Abstract C18: A phase I study of enavatuzumab (PDL192, ABT-361), a first-in-class human monoclonal antibody targeting TWEAK (tumor necrosis factor-like inducer of apoptosis) receptor, in patients (Pts) with advanced solid tumors.

Background: TWEAK receptor (TweakR, TNFRSF12A, CD266) is a member of the TNF receptor superfamily and is expressed on a range of solid tumors. Enavatuzumab is a humanized IgG1 antibody to TweakR that exhibits anti-tumor activity in preclinical models through two mechanisms: direct signaling through TweakR and antibody-dependent cellular cytotoxicity. Methods: This phase I, multicenter study was designed to determine the maximum tolerated dose (MTD) and to evaluate the safety and pharmacokinetic (PK) profiles of enavatuzumab, given intravenously over 60 minutes on days 1 and 15 of each 28-day cycle. Pts with advanced solid tumors; ECOG ≤1; adequate hematologic, renal, and hepatic function; no brain metastasis; no history of cirrhosis or pancreatitis; no recent history of acute cholecystitis; and not on immunosuppressive drugs were enrolled. Cohorts of 3–6 pts were treated at escalating dose levels of enavatuzumab ranging from 0.1 mg/kg to 1.5 mg/kg. Dose limiting toxicity (DLT) was defined as grade (G) 3 AST or ALT lasting >14 days or associated with clinical hepatitis and/or bilirubin ≥G2; G3 amylase or lipase lasting >14 days; ≥G3 bilirubin; any G4 AST, ALT, amylase, or lipase; acute pancreatitis; ≥G3 hematologic and non-hematologic toxicities; G4 cytokine release syndrome (CRS) or G3 CRS despite premedication. MTD was defined as the highest dose level with 0/3 or ≤1 of 6 pts experiencing a first-cycle DLT. PK sampling was performed on cycle 1 day 1 (C1D1), C1D2, C1D8, Day 15 of all cycles, C1D16, C2D1, and C3D1. Response was assessed by RECIST every 8 weeks. Results: Thirty pts [12 male, 18 female; median age 64.5 (range 36–82)] were enrolled at 6 dose levels: 0.1, 0.3, 0.5, 0.7, 1.0, and 1.5 mg/kg. Tumor types included colorectal (15); pancreas (4); ovarian (4); and tongue, cervical, prostate, endometrial, breast, hepatocellular, and thyroid (1 each). Sixteen pts had liver metastases. DLTs included G4 lipase and G3 bilirubin in 1 of 6 pts at the 1.0 mg/kg level and G4 lipase and G4 amylase in 1 pt at the 1.5 mg/kg level. Grade 3/4 toxicities in ≥5% of subjects included fatigue, pneumonia, hyponatremia, hypoxia, dyspnea, and elevated AST, ALT, GGT, lipase, and amylase. There was no apparent correlation of liver or pancreatic enzyme elevation with tumor type or presence of liver metastases. Of the disease evaluable pts, 11 had disease progression as their best response and 2 had stable disease (2 and 4 month duration). Enavatuzumab followed a two-compartment linear PK model. The estimated clearance was 23–33 mL/hr and elimination half-life was 7–18 days. The mean C max after the first dose was 2.0 mcg/mL and 28.1 mcg/mL for the 0.1 mg/kg and 1.0 mg/kg cohorts, respectively. Mean C ss was reached following the second dose and was within the target efficacious peak and trough levels for the 1.0 mg/kg cohort. Conclusions: The MTD for this first-in-class drug was reached at 1.0 mg/kg. Six of 7 pts at 1.0 mg/kg and 1 of 1 pts at 1.5 mg/kg had ≥G3 liver and/or pancreatic enzyme elevations; therefore higher doses are not being tested. The mechanisms of liver and pancreatic enzyme toxicity are currently being investigated and preclinical studies are ongoing to assess potential combination strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C18.