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A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors

Lookup NU author(s): Professor Alastair GreystokeORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.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.

Publication metadata

Author(s): Juric D, Barve M, Vaishampayan U, Roda D, Calvo A, Janez NM, Trigo J, Greystoke A, Harvey RD, Olszanski AJ, Opyrchal M, Spira A, Thistlethwaite F, Jimenez B, Sappal JH, Kannan K, Riley J, Li C, Li C, Gregory RC, Miao H, Wang S

Publication type: Article

Publication status: Published

Journal: Cancer Medicine

Year: 2024

Volume: 13

Issue: 5

Print publication date: 01/03/2024

Online publication date: 19/03/2024

Acceptance date: 22/11/2023

Date deposited: 04/04/2024

ISSN (print): 2045-7634

ISSN (electronic): 2045-7634

Publisher: John Wiley and Sons Inc


DOI: 10.1002/cam4.6776

PubMed id: 38501219


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Funder referenceFunder name
Takeda Development Center Americas, Inc.