424 Background: Advanced urothelial cancer progressing after first line systemic therapy is fatal. No agent in the second line or later setting has demonstrated improved survival although taxanes, pemetrexed, gemcitabine & vinflunine have activity & are used as palliative therapy. The Her2 pathway is up-regulated in some urothelial cancers and Her2 targeted therapy has enhanced chemotherapy effect in other cancers. We tested docetaxel with lapatinib, a Her1/Her2 TKI in urothelial cancer patients. Methods: Pts with measurable or evaluable urothelial cancerentered a single arm 2-stage phase II clinical trial, with PFS rate at 12 weeks as the primary endpoint in a Simon 2-stage design of 14+26 patients. The goal was a 12 week non progression rate of 60% - seen as promising compared to a rate of < 40% seen as not. In a 2-stage design if ≥ 6 of 14 patients had not progressed by 12 weeks the trial would continue to 40 pts. Secondary endpts: ORR, safety & OS. First 6 patients were given lapatinib 1250mg PO daily & docetaxel 60mg/m2 IV q3wk; docetaxel dose then increased to 75mg/m2 q3wk. Tumor tissue & circulating microenvironment were evaluated. Results: From July 2011 to July 2013, 15 pts were accrued. Median age 65 y, male 80%, ECOG 0 73%, Caucasian 73%, Mets: Liver 20%, Lung 20%, Bone 20%. PFS at 12 weeks 40%+/-13% - the trial was terminated after first stage. Reason off therapy: PD 10 (67%), toxicity 4 (27%). RECIST 1.1 best response: CR 1 (8%), SD 4 (31%), PD 8 (62%). Median OS: 6.3 (2.2, 12.7), PFS 2.0 (1.3, 6.6) months; 2 pts alive, follow up at 6.9 & 8.1 months. Common toxicities: diarrhea 80% (gr3 33%), vomiting 40% (gr3 26.7%), nausea 67% (gr3 26.7%) & fatigue 73.3% (gr3 6.7%). Conclusions: This phase II study of docetaxel with lapatinib in advanced urothelial cancer patients failed to provide sufficient efficacy for us to complete full accrual. One patient had a complete response and molecular correlatives may shed light on what may have predisposed to this. Intercurrently, another trial of maintenance lapatinib or placebo after chemotherapy in Her2+ patients reports no benefit (Powles ASCO 2015). Lapatinib alone or in combination is not recommended as therapy in urothelial cancer patients unless new tractable markers of response are developed. Clinical trial information: NCT01382706.