A phase 1/1B trial of ADI‐PEG 20 plus nab‐paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma

Lowery, Maeve A.; Yu, Kenneth H.; Kelsen, David P.; Harding, James J.; Bomalaski, John S.; Glassman, Danielle; Covington, Christina M.; Brenner, Robin; Hollywood, Ellen; Barba, Adalberto; Johnston, Amanda; Liu, Kay Chia Wei; Feng, Xiaoxing; Capanu, Marinela; Abou‐Alfa, Ghassan K.; O’Reilly, Eileen M.

doi:10.1002/cncr.30897

Cited by 67 publications

(55 citation statements)

References 27 publications

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“…Alternatively, methylation of ASS1 intron 1 may be a more important determinant than promoter methylation in clinical samples as shown in mesothelioma (11). Also, ASS1-deficiency appears to be less important for medical benefit when ADI-PEG20 is combined with chemotherapy, as has been shown with gemcitabine and nabpaclitaxel in pancreatic cancer and with folinic acid, fluorouracil, and oxaliplatin in hepatocellular carcinoma (39,40).…”

Section: Discussionmentioning

confidence: 99%

A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma

Hall

Lewis

Syed

et al. 2019

Clinical Cancer Research

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Purpose: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy AE bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. Patients and Methods: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16-06/17) to receive weekly ADI-PEG20 36 mg/m 2 intramuscularly plus pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary end-points were safety, tolerability, and preliminary estimates of efficacy. Results: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5-20.8) and overall survival was 6.3 months (95% CI, 1.8-9.7). Conclusions: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls.

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Section: Discussionmentioning

confidence: 99%

A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma

Hall

Lewis

Syed

et al. 2019

Clinical Cancer Research

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“…The enzyme arginine deiminase (ADI), which allows many microorganisms to utilize arginine as a major energy source, was recently included in clinical trials as an anti-cancer drug to treat arginine-auxotrophic tumors, with positive effects reported on reducing disease progression in hepatocellular carcinoma, advanced pancreatic adenocarcinoma and acute myeloid leukemia patients (Izzo et al, 2004; Lowery et al, 2017; Tsai et al, 2017). Since NO is an important product of arginine in cancer cells, it is plausible that arginine depletion might contribute to tumor inhibition by reducing the cellular levels of NO.…”

Section: No-related Drugs For Cancer Therapymentioning

confidence: 99%

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

Keshet

Erez

2018

Disease Models &Amp; Mechanisms

110

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Nitric oxide (NO) is a signaling molecule that plays important roles in diverse biological processes and thus its dysregulation is involved in the pathogenesis of various disorders. In cancer, NO has broad and sometimes dichotomous roles; it is involved in cancer initiation and progression, but also restricts cancer proliferation and invasion, and contributes to the anti-tumor immune response. The importance of NO in a range of cellular processes is exemplified by its tight spatial and dosage control at multiple levels, including via its transcriptional, post-translational and metabolic regulation. In this Review, we focus on the regulation of NO via the synthesis and availability of its precursor, arginine, and discuss the implications of this metabolic regulation for cancer biology and therapy. Despite the established contribution of NO to cancer pathogenesis, the implementation of NO-related cancer therapeutics remains limited, likely due to the challenge of targeting and inducing its protective functions in a cell- and dosage-specific manner. A better understanding of how arginine regulates the production of NO in cancer might thus support the development of anti-cancer drugs that target this key metabolic pathway, and other metabolic pathways involved in NO production.

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“…Originally described in malignant melanoma (60-100 %) and hepatocellular carcinoma (HCC, 100 %), arginine auxotrophy has been found in many other advanced, solid tumors. These include: prostate (100 %), pancreatic (>80 %), breast (up to 60 %), and small cell lung cancer (44 %), malignant pleural mesothelioma (~60 %), head and neck squamous cell carcinoma (50 %), as well as Glioblastoma multiforme (GBM, ~20 %) [8,11,[24][25][26]. Among hematological malignancies, 60 -100 % of all acute myeloid leukemia (AML) cases, as well as primary and relapsed lymphomas, show this metabolic defect [7,11].…”

Section: Arginine Auxotrophy In Human Malignanciesmentioning

confidence: 99%

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

Riess

Shokraie

Classen

et al. 2018

Cell Physiol Biochem

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Arginine auxotrophy occurs in certain tumor types and is usually caused by the silencing of argininosuccinate synthetase 1 or arginine lyase genes. Such tumors are often associated with an intrinsic chemoresistance and thus a poor prognosis. Arginine auxotrophy however renders these tumors vulnerable to treatment with arginine-degrading enzymes. Among the most frequently applied arginine-degrading agents are bacterial arginine deiminases (ADI). The anti-cancerous effects of ADI derived from different bacteria were extensively studied in numerous preclinical cell culture and xenograft models. Mycoplasma-derived ADI-PEG20 is most commonly used and is currently under clinical investigation as a single agent therapeutic as well as in combination with different antineoplastic compounds. Mechanistically, ADI is capable of reducing metabolic activity in tumor cells, contributing to autophagy, senescence and apoptosis in arginine auxotrophic cells. Although clinical trials are promising, the resistance development upon initial treatment response is an increasing challenge. Furthermore, interference of ADI with the tumor microenvironment is poorly understood. In the present review, we outline recent experimental ADI-based treatment approaches and their translation into the clinic. Furthermore, we summarize new insights into the molecular mechanisms underlying the anti-cancer effects of ADI that might facilitate the refinement of ADI-based combination therapy approaches.

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A phase 1/1B trial of ADI‐PEG 20 plus nab‐paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma

Cited by 67 publications

References 27 publications

A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma

A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

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