A phase 1/1B trial of ADI‐PEG 20 plus nab‐paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma

BACKGROUND ADI‐PEG 20 is a pegylated form of the arginine‐depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI‐PEG 20 selectively targets malignant cells, which lack ASS1. METHODS A single‐arm, nonrandomized, open‐label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose‐escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/m2) and nab‐paclitaxel (125 mg/m2) for 3 of 4 weeks and intramuscular ADI‐PEG 20 at 18 mg/m2 weekly (cohort 1) or at 36 mg/m2 weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI‐PEG 20 in combination with nab‐paclitaxel and gemcitabine. RESULTS Eighteen patients were enrolled. No dose‐limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI‐PEG 20 was 36 mg/m2 weekly in combination with standard‐dose gemcitabine and nab‐paclitaxel. The overall response rate among patients treated at the RP2D in the first‐line setting was 45.5% (5 of 11).The median progression‐free survival time for these patients treated at the RP2D was 6.1 months (95% confidence interval, 5.3‐11.2 months), and the median overall survival time was 11.3 months (95% confidence interval, 6.7 months to not reached). CONCLUSIONS ADI‐PEG 20 was well tolerated in combination with gemcitabine and nab‐paclitaxel. Activity was observed in previously treated and untreated patients with advanced pancreatic cancer and in patients with ASS1‐deficient and ‐proficient tumors. Cancer 2017;123:4556‐4565. © 2017 American Cancer Society. The combination of gemcitabi