In the dose-escalation cohort, a “3 + 3 + 3” design was applied. The starting dose in cohort 1 was ADI-PEG 20 at 36 mg/m2 weekly, which represented 100% of the typical dose, and 1 mg/kg pembrolizumab every three weeks, which was 50% of the USA FDA approval dose for melanoma.19 The safety of ADI-PEG 20 at this dose has been demonstrated either as monotherapy or in combination with chemotherapy.1–9 The first subject received two drugs on the same day with a week of safety follow up before the next 2 subjects were to be enrolled. Dose-limiting toxicities (DLTs) were assessed during the first cycle. Without any DLT occurring, the enrollment would escalate into cohort 2, with pembrolizumab increased to 200 mg. In all cohorts, if 1/3 had reported a DLT, additional enrollment of 3 patients was required for up to two times. If the DLT rate occurred in 2/3, 3/6, 3/9, or more, the cohort would meet the maximum administered dose and require de-escalation for MTD search.

After dose determination, up to 20 subjects could be enrolled into an expansion MTD cohort with the additional criteria of pre-treatment tissue confirming low PD-L1, defined as ≤49% expression by immunohistochemical (IHC) staining (Dako 22C3 pharmDx). The subjects first received ADI-PEG 20 monotherapy on days 1, 8 and 15. The subjects underwent re-biopsy 24–28 h after the 3rd dose of ADI-PEG 20, followed by administration of pembrolizumab. Subjects then continued on the scheduled regimen. Baseline tomography images for tumor assessment were conducted, and then every 9 weeks while on treatment. Subjects received the combination regimen for up to 24 weeks if the tumor showed stable disease (SD) or better, then ADI-PEG 20 monotherapy after 24 weeks. RECIST 1.1 was used for determining progressive disease (PD) and study drug discontinuation. Subjects with PD might remain on study upon investigators’ decision and if PD was not confirmed in 4 to 6 weeks with repeat imaging.

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