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/m2 (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/m2 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/m2 weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients.
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/m2 (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/m2 weekly with mFOLFOX6. The most common any grade adverse events (AEs) were thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among the 23 HCCpatients, 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/m2 weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCCpatients.
Authors: G K Abou-Alfa; S Qin; B-Y Ryoo; S-N Lu; C-J Yen; Y-H Feng; H Y Lim; F Izzo; M Colombo; D Sarker; L Bolondi; G Vaccaro; W P Harris; Z Chen; R A Hubner; T Meyer; W Sun; J J Harding; E M Hollywood; J Ma; P J Wan; M Ly; J Bomalaski; A Johnston; C-C Lin; Y Chao; L-T Chen Journal: Ann Oncol Date: 2018-06-01 Impact factor: 32.976
Authors: Chun A Changou; Yun-Ru Chen; Li Xing; Yun Yen; Frank Y S Chuang; R Holland Cheng; Richard J Bold; David K Ann; Hsing-Jien Kung Journal: Proc Natl Acad Sci U S A Date: 2014-08-13 Impact factor: 11.205
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162
Authors: Linda J Nicholson; Paul R Smith; Louise Hiller; Peter W Szlosarek; Christopher Kimberley; Jalid Sehouli; Dominique Koensgen; Alexander Mustea; Peter Schmid; Tim Crook Journal: Int J Cancer Date: 2009-09-15 Impact factor: 7.396
Authors: Josep M Llovet; Sergio Ricci; Vincenzo Mazzaferro; Philip Hilgard; Edward Gane; Jean-Frédéric Blanc; Andre Cosme de Oliveira; Armando Santoro; Jean-Luc Raoul; Alejandro Forner; Myron Schwartz; Camillo Porta; Stefan Zeuzem; Luigi Bolondi; Tim F Greten; Peter R Galle; Jean-François Seitz; Ivan Borbath; Dieter Häussinger; Tom Giannaris; Minghua Shan; Marius Moscovici; Dimitris Voliotis; Jordi Bruix Journal: N Engl J Med Date: 2008-07-24 Impact factor: 91.245
Authors: Peter W Szlosarek; Jeremy P Steele; Luke Nolan; David Gilligan; Paul Taylor; James Spicer; Michael Lind; Sankhasuvra Mitra; Jonathan Shamash; Melissa M Phillips; Phuong Luong; Sarah Payne; Paul Hillman; Stephen Ellis; Teresa Szyszko; Gairin Dancey; Lee Butcher; Stephan Beck; Norbert E Avril; Jim Thomson; Amanda Johnston; Marianne Tomsa; Cheryl Lawrence; Peter Schmid; Timothy Crook; Bor-Wen Wu; John S Bomalaski; Nicholas Lemoine; Michael T Sheaff; Robin M Rudd; Dean Fennell; Allan Hackshaw Journal: JAMA Oncol Date: 2017-01-01 Impact factor: 31.777
Authors: Jennifer X Ji; Dawn R Cochrane; Basile Tessier-Cloutier; Shary Yutin Chen; Germain Ho; Khyatiben V Pathak; Isabel N Alcazar; David Farnell; Samuel Leung; Angela Cheng; Christine Chow; Shane Colborne; Gian Luca Negri; Friedrich Kommoss; Anthony Karnezis; Gregg B Morin; Jessica N McAlpine; C Blake Gilks; Bernard E Weissman; Jeffrey M Trent; Lynn Hoang; Patrick Pirrotte; Yemin Wang; David G Huntsman Journal: Clin Cancer Res Date: 2020-05-14 Impact factor: 12.531
Authors: Jeremy P H Chow; Yijun Cai; Daniel T L Chow; Steven H K Chung; Ka-Chun Chau; Ka-Ying Ng; Oscar M Leung; Raymond M H Wong; Alan W L Law; Yu-On Leung; Sui-Yi Kwok; Yun-Chung Leung Journal: PLoS One Date: 2020-04-30 Impact factor: 3.240