RESUMEN
PURPOSE: LY3022859 is an anti-TGFßRII IgG1 monoclonal antibody that inhibits receptor-mediated signaling activation. The primary objective of this phase I study was to determine a phase II dose in patients with advanced solid tumors. Secondary objectives were to assess safety and pharmacokinetics (PK). METHODS: LY3022859 was infused intravenously (IV) at 1.25 mg/kg over 1 h every 2 weeks (Q2W) (cohort 1A) and at flat doses of 12.5 mg (cohort 1B) and 25 mg (cohort 2) over 3 h Q2W. RESULTS: Fourteen patients were enrolled in cohorts 1A (n = 2), 1B (n = 5), and 2 (n = 7). DLTs were experienced by both patients in cohort 1A (infusion-related reaction) and 2 patients in cohort 2 (cytokine release syndrome and infusion-related reaction). No MTD was determined. At the 25 mg dose level (cohort 2), after fifth infusion, LY3022859 had a short t1/2 (4.37-7.80 h) and rapid clearance (CLss, 0.412 L/h). Exposure increased twofold (from 28.5 to 60.2 µg·h/mL) with increase in dose from 12.5 to 25 mg. No accumulation was observed after repeat administration. CONCLUSIONS: The MTD for LY3022859 was not determined. Dose escalation beyond 25 mg was considered unsafe due to worsening symptoms (uncontrolled cytokine release) despite prophylaxis (corticosteroids and antihistamines). TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01646203.