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Abstract Mivavotinib (TAK‐659/CB‐659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti‐PD‐1 therapy in cancer models. This dose‐escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60–100 mg once‐daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28‐day cycles until disease progression or unacceptable toxicity. The dose‐escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple‐negative breast cancer (TNBC). During dose‐escalation (n = 24), two dose‐limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once‐daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment‐emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose‐proportional (60–100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single‐agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. Trial registration ID NCT02834247.