A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies Journal Article


Authors: Harding, J. J.; Do, R. K.; El Dika, I.; Hollywood, E.; Uhlitskykh, K.; Valentino, E.; Wan, P.; Hamilton, C.; Feng, X.; Johnston, A.; Bomalaski, J.; Li, C. F.; O’Reilly, E. M.; Abou-Alfa, G. K.
Article Title: A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies
Abstract: 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. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
Keywords: hepatocellular carcinoma; arginine; folfox; arginine deiminase; adi-peg 20; argininosuccinate synthetase-1
Journal Title: Cancer Chemotherapy and Pharmacology
Volume: 82
Issue: 3
ISSN: 0344-5704
Publisher: Springer  
Date Published: 2018-09-01
Start Page: 429
End Page: 440
Language: English
DOI: 10.1007/s00280-018-3635-3
PROVIDER: scopus
PUBMED: 29971467
DOI/URL:
Notes: Article -- Export Date: 4 September 2018 -- Source: Scopus
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MSK Authors
  1. James Joseph Harding
    66 Harding
  2. Ghassan Abou-Alfa
    225 Abou-Alfa
  3. Kinh Gian Do
    115 Do
  4. Eileen O'Reilly
    321 O'Reilly
  5. Peter Justin Wan
    7 Wan
  6. Imane El Dika
    10 El Dika