A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors

• DOI: 10.1007/s00280-017-3245-5
• Publication Date: 2017-03-09T00:52:28Z
• Authors: Anthony W. Tolcher; Jordan D. Berlin; Jan Cosaert; John Kauh; Emily Chan; Sarina A. Piha-Paul; Alex Amaya; Shande Tang; Kyla Driscoll; Richard Kimbung; S. R. Prasad Kamb...; Ivelina Gueorguieva; David S. Hong
• Keywords: Cytokine Release Syndrome

LY3022859 is an anti-TGFβRII 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).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.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.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).clinicaltrials.gov Identifier: NCT01646203.