First-in-human study to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-CD27L antibody-drug conjugate AMG 172 in patients with relapsed/refractory renal cell carcinoma

  • Cancer Chemother Pharmacol. 2019 Jun;83(6):1057-1063. doi: 10.1007/s00280-019-03796-4.
Christophe Massard  1 ,  Jean-Charles Soria  2 ,  Jürgen Krauss  3 ,  Michael Gordon  4 ,  Albert Craig Lockhart  5 ,  Erik Rasmussen  6 ,  Vijay V Upreti  7 ,  Sonal Patel  7 ,  Gataree Ngarmchamnanrith  6 ,  Haby Henary  6
Affiliations
  • 1. Drug Development Department (DITEP), Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France. [email protected].
  • 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.
PMID: 30915497 DOI: 10.1007/s00280-019-03796-4
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.

Keywords
AMG 172; Antibody-drug conjugate; CD27L; CcRCC; Pharmacokinetics; Phase 1.
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