ADI-PEG 20 (pegargiminase) is PEGylated arginine deiminase, an enzyme that depletes the amino acid arginine from the bloodstream. It is developed by Polaris Pharmaceuticals. Many tumors lose the ability to make their own arginine (a state called arginine auxotrophy, typically caused by loss of the ASS1 or ASL enzyme) and become dependent on arginine in the blood. By depleting circulating arginine, ADI-PEG 20 selectively starves these tumors while sparing most normal cells. It is not yet FDA-approved; multiple Phase 3 trials are ongoing.

ADI-PEG 20 Clinical Trials (May 2026): 6 Recruiting Interventional Studies

Last updated: May 19, 2026

About ADI-PEG 20

Drug profile:

ADI-PEG 20 (international nonproprietary name pegargiminase) is a recombinant PEGylated arginine deiminase developed by Polaris Pharmaceuticals. Arginine deiminase is a bacterial enzyme that converts the amino acid arginine into citrulline; PEGylation extends its circulating half-life from minutes to days, enabling once-weekly intramuscular dosing.

Mechanism of action:

ADI-PEG 20 depletes circulating arginine. Most normal cells can resynthesize arginine through the urea cycle using the enzymes argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL). Many tumors lose ASS1 expression and become arginine auxotrophs — they cannot make their own arginine and rely on dietary/circulating supply. Depleting serum arginine selectively starves these tumors while sparing most normal tissues.

Regulatory status:

Not yet FDA-approved. The Phase 3 ATOMIC-Meso trial in first-line malignant pleural mesothelioma reported positive overall survival data in 2024 (ADI-PEG 20 + cisplatin/pemetrexed vs cisplatin/pemetrexed alone); regulatory filings are anticipated. Additional Phase 3 trials in hepatocellular carcinoma and leiomyosarcoma are currently recruiting.

Active Research Directions in 2026

High-arginine HCC Phase 3 — ADI-PEG 20 vs placebo in unresectable hepatocellular carcinoma patients with elevated serum arginine (the most clinically advanced ongoing oncology trial)
Leiomyosarcoma Phase 3 (ARGSARC) — ADI-PEG 20 added to gemcitabine + docetaxel as second-line for previously-treated advanced/metastatic LMS
HCC + lenvatinib combination — Phase 2 testing whether arginine depletion potentiates the standard TKI backbone in unresectable HCC
Aggressive variant prostate cancer (AVPC) — Phase 1/2 ADI-PEG 20 + carboplatin + cabazitaxel in men with AR-independent / neuroendocrine-feature prostate cancers (an ASS1-deficiency-enriched subset)
Glioblastoma platform inclusion — ADI-PEG 20 is one investigational arm within GBM AGILE, the adaptive randomization platform for newly-diagnosed and recurrent glioblastoma
Non-oncology — NASH — arginine depletion is also being tested as a metabolic intervention in non-alcoholic steatohepatitis; separate development program

Recruiting Trials by Indication

Hepatocellular Carcinoma (HCC)

The largest current oncology focus. Two trials with distinct strategies — biomarker-enriched monotherapy and combination-with-TKI:

NCT05317819 - Phase 3 ADI-PEG 20 vs placebo in unresectable HCC patients with high serum arginine levels. The biomarker-enrichment Phase 3.
NCT06034977 - Phase 2 ADI-PEG 20 + lenvatinib vs lenvatinib alone in BCLC stage C unresectable HCC. Combination-with-TKI strategy.

Soft Tissue Sarcoma (Leiomyosarcoma)

Leiomyosarcoma is a known arginine-auxotroph tumor type. The ARGSARC Phase 3 evaluates ADI-PEG 20 in the post-anthracycline setting:

NCT05712694 - ARGSARC Phase 3: ADI-PEG 20 + gemcitabine + docetaxel vs placebo + gemcitabine + docetaxel in advanced/metastatic LMS previously treated with an anthracycline.

Prostate Cancer (Aggressive Variant)

Aggressive variant prostate cancer (AVPC) is a lineage-plastic subset of mCRPC, often after AR-pathway failure, with frequent ASS1-deficiency:

NCT06085729 - Phase 1/2 ADI-PEG 20 + carboplatin + cabazitaxel in aggressive variant prostate cancers. Combination platinum + taxane + arginine depletion.

Glioblastoma (GBM AGILE Platform)

Glioblastoma is increasingly recognized as arginine-dependent; ADI-PEG 20 is integrated as one arm within the international GBM AGILE adaptive platform:

NCT03970447 - GBM AGILE Phase 2/3 adaptive randomization platform in newly-diagnosed and recurrent glioblastoma. ADI-PEG 20 is one of the investigational therapies evaluated; the platform also tests other agents.

Non-Oncology — NASH

Arginine depletion as a metabolic intervention in non-alcoholic steatohepatitis — a distinct development pathway, included here for completeness:

NCT05842512 - Phase 2 ADI-PEG 20 vs placebo in NASH.

Showing all 6 recruiting interventional trials. View the latest on ClinicalTrials.gov.

ASS1-Deficiency and Arginine Auxotrophy as Biomarkers

The clinical premise behind ADI-PEG 20 is that some tumors have lost the ability to make their own arginine and depend on circulating supply. The two most-studied molecular indicators are:

ASS1 immunohistochemistry (IHC) — loss of argininosuccinate synthetase 1 protein on tumor cells, assessed on archival or fresh biopsy material. ASS1 deficiency is variably common across mesothelioma (~50–65%), HCC, melanoma, sarcoma, prostate, and selected gliomas.
Serum arginine level — the HCC Phase 3 (NCT05317819) uses a high-baseline-arginine threshold as an additional enrichment criterion, on the hypothesis that patients with higher reservoir arginine derive greater benefit from depletion.

Most trials do not require pre-confirmed ASS1 status for enrollment, but discussing tissue testing with your oncologist can help inform trial choice.

Side Effects and Practical Considerations

Generally tolerable safety profile — especially compared to cytotoxic chemotherapy. Most patients continue weekly intramuscular dosing without significant interruption.
Injection-site reactions and mild allergic-type reactions (rash, low-grade fever) are the most common Grade 1–2 events.
Anti-drug antibodies — as a non-human (mycoplasma-derived) PEGylated protein, ADI-PEG 20 can elicit anti-drug antibodies that gradually reduce serum-arginine-depleting activity. Trials monitor arginine levels.
Neutropenia — mostly seen in combination regimens with chemotherapy (gem/doc, carbo/cabazitaxel).
Rare serious events — hyperammonemia (impaired urea-cycle function), allergic anaphylaxis (rare).
Combination-specific toxicities — trials adding chemotherapy or lenvatinib carry the toxicity profile of the partner drug.

Frequently Asked Questions

What is ADI-PEG 20?

ADI-PEG 20 (pegargiminase) is PEGylated arginine deiminase — a recombinant bacterial enzyme that depletes circulating arginine. Developed by Polaris Pharmaceuticals, it exploits the fact that many tumors are arginine auxotrophs (typically because they have lost the ASS1 enzyme) and cannot make their own arginine. Not yet FDA-approved; multiple Phase 3 trials are ongoing.

Which cancers does ADI-PEG 20 target?

The most clinically advanced indications are pleural mesothelioma (Phase 3 ATOMIC-Meso reported positive first-line data in 2024), hepatocellular carcinoma (HCC), leiomyosarcoma, aggressive variant prostate cancer, and selected gliomas. ASS1-deficiency by immunohistochemistry is the typical underlying biomarker. The HCC Phase 3 uses a high-serum-arginine eligibility threshold as an additional enrichment criterion.

What ADI-PEG 20 trials are currently recruiting?

There are 6 recruiting interventional ADI-PEG 20 trials as of May 2026, plus the GBM AGILE adaptive platform which includes ADI-PEG 20 as one investigational arm. The two Phase 3 oncology trials are in high-arginine unresectable HCC (vs placebo, NCT05317819) and in previously-treated leiomyosarcoma (ARGSARC: ADI-PEG 20 + gem/doc, NCT05712694). Phase 2 trials include ADI-PEG 20 + lenvatinib in HCC and ADI-PEG 20 + carboplatin + cabazitaxel in aggressive variant prostate cancer. A separate Phase 2 trial in non-alcoholic steatohepatitis (NASH) is also recruiting.

What are the main side effects of ADI-PEG 20?

ADI-PEG 20 is generally well-tolerated relative to cytotoxic chemotherapy. The most common side effects are mild allergic-type reactions (often at the injection site), low neutrophil counts (manageable, more common in combination regimens), and fatigue. Anti-drug antibodies against the PEGylated enzyme can develop and gradually reduce arginine-depleting activity. Rare but serious hyperammonemia has been reported in patients with impaired urea-cycle function. Combination regimens add the toxicities of the partner drug.

Find ADI-PEG 20 and Arginine-Depletion Trials Matched to Your Situation

Use ClinTrialFinder's AI-powered matching to find ADI-PEG 20 and other arginine-depletion or biomarker-targeted trials based on your specific cancer type, prior treatments, and ASS1 status.

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