Phase 1 Trials of anti-ENPP3 antibody drug conjugates in advanced refractory renal cell carcinomas

Purpose: To determine the safety, pharmacokinetics, and recommendedphase2 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). Experimental Design: Two phase 1 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/kguntil unacceptable toxicity or progression. The study was terminated before reaching the maximum tolerated dose (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 remission (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 de-escalations. 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 (8) 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.

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