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

• Published in: Clinical Cancer Research Vol. 24; no. 18; pp. 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: Journal Article
• Language: English
• Published: United States American Association for Cancer Research (AACR) 15.09.2018
• Subjects: Aged; Aged, 80 and over; Animals; Antibodies, Anti-Idiotypic; Antibodies, Anti-Idiotypic - administration & dosage; Antibodies, Anti-Idiotypic - adverse effects; Carcinoma, Renal Cell; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Female; Humans; Immunoconjugates; Immunoconjugates - administration & dosage; Immunoconjugates - adverse effects; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Oligopeptides; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Phosphoric Diester Hydrolases; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - immunology; Pyrophosphatases; Pyrophosphatases - genetics; Pyrophosphatases - immunology
• DOI: 10.1158/1078-0432.ccr-18-0481
• ISSN: 1078-0432; 1557-3265

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 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). Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. Clin Cancer Res; 24(18); 4399–406. ©2018 AACR.