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

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.

Keywords: TNBC; immunotherapy; mivavotinib; phase Ib; solid tumors.

FIGURE 1

(A) Tumor growth inhibition curves for single and combination therapy of mivavotinib and anti‐PD‐1 in the CT26 syngeneic mouse tumor model. (B) Tumor rechallenge. (C) Pharmacodynamic assessment. M1/M2, M1/M2 macrophages; PD‐1, programmed death‐1 receptor; TNFa, tumor necrosis factor alfa. *p ≤ 0.05, **p ≤ 0.01, and ***p ≤ 0.001. One‐Way ANOVA with Dunnett's multiple comparisons test, with a single pooled variance.

FIGURE 2

Change from screening to day 15 in (A) CD4, CD8 and Treg cells expression, (B) memory T cells and PD‐L1 positivity, (C) monocytes, B cells and PD‐L1 expression, assessed by multiplex fluorescence immunohistochemistry of paired tumor biopsies from one patient with TNBC treated with single‐agent mivavotinib. Change from screening to day 15 in (D) tumoral T cells, (E) monocytes, NK cells, and B cells, and (F) CD68+ monocytes/macrophages, assessed by multiplex fluorescence immunohistochemistry of paired tumor biopsies from three TNBC patients in the expansion phase. C, cycle; D, day; H&E, hematoxylin and eosin staining; NK, natural killer; PanCK, pan‐cytokeratin; PD‐L1, programmed death‐ligand 1; TNBC, triple‐negative breast cancer; Treg, regulatory T cells.

FIGURE 3

Changes in peripheral T cells, B cells, and monocytes in patients treated with mivavotinib and nivolumab assessed by flow cytometry. C, cycle; D, day; EOT, end of treatment; SCR, screening; Treg, regulatory T cells.

FIGURE 4

Mean (SD) plasma mivavotinib concentration–time profiles after a single‐dose of mivavotinib on (A) day 1 of cycle 1 and after multiple‐dose administration on (B) day 15 of cycle 1 in patients receiving mivavotinib at 60 mg, 80 mg, or 100 mg QD in combination with nivolumab 3 mg/kg. QD, once daily; SD, standard deviation. Plasma concentrations below the lower limit of quantification of the assay (<0.5 ng/mL) were recorded as zero.