Final results of phase II trial of pegylated arginine deiminase (ADI-PEG20) in metastatic melanoma (MM).

Abstract

8528 Background: ADI-PEG20 catabolizes arginine (Arg), a nonessential amino acid in human adults, to citrulline and ammonia. Tumor cells which lack argininosuccinate synthetase (ASS) are unable to synthesize Arg which can lead to cell death. A phase I/II trial of ADI- PEG20 showed activity in MM (JCO 23:7660) and the optimum biologic dose (OBD) was considered to be 160 IU/m2/week which lowered blood Arg to nondetectable levels. In this phase II study, we obtained tumor samples, when accessible, for ASS staining prior to therapy in patients (pts) with MM and correlated the ASS staining with tumor response. Methods: MM pts were treated with ADI- PEG20 (provided by Polaris, Inc.) at 160-320 IU/m2 I.M. weekly. Tumor measurements were done every 8 weeks. Pretreatment tumor samples were available in 26 pts for ASS staining by immunohistochemistry and/or real time PCR. Results: 36 pts were evaluable for response. 4 (11%) had tumor shrinkage at > 30%, 4 had minor response (< 30% shrinkage), 2 had stable disease and 4 had mixed response. ASS staining correlated with tumor response: for the 16 pts with ASS(−) tumors, 3 (19%) had response and clinical benefit (partial response, minor response and stable disease) was noted in 8 (50%). Including mixed responses, 10/16 (63%) with ASS (−) tumors showed some evidence of antitumor effect, while only 1 of 10 pts had stable disease when tumor was ASS (+) (P value = 0.01). Response also correlated with the dose of ADI-PEG20, independent of ASS staining. Of 20 pts treated with 320 IU/m2/week, 4 had response, while no pt had response when dosage was < 320 IU/m2/week. Toxicity was uncommon, consisting mainly of discomfort at the injection site. Repeat biopsies were done in 2 ASS(−) pts and found to be positive at the time of relapse. This finding also was seen in the laboratory in certain melanoma cell lines in which ASS can be induced upon repeated exposure to ADI-PEG20/Arg deprivation (MCT 12:3223,2009). Conclusions: This is the first study using Arg depleting therapy with ADI-PEG20 to show correlation of response with ASS (−) staining. Future studies with ADI-PEG20 should target only MM pts with ASS(−) tumors. Furthermore, the dose required for response in certain MM pts may exceed the OBD. Supported by RO1CA109578. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Polaris