A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors.
Dejan JuricMinal BarveUlka N VaishampayanDesamparados RodaAitana CalvoNoelia Martinez JañezJose TrigoAlastair GreystokeR Donald HarveyAnthony J OlszanskiMateusz OpyrchalAlexander SpiraFiona ThistlethwaiteBegoña JiménezJessica Huck SappalKaruppiah KannanJason RileyCheryl LiCong LiRichard C GregoryHarry MiaoShining WangPublished in: Cancer medicine (2024)
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.
Keyphrases
- phase ii
- open label
- clinical trial
- end stage renal disease
- chronic kidney disease
- newly diagnosed
- phase iii
- ejection fraction
- acute myeloid leukemia
- physical activity
- peritoneal dialysis
- tyrosine kinase
- randomized controlled trial
- study protocol
- healthcare
- high resolution
- papillary thyroid
- high dose
- young adults
- patient reported outcomes
- bone marrow
- lymph node metastasis
- palliative care
- childhood cancer
- smoking cessation
- cone beam