Study Procedures and Assessments
tumor, DLTs, Tumor
TUMOR, TUMOR, CPS, BLOOD, TUMOR STROMAL
The tolerability of each cohort was assessed mainly by the incidence of DLTs during cycle 1 of phase Ib. DLTs were treatment-related TEAEs/toxicities listed in Blood samples for pharmacokinetic analyses of E7389-LF were collected predose, 5 minutes, 0.5, 1, 2, 4, 6, 8, 24, 72, and 168 hours after the end of the infusion on cycle 1 day 1 (cycle # day #; C#D#). Plasma concentrations of eribulin were measured by a validated LC/MS-MS method. For nivolumab, blood samples were collected predose and postdose (just before completion of infusion) on C1D1, predose on C2D1, C3D1, and C4D1, predose and postdose on C5D1, and predose on C9D1 and C13D1. For the every-2-weeks dosing schedule, predose samples on C1D15 and C5D15 were also taken. Serum concentrations of nivolumab were measured by validated electrochemiluminescence immunoassay. For the biomarker analyses, blood samples were collected as follows: for the every-2-weeks schedule, blood samples were collected predose on C1D1, C1D8, C1D15, C1D22, each day 1 of cycle 2 and subsequent cycles (until cycle 7) and off-treatment. For the every-3-weeks schedule, samples were collected predose on C1D1, C1D8, C1D15, each day 1 of cycle 2 and subsequent cycles (until cycle 9) and off-treatment. Biomarkers were investigated with Angiogenesis MAP, Multiplex, and Simoa systems.For efficacy analyses, tumor assessments were conducted by the investigator using RECIST version 1.1 (RECIST v1.1) every 6 weeks, at the off-treatment visit, and if clinically indicated.Tumor biopsies were conducted at screening and on C2D1. Samples were used to investigate PD-L1 expression [by an approved IHC 28-8 pharmDx assay (Agilent Dako, Agilent Technologies)], assess PD-L1 combined positive score (CPS; %) based on PD-L1 expression in viable tumor cells and immune cells and categorize immune phenotypes (by panCK/CD8 IHC analysis). For the determination of immune phenotype, panCK-CD8 was scored by a pathologist according to the density proportion score (DPS). The DPS creates a distribution of inflammatory cell densities within a tumor ranging from areas with few or no inflammatory cells to regions densely populated with inflammatory cells. The DPSs for stained immune cells were assessed in two compartments: tumor stroma and tumor epithelial nests. The definition and terminology of phenotype classification were modified from those used in the ABACUS (