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

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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.

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Acknowledgements

We would like to thank Marinela Capanu for her critical review of the manuscript.

Funding

The trial was funded by Polaris Pharmaceuticals, Inc. This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

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Authors and Affiliations

  1. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    James J. Harding, Richard K. Do, Imane El Dika, Ellen Hollywood, Khrystyna Uhlitskykh, Emily Valentino, Peter Wan, Casey Hamilton, Eileen M. O’Reilly & Ghassan K. Abou-Alfa

  2. Weill Cornell Medical College, New York, NY, USA

    James J. Harding, Richard K. Do, Eileen M. O’Reilly & Ghassan K. Abou-Alfa

  3. Polaris Pharmaceuticals, Inc., San Diego, CA, USA

    Xiaoxing Feng, Amanda Johnston & John Bomalaski

  4. Chi Mei Medical Center, Tainan, Taiwan, Republic of China

    Chien-Feng Li

  5. Department of Medicine, Gastrointestinal Oncology Service, 300 East 66th Street, New York, NY, 10065, USA

    James J. Harding

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  1. James J. Harding
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  2. Richard K. Do
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  14. Ghassan K. Abou-Alfa
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Correspondence to James J. Harding.

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Conflict of interest

Xiaoxing Feng, Amanda Johnston, and John Bomalaski are employees of Polaris Pharmaceuticals Inc. There are no other conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Harding, J.J., Do, R.K., Dika, I.E. et al. A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies. Cancer Chemother Pharmacol 82, 429–440 (2018). https://doi.org/10.1007/s00280-018-3635-3

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