate organ function are enrolled. All patients received sorafenib (400mg Bid) combined with GC (cisplatin: 25mg/m², d1-3; gemcitabine: 1000 mg/m², d1,d8, for 4 cycles) until disease progression, unacceptable toxicity, or study discontinuation for any other reason. The primary endpoint is PFS. Overall survival, disease control rate, and safety will also be assessed. Results: Between Jun 2012 and Dec 2015, 26 patients with metastatic CDC were enrolled at 5 Chinese centers after central pathological confirmation. In these patients, 25 patients received prior nephrectomy. The sites of metastases included lung, mediastinal lymph node, local recurrence, retroperitoneal lymph node, skeleton and peritoneum. There were 0 complete and 8 partial responses for an objective response rate of 30.8% (95% CI: 13.1 to 48.5%). Fourteen patients (53.8%) were noted to have stable disease. The disease control rate was 83.8%. Median PFS and OS was 8.3 (95% CI: 2.9 to 13.7) and 11.5 months (95% CI 10.5 to 12.5), respectively. The treatment was well tolerated and toxicities were most grade 1/2. Grade 3/4 toxicities included neutropenia (5/26), thrombocytopenia (3/26), hand-foot syndrome (9/26). Conclusions: This is the largest study about advanced CDC and is the first prospective, multicenter, phase II study showing that sorafenib combined with GC regimen is active and safe as first line therapy in patients with advanced CDC. Clinical trial information: NCT01762150