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

Abstract

Purpose: 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).

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.

Keywords: Monoclonal antibody; Solid tumors; TGFβ; TGFβ receptor; Therapy resistance.

Figures

Fig. 1

Patient disposition

Fig. 2

Serum concentration-time profiles of LY3022859 following first (left) and fifth (right) intravenous infusions at doses of 12.5 mg (cohort 1B) or 25 mg (cohort 2) over 3 hours every 2 weeks. Data are presented as arithmetic means (SD) on a semilogarithmic scale