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Clinical Trial
. 2022 Jan;11(2):340-347.
doi: 10.1002/cam4.4446. Epub 2021 Nov 28.

Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors

Shuyang Yao  1   2 , Filip Janku  1 , Kimberly Koenig  3 , Apostolia Maria Tsimberidou  1 , Sarina Anne Piha-Paul  1 , Nai Shi  1 , John Stewart  4 , Amanda Johnston  5 , John Bomalaski  5 , Funda Meric-Bernstam  1 , Siqing Fu  1
Affiliations
Clinical Trial

Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors

Shuyang Yao et al. Cancer Med. 2022 Jan.

Abstract

Background: Arginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI-PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI-PEG 20 and PLD in patients with metastatic solid tumors.

Methods: Patients with advanced ASS1-deficient solid tumors were enrolled in this phase 1 trial of ADI-PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI-PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively.

Results: Of 15 enrolled patients, 9 had metastatic HER2-negative breast carcinoma. We observed no dose-limiting toxicities or treatment-related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression-free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti-ADI-PEG 20 antibodies by week 8 in one third of patients.

Conclusion: Concurrent IM injection of ADI-PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1-deficient solid tumors. Further evaluation of this combination is under discussion.

Keywords: ADI-PEG 20; advanced solid tumor; arginine deprivation; argininosuccinate synthetase; breast carcinoma; liposomal doxorubicin.

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Conflict of interest statement

Amanda Johnston and John Bomalaski are employees of Polaris Pharmaceuticals, Inc.

Figures

FIGURE 1
FIGURE 1
A waterfall plot shows best tumor responses in 15 patients with metastatic ASS1 deficient solid tumors treated with ADI‐PEG20 and liposomal doxorubicin
FIGURE 2
FIGURE 2
Kaplan–Meier curves of progression survival (PFS, blue, 3.95 months, 95% confidence interval, 0.86–7.04) and overall survival (OS, red, not evaluable with 11 patients censored) in 15 patients with metastatic ASS1 deficient solid tumors treated with ADI‐PEG20 and liposomal doxorubicin
FIGURE 3
FIGURE 3
Pharmacodynamic changes detected in the plasma obtained from the study patients (n = 15): (A) Median arginine levels in peripheral blood by timepoint; (B) Median citrulline levels in peripheral blood by timepoint; (C) Anti‐ADI‐PEG20 antibody levels in peripheral blood by timepoint
See this image and copyright information in PMC

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