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

Autor:	Juric D; Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA., Barve M; Medical Oncology, Mary Crowley Cancer Research, Dallas, Texas, USA., Vaishampayan U; Internal Medicine/Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA., Roda D; Department of Medical Oncology, University Hospital, Valencia, Spain., Calvo A; Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain., Jañez NM; Department of Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain., Trigo J; Medical Oncology, Hospital Universitario Virgen de la Victoria, Málaga, Spain., Greystoke A; Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Harvey RD; Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA., Olszanski AJ; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA., Opyrchal M; Division of Oncology, Washington University School of Medicine in St Louis, St Louis, Missouri, USA., Spira A; Medical Oncology, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.; Medical Oncology, Virginia Cancer Specialists, US Oncology Research, NEXT Oncology Virginia, Leesburg, Virginia, USA., Thistlethwaite F; Medical Oncology, The Christie NHS Foundation Trust and University of Manchester, Manchester, UK., Jiménez B; Medical Oncology, Hospital Universitario Virgen de la Victoria, Málaga, Spain., Sappal JH; Precision and Translational Medicine, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts, USA., Kannan K; Oncology Therapeutic Area Unit, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts, USA., Riley J; Gastroenterology, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts, USA., Li C; Quantitative Clinical Pharmacology, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts, USA., Li C; Statistical and Quantitative Sciences, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts, USA., Gregory RC; Precision and Translational Medicine, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts, USA., Miao H; Clinical Development, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts, USA., Wang S; Takeda Oncology Clinical Science, Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Cancer medicine [Cancer Med] 2024 Mar; Vol. 13 (5).
DOI:	10.1002/cam4.6776
Abstrakt:	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. (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
Databáze:	MEDLINE
Externí odkaz: