PMID- 29971467 OWN - NLM STAT- MEDLINE DCOM- 20190809 LR - 20191114 IS - 1432-0843 (Electronic) IS - 0344-5704 (Print) IS - 0344-5704 (Linking) VI - 82 IP - 3 DP - 2018 Sep TI - A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies. PG - 429-440 LID - 10.1007/s00280-018-3635-3 [doi] AB - PURPOSE: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. METHODS: This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m(2) (Cohort 2 and RP2D expansion). RESULTS: Twenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m(2) weekly with mFOLFOX6. The most common any grade adverse events (AEs) were thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among the 23 HCC patients, the most frequent treatment-related Grade >/= 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%). The ORR for this group was 21% (95% CI 7.5-43.7). Median PFS and OS were 7.3 and 14.5 months, respectively. Arginine levels were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. Arginine depletion at 4 and 8 weeks and archival tumoral argininosuccinate synthetase-1 levels did not correlate with response. CONCLUSIONS: Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m(2) weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients. FAU - Harding, James J AU - Harding JJ AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hardinj1@mskcc.org. AD - Weill Cornell Medical College, New York, NY, USA. Hardinj1@mskcc.org. AD - Department of Medicine, Gastrointestinal Oncology Service, 300 East 66th Street, New York, NY, 10065, USA. Hardinj1@mskcc.org. FAU - Do, Richard K AU - Do RK AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Weill Cornell Medical College, New York, NY, USA. FAU - Dika, Imane El AU - Dika IE AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Hollywood, Ellen AU - Hollywood E AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Uhlitskykh, Khrystyna AU - Uhlitskykh K AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Valentino, Emily AU - Valentino E AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Wan, Peter AU - Wan P AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Hamilton, Casey AU - Hamilton C AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Feng, Xiaoxing AU - Feng X AD - Polaris Pharmaceuticals, Inc., San Diego, CA, USA. FAU - Johnston, Amanda AU - Johnston A AD - Polaris Pharmaceuticals, Inc., San Diego, CA, USA. FAU - Bomalaski, John AU - Bomalaski J AD - Polaris Pharmaceuticals, Inc., San Diego, CA, USA. FAU - Li, Chien-Feng AU - Li CF AD - Chi Mei Medical Center, Tainan, Taiwan, Republic of China. FAU - O'Reilly, Eileen M AU - O'Reilly EM AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Weill Cornell Medical College, New York, NY, USA. FAU - Abou-Alfa, Ghassan K AU - Abou-Alfa GK AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Weill Cornell Medical College, New York, NY, USA. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180703 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Biomarkers, Tumor) RN - 0 (Organoplatinum Compounds) RN - 3WJQ0SDW1A (Polyethylene Glycols) RN - EC 3.- (Hydrolases) RN - EC 3.5.3.6 (ADI PEG20) RN - Q573I9DVLP (Leucovorin) RN - U3P01618RT (Fluorouracil) RN - Folfox protocol MH - Adult MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/*adverse effects MH - Biomarkers, Tumor/analysis MH - Carcinoma, Hepatocellular/diagnostic imaging/*drug therapy MH - Female MH - Fluorouracil/administration & dosage/adverse effects MH - Gastrointestinal Neoplasms/*drug therapy MH - Humans MH - Hydrolases/administration & dosage/adverse effects MH - Leucovorin/administration & dosage/adverse effects MH - Liver Neoplasms/diagnostic imaging/*drug therapy MH - Male MH - Middle Aged MH - Organoplatinum Compounds/administration & dosage/adverse effects MH - Polyethylene Glycols/administration & dosage/adverse effects MH - Progression-Free Survival PMC - PMC6850802 MID - NIHMS1050078 OTO - NOTNLM OT - ADI-PEG 20 OT - Arginine OT - Arginine deiminase OT - Argininosuccinate synthetase-1 OT - FOLFOX OT - Hepatocellular carcinoma COIS- Conflict of interest Xiaoxing Feng, Amanda Johnston, and John Bomalaski are employees of Polaris Pharmaceuticals Inc. There are no other conflicts of interest. EDAT- 2018/07/05 06:00 MHDA- 2019/08/10 06:00 PMCR- 2019/11/12 CRDT- 2018/07/05 06:00 PHST- 2018/04/16 00:00 [received] PHST- 2018/06/27 00:00 [accepted] PHST- 2018/07/05 06:00 [pubmed] PHST- 2019/08/10 06:00 [medline] PHST- 2018/07/05 06:00 [entrez] PHST- 2019/11/12 00:00 [pmc-release] AID - 10.1007/s00280-018-3635-3 [pii] AID - 10.1007/s00280-018-3635-3 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2018 Sep;82(3):429-440. doi: 10.1007/s00280-018-3635-3. Epub 2018 Jul 3.