Background: TAK-659 is an investigational, reversible, potent dual inhibitor of SYK and FLT-3. In ongoing early-phase studies (NCT02000934; NCT02323113), TAK-659 demonstrated an acceptable pharmacokinetic and safety profile, with evidence of preliminary activity in pts with DLBCL, follicular lymphoma, CLL, and AML (Kaplan et al. Blood 2016;128:624/2834). In preclinical studies, TAK-659 in combination with nivolumab, an anti-PD-1 checkpoint inhibitor, resulted in loss of myeloid suppressor cells (MDSCs), increased T-cell activation, and complete tumor growth suppression (Kannan et al. Eur J Cancer 2016;69:S92). This first-in-human combination study will investigate the efficacy and safety of TAK-659 and nivolumab in pts with advanced solid tumors. Methods: This open-label, multicenter, phase 1b study (NCT02834247) will include dose-escalation and expansion phases. Pts with advanced solid tumors who have failed ≥1 prior lines of therapy and have no effective therapeutic options available by investigator assessment will be eligible for the dose-escalation phase. Pts will receive oral TAK-659 at doses of 60–100 mg QD in a standard 3+3 schema, plus nivolumab 3 mg IV on days 1 and 15 of 28-day cycles. The expansion phase at the recommended phase 2 dose (RP2D) will include 3 cohorts of pts with relapsed/refractory metastatic triple-negative breast cancer, locally advanced/metastatic NSCLC, or locally advanced/metastatic head and neck squamous cell carcinoma (n = 30 response-evaluable pts in each cohort; 24 naïve, 6 relapsed/refractory to prior anti-PD-1/PD-L1 therapy). Ten pts in each cohort will receive 2 weeks of single-agent TAK-659 before starting combination therapy; the other 20 pts will receive combination therapy throughout. The primary endpoints are maximum tolerated dose/RP2D (dose-escalation phase) and overall response rate by investigator per RECIST v1.1 (expansion phase). Secondary endpoints include adverse events, disease control rate, duration of response, progression-free survival, overall survival, and TAK-659 pharmacokinetics. There are currently 7 pts enrolled; recruitment to the 100 mg dose-escalation cohort is ongoing. Clinical trial information: NCT02834247