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

Autor: Shuyang Yao, Funda Meric-Bernstam, Amanda Johnston, Nai Shi, John S. Bomalaski, Kimberly Koenig, Filip Janku, Siqing Fu, Sarina Anne Piha-Paul, John Stewart, Apostolia Maria Tsimberidou
Rok vydání: 2021
Předmět:
Adult
Male
Cancer Research
medicine.medical_specialty
Arginine
Hydrolases
Argininosuccinate synthase
Kaplan-Meier Estimate
Argininosuccinate Synthase
Gastroenterology
Polyethylene Glycols
Neoplasms
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Radiology
Nuclear Medicine and imaging
Doxorubicin
breast carcinoma
arginine deprivation
Research Articles
RC254-282
biology
business.industry
Clinical Cancer Research
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Common Terminology Criteria for Adverse Events
Middle Aged
Progression-Free Survival
Survival Rate
advanced solid tumor
liposomal doxorubicin
Oncology
Tolerability
Response Evaluation Criteria in Solid Tumors
Toxicity
Cancer cell
biology.protein
argininosuccinate synthetase
Female
business
ADI‐PEG 20
Research Article
medicine.drug
Zdroj: Cancer Medicine, Vol 11, Iss 2, Pp 340-347 (2022)
Cancer Medicine
ISSN: 2045-7634
Popis: 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.
This combination therapy with ADI‐PEG 20 and Doxil had a reversible and manageable toxicity profile, and patients tolerated the treatment. Tumor shrinkage and prolonged duration of therapy were observed in several patients.
Databáze: OpenAIRE
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