A phase I trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies

摘要: A phase I dose escalation study was performed to determine the maximum tolerated (MTD) of intercalated dosing BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. Patients received fixed doses P (200 mg/m2) C (AUC 6 mg/mL min) q21 days BMS-690514 (Days 4–19) starting at 100 mg/day increasing by 50 mg/day using 3 + 3 design until MTD reached. Twenty additional patients were enrolled expansion cohort recommended II (RP2D). The reached 150 mg/day. DLTs grade 3 thrombosis 100 mg (1 patient) diarrhea 150 mg 200 mg (2 patients). Serious adverse events (AEs) occurring 20/37 neutropenia (n = 5), (n = 4), pulmonary embolism (n = 3), simultaneous dehydration, acute renal failure, febrile (n = 2). BMS-690514-related AEs (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), anorexia (30 %). There no treatment-related deaths. Sequential intermittent administration PC did not affect PK BMS-690514. Of 32 evaluable for efficacy, there 12 partial responses including five non-small-cell lung cancer stable disease. BMS-609514 This approach tolerable manageable toxicities antitumor activity variety tumor types.