Christophe Massard1, Jean-Charles Soria2, Jürgen Krauss3, Michael Gordon4, Albert Craig Lockhart5, Erik Rasmussen6, Vijay V Upreti7, Sonal Patel7, Gataree Ngarmchamnanrith6, Haby Henary6. 1. Drug Development Department (DITEP), Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France. christophe.massard@gustaveroussy.fr. 2. Drug Development Department (DITEP), Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France. 3. Department of Medical Oncology, National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. 4. HonorHealth Research Institute, 9055 E Del Camino Dr. #100, Scottsdale, AZ, 85258, USA. 5. Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW 12th Ave, Miami, FL, 33136, USA. 6. Amgen Inc., Thousand Oaks, CA, 91320, USA. 7. Amgen Inc., South San Francisco, CA, 94080, USA.
Abstract
PURPOSE: This study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-CD27L antibody-drug conjugate AMG 172 in patients with relapsed/refractory clear cell renal cell carcinoma (ccRCC). METHODS: This was an open-label, adaptive dose-exploration study in patients with relapsed/refractory ccRCC. The study was conducted in two parts for dose exploration and dose expansion on a biweekly dosing schedule. AMG 172 doses of 0.15, 0.3, 0.6, 1.2, 1.6, 1.8, and 2.4 mg/kg were studied in the dose-exploration phase. RESULTS: The 1.6 mg/kg dose of AMG 172 was identified as the maximum tolerated dose (MTD). The most common adverse events were thrombocytopenia (59%), nausea (54%), decreased appetite (49%), vomiting (46%), and fatigue (35%). The most common dose-limiting toxicity (DLT) was thrombocytopenia. Thrombocytopenia and liver injury constituted DLTs that required discontinuation of treatment. Of the 10 patients treated at the MTD in part 2 of the study, 2 patients had grade 3 hepatocellular injury with aspartate aminotransferase or alanine aminotransferase elevation. Pharmacokinetic profiles indicated low levels of circulating unconjugated antibody and unconjugated cytotoxin. Dose-proportional increases in plasma exposure were observed over the dose range of 0.3-2.4 mg/kg. Following multiple biweekly doses, plasma accumulation was less than two-fold. Two patients (5.4%) had a partial response, 6 patients (16.2%) had stable disease, and 13 patients (35.1%) had progressive disease. CONCLUSION: AMG 172 exhibited a favorable pharmacokinetic profile in patients with relapsed/refractory ccRCC and showed evidence suggestive of limited antitumor activity. Safety and tolerability were as expected for a maytansinoid antibody-drug conjugate.
PURPOSE: This study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-CD27L antibody-drug conjugate AMG 172 in patients with relapsed/refractory clear cell renal cell carcinoma (ccRCC). METHODS: This was an open-label, adaptive dose-exploration study in patients with relapsed/refractory ccRCC. The study was conducted in two parts for dose exploration and dose expansion on a biweekly dosing schedule. AMG 172 doses of 0.15, 0.3, 0.6, 1.2, 1.6, 1.8, and 2.4 mg/kg were studied in the dose-exploration phase. RESULTS: The 1.6 mg/kg dose of AMG 172 was identified as the maximum tolerated dose (MTD). The most common adverse events were thrombocytopenia (59%), nausea (54%), decreased appetite (49%), vomiting (46%), and fatigue (35%). The most common dose-limiting toxicity (DLT) was thrombocytopenia. Thrombocytopenia and liver injury constituted DLTs that required discontinuation of treatment. Of the 10 patients treated at the MTD in part 2 of the study, 2 patients had grade 3 hepatocellular injury with aspartate aminotransferase or alanine aminotransferase elevation. Pharmacokinetic profiles indicated low levels of circulating unconjugated antibody and unconjugated cytotoxin. Dose-proportional increases in plasma exposure were observed over the dose range of 0.3-2.4 mg/kg. Following multiple biweekly doses, plasma accumulation was less than two-fold. Two patients (5.4%) had a partial response, 6 patients (16.2%) had stable disease, and 13 patients (35.1%) had progressive disease. CONCLUSION:AMG 172 exhibited a favorable pharmacokinetic profile in patients with relapsed/refractory ccRCC and showed evidence suggestive of limited antitumor activity. Safety and tolerability were as expected for a maytansinoid antibody-drug conjugate.
Authors: Tal Flieswasser; Astrid Van den Eynde; Jonas Van Audenaerde; Jorrit De Waele; Filip Lardon; Carsten Riether; Hans de Haard; Evelien Smits; Patrick Pauwels; Julie Jacobs Journal: J Exp Clin Cancer Res Date: 2022-01-06