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

• Published in: Clinical cancer research 2018-09, Vol.24 (18), p.4399-4406
• Main Authors: Thompson, John A, Motzer, Robert J, Molina, Ana M, Choueiri, Toni K, Heath, Elisabeth I, Redman, Bruce G, Sangha, Randeep S, Ernst, D Scott, Pili, Roberto, Kim, Stella K, Reyno, Leonard, Wiseman, Aya, Trave, Fabio, Anand, Banmeet, Morrison, Karen, Doñate, Fernando, Kollmannsberger, Christian K
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Animals; Antibodies, Anti-Idiotypic - administration & dosage; Antibodies, Anti-Idiotypic - adverse effects; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Female; Humans; Immunoconjugates - administration & dosage; Immunoconjugates - adverse effects; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - immunology; Pyrophosphatases - genetics; Pyrophosphatases - immunology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-0481

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). 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. The AGS-16M8F study ( = 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 ( = 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 determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100-143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5-141 weeks). AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. .