Trial: Study of ADI-PEG 20 or Placebo Plus Gem…

Trial Details

Sponsor: Polaris Group (industry)

Phase: 3

Start date: Nov. 29, 2023

Planned enrollment: 300

Trial ID: NCT05712694

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: ADI PEG20 (Pegargiminase, Hepacid, Melanocid)

Overview

ADI-PEG20 (pegargiminase; also known as Hepacid, Melanocid) is a pegylated arginine deiminase that systemically depletes extracellular arginine. Many tumors (often those lacking argininosuccinate synthetase 1, ASS1) are arginine-auxotrophic and may be vulnerable to pharmacologic arginine deprivation. The most mature clinical data are from the phase 2/3 ATOMIC-Meso trial in nonepithelioid malignant pleural mesothelioma, where adding pegargiminase to first-line pemetrexed/platinum chemotherapy improved overall and progression‑free survival versus placebo. In contrast, pegargiminase monotherapy did not improve survival in a large phase 3 second‑line hepatocellular carcinoma (HCC) study. (jamanetwork.com)

Mechanism of action

Target/process: ADI-PEG20 enzymatically converts arginine to citrulline and ammonia, depleting circulating arginine. Normal cells can resynthesize arginine from citrulline via ASS1, but many cancers silence ASS1, creating selective vulnerability. Resistance can emerge through ASS1 re‑expression and microenvironmental protein scavenging pathways. (aacrjournals.org)
Rationale for combinations: Arginine deprivation rewires pyrimidine metabolism and can sensitize ASS1‑deficient tumors to antifolates (e.g., pemetrexed); preclinical work also supports combinations with taxanes/gemcitabine and autophagy inhibitors. (jamanetwork.com)

Efficacy

Malignant pleural mesothelioma (nonepithelioid subtypes; first line, with chemotherapy)
ATOMIC‑Meso (phase 2/3, double‑blind, n=249): Pegargiminase + pemetrexed/platinum vs placebo + pemetrexed/platinum.
- Overall survival: median 9.3 vs 7.7 months; HR 0.71 (95% CI 0.55–0.93; P=0.02).
- Progression‑free survival: median 6.2 vs 5.6 months; HR 0.65 (95% CI 0.46–0.90; P=0.02).
- Three‑year survival was increased (authors note a fourfold improvement). (jamanetwork.com)
Prior phase 1/expansion (ASS1‑deficient thoracic cancers/mesothelioma): high disease control (93.5%) and partial response rate 35.5% with ADI‑PEG20 + pemetrexed + cisplatin; recommended weekly dose 36 mg/m². (pubmed.ncbi.nlm.nih.gov)
Hepatocellular carcinoma (second line, monotherapy)
Phase 3, randomized, n=635: ADI‑PEG20 vs placebo; no OS benefit (median 7.8 vs 7.4 months; HR 1.02; P=0.88). Post hoc analyses suggested longer survival with more prolonged arginine depletion, but primary endpoint was negative. Earlier small studies showed disease stabilization without objective responses. (pubmed.ncbi.nlm.nih.gov)
Melanoma (phase 1/2, monotherapy)
No objective responses; some patients achieved stable disease; toxicities mostly grade 1–2. (pubmed.ncbi.nlm.nih.gov)
Other tumor types
Early-phase clinical exploration includes ASS1‑deficient recurrent high‑grade glioma (stable disease in 80% in a small phase 1 cohort with ADI‑PEG20 + pemetrexed/cisplatin); additional trials in lung and sarcoma settings are ongoing or early‑stage. Preclinical data support activity in ASS1‑deficient ovarian cancers (including SCCOHT). (pubmed.ncbi.nlm.nih.gov)

Safety

In ATOMIC‑Meso, adding pegargiminase to chemotherapy was generally well tolerated; grade 3–4 adverse events occurred in 28.8% vs 16.9% with placebo. Reported events included drug hypersensitivity (2.4%) and skin reactions (1.6%) in the experimental arm; no new safety signals were identified. Weekly intramuscular dosing (36.8 mg/m²) was continued until progression/toxicity or up to 24 months. (jamanetwork.com)
In second‑line HCC monotherapy, common adverse events were fatigue and decreased appetite (<5% grade ≥3); rare grade ≥3 anaphylactic reactions occurred. Immunogenicity (anti‑ADI antibodies) and injection‑site reactions are known risks. (pubmed.ncbi.nlm.nih.gov)

HealthScout AI Analysis

Goal: To determine whether adding the arginine-degrading enzyme ADI‑PEG 20 to gemcitabine/docetaxel improves progression-free survival, with supporting analyses of response, overall survival, and safety, in previously treated advanced or metastatic leiomyosarcoma (LMS) after anthracycline exposure.

Patients: Adults with histologically or cytologically confirmed grade 2–3 uterine or non-uterine leiomyosarcoma, measurable disease by RECIST 1.1, ECOG 0–1, and 1–2 prior systemic regimens including doxorubicin. Adequate marrow, hepatic, and renal function required. Key exclusions include prior gemcitabine or docetaxel within the last year in non-adjuvant settings, prior pelvic radiation, brain metastases, significant uncontrolled comorbidities, grade ≥2 neuropathy, active HIV, and pregnancy or breastfeeding.

Design: Global, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial. Approximately 300 participants will be randomized to experimental versus placebo arms. Blinded independent central review will assess imaging endpoints.

Treatments: Experimental arm: ADI‑PEG 20 at 36 mg/m2 on Day −7 of Cycle 1 and Days 1, 8, and 15 of each 21‑day cycle plus gemcitabine 600 mg/m2 on Days 1 and 8 and docetaxel 60 mg/m2 on Day 8. Control arm: matched placebo on the same schedule plus gemcitabine 900 mg/m2 on Days 1 and 8 and docetaxel 75 mg/m2 on Day 8. ADI‑PEG 20 (pegargiminase) is an investigational, pegylated arginine deiminase that depletes extracellular arginine, targeting tumors with ASS1 loss (arginine auxotrophy). In a randomized phase 2/3 study in nonepithelioid malignant pleural mesothelioma, adding ADI‑PEG 20 to platinum–pemetrexed improved overall and progression-free survival versus chemotherapy alone; activity in other cancers has been mixed, with combination strategies showing more promise than monotherapy. Safety is generally acceptable; added toxicities include hypersensitivity and skin reactions, while hematologic toxicity mainly reflects the chemotherapy backbone.

Outcomes: Primary: Progression-free survival by RECIST 1.1 per blinded independent central review. Secondary: Objective response rate (CR+PR) by RECIST 1.1, overall survival, and safety/tolerability per NCI CTCAE v5. Time on combination therapy is in 21‑day cycles with allowance to continue chemotherapy beyond 8 cycles up to approximately 2 years; thereafter, weekly monotherapy ADI‑PEG 20 or placebo may continue per protocol.

Burden on patient: Moderate. The regimen requires frequent clinic visits during 21‑day cycles with weekly injections of ADI‑PEG 20 or placebo and day 1/8 gemcitabine with day 8 docetaxel, mandating regular labs for cytopenia and organ function monitoring and periodic imaging for RECIST assessments. There are no intensive phase 1–type pharmacokinetic schedules or mandatory research biopsies described, but visit frequency, potential growth-factor support, and toxicity management typical of gemcitabine/docetaxel contribute to logistical and symptom burden. Continuation up to two years further increases cumulative visit and travel demands.

Last updated: Oct 2025

Eligibility

Show Criteria

Inclusion Criteria:

* A subject will be eligible for study participation if he/she meets the following criteria:

1. Histologically or cytologically confirmed, grade 2 or 3, LMS STS that would be standardly treated with Gem or GemDoc.

2. Determination of LMS subtype: uterine or non-uterine.

3. Measurable disease per RECIST 1.1 (Appendix A), defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.

4. Previous treatment with up to 2 systemic regimens, including at least 1 systemic regimen containing doxorubicin.

5. Treatment \> one year ago in the adjuvant/neoadjuvant setting with Gem or Doc is allowed.

6. Age \>18 years.

7. Eastern Cooperative Oncology Group (ECOG) performance status of \< 1 at enrollment (Appendix B).

8. Leukocytes ≥ 3,000/mcL.

9. Absolute neutrophil count ≥ 1,500/mcL.

10. Platelets ≥ 100,000/mcL.

11. Hemoglobin ≥ 8.0 g/dL

12. Total bilirubin ≤ 2 x ULN. (≤ 3 x ULN for potential subjects with Gilbert's Disease)

13. AST(SGOT)/ALT(SGPT) ≤ 3 x ULN (or ≤ 5 x ULN if liver metastases are present)

14. Creatinine clearance ≥ 60 mL/min (by Cockcroft-Gault equation).

15. Serum uric acid ≤ 8 mg/dL (with or without medication control).

16. QTc interval range from 350 to 450 ms for adult men and from 360 to 460 ms for adult women.

17. Subjects and their partners must be asked to use appropriate contraception. They must agree to use 2 forms of contraception or agree to refrain from intercourse for the duration of the study and for 35 days after the last dose of ADI-PEG 20 or for at least 3 months (male subjects) or 6 months (female subjects) after treatment with gemcitabine, whichever is the longer duration.

18. Ability to understand and willingness to sign the informed consent form.

19. No concurrent investigational drug studies are allowed.

Exclusion Criteria:

* A subject will not be eligible for study participation if he/she meets any of the exclusion criteria:

1. Subjects with history of another primary cancer, including co-existent second malignancy, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present in the opinion of the Investigator will not affect subject outcome in the setting of current diagnosis.

2. Currently receiving chemotherapy, immunotherapy, interferon, radiation therapy or other investigational agents. Note: Chemotherapy agent washout period is 5 half-lives prior to randomization. Radiation washout period is 7 days prior to randomization.

3. Prior treatment with ADI-PEG 20, Gem or Doc. Patients treated \> one year ago in the adjuvant/neoadjuvant setting with Gem or Doc are allowed to be enrolled.

4. Prior pelvic radiation.

5. Known brain metastases. Such patients must be excluded from this trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

6. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ADI-PEG 20, Gem, Doc, polysorbate 80, pegylated compounds, or other agents used in this study.

7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

8. History of seizure disorder not related to underlying cancer.

9. Grade 2 or higher neuropathy.

10. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.

11. Known HIV-positivity. Because of the potential for pharmacokinetic interactions of antiretroviral therapy with the study treatment. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

12. Currently receiving other immunosuppressive agents.

13. Subjects under guardianship, curatorship, under legal protection or deprived of liberty by an administrative or judicial decision