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Erschienen in: Cancer Chemotherapy and Pharmacology 3/2018

03.07.2018 | Original Article

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

verfasst von: James J. Harding, Richard K. Do, Imane El Dika, Ellen Hollywood, Khrystyna Uhlitskykh, Emily Valentino, Peter Wan, Casey Hamilton, Xiaoxing Feng, Amanda Johnston, John Bomalaski, Chien-Feng Li, Eileen M. O’Reilly, Ghassan K. Abou-Alfa

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2018

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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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Metadaten
Titel
A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies
verfasst von
James J. Harding
Richard K. Do
Imane El Dika
Ellen Hollywood
Khrystyna Uhlitskykh
Emily Valentino
Peter Wan
Casey Hamilton
Xiaoxing Feng
Amanda Johnston
John Bomalaski
Chien-Feng Li
Eileen M. O’Reilly
Ghassan K. Abou-Alfa
Publikationsdatum
03.07.2018
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 3/2018
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3635-3

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