Phase I Trials of Anti-ENPP3 Antibody-Drug Conjugates in Advanced Refractory Renal Cell Carcinomas

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
John A ThompsonChristian K Kollmannsberger

Abstract

Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody-drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC).Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary-derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks.Results: The AGS-16M8F study (n = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7-83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was det...Continue Reading

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Citations

Jun 5, 2019·Marine Drugs·David J Newman
Mar 21, 2020·SLAS Discovery·Laurence Gauzy-LazoMarie-Priscille Brun
Sep 3, 2020·Future Oncology·Semira SheikhSuzanne Trudel
Feb 13, 2020·Current Oncology Reports·Shuchi Gulati, Ulka Vaishampayan
Jan 14, 2021·Nature Reviews. Clinical Oncology·David A BraunToni K Choueiri
Dec 20, 2020·Biochemical Pharmacology·Gennady G Yegutkin
Mar 5, 2020·Seminars in Nephrology·David C Yang, Ching-Hsien Chen
Jun 26, 2021·Pharmacology & Therapeutics·Yiming JinAndrew J Wiemer
Sep 2, 2021·Clinical Pharmacology and Therapeutics·Geraldine Ferron-BradyRoxanne C Jewell
Jul 30, 2020·Anti-cancer Agents in Medicinal Chemistry·Suresh MadheswaranStefan Barth

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