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

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Investigational Drug AI Analysis

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

Overview

ADI‑PEG 20 (pegargiminase) is a pegylated arginine deiminase that depletes extracellular arginine and targets tumors with argininosuccinate synthetase 1 (ASS1) loss (arginine auxotrophy). The most mature clinical data are in nonepithelioid malignant pleural mesothelioma (MPM) where adding pegargiminase to platinum–pemetrexed chemotherapy improved overall survival in a randomized phase 2/3 trial. Earlier studies in hepatocellular carcinoma (HCC), melanoma, and sarcomas showed variable activity, often limited as monotherapy but with signals in combinations. (pmc.ncbi.nlm.nih.gov)

Mechanism of action

Pegargiminase converts L‑arginine to citrulline and ammonia, depleting circulating arginine. Tumors with reduced ASS1 cannot resynthesize arginine and are selectively vulnerable. ASS1 deficiency is frequent in MPM, melanoma, HCC, and several sarcomas. Pegylation extends half‑life and reduces immunogenicity relative to native microbial ADI. (pmc.ncbi.nlm.nih.gov)
Anti‑drug antibodies can emerge and blunt sustained arginine depletion; combinations with chemotherapy and steroids may prolong suppression. (pmc.ncbi.nlm.nih.gov)

Efficacy

Malignant pleural mesothelioma (nonepithelioid histology; first‑line with chemotherapy)
- ATOMIC‑meso randomized phase 2/3 (n=249): Pegargiminase (36.8 mg/m² IM weekly) plus pemetrexed–platinum vs placebo plus chemotherapy. Median overall survival 9.3 vs 7.7 months (HR 0.71; P=0.02); median PFS 6.2 vs 5.6 months (HR 0.65; P=0.02). Objective response rates were similar (~14%) in the phase 2 portion; longer‑term survival favored pegargiminase. (pmc.ncbi.nlm.nih.gov)
- Phase 1/expansion and translational studies of the same triplet reported high disease‑control rates (≈94%) and partial responses ≈36% in ASS1‑deficient MPM, supporting the phase 3 design. (pubmed.ncbi.nlm.nih.gov)

Hepatocellular carcinoma
- Randomized phase 3 (second line, ADI‑PEG 20 monotherapy; n≈600): no OS benefit vs placebo (median OS 7.8 vs 7.4 months); exploratory analyses suggested longer survival among patients with sustained arginine depletion. (ascopubs.org, targetedonc.com)
- Combination with modified FOLFOX6 (phase 1; HCC cohort n=23): ORR 21% with median PFS 7.3 months and OS 14.5 months; however, a subsequent international single‑arm phase 2 of ADI‑PEG 20+FOLFOX showed limited activity and was stopped early. (pubmed.ncbi.nlm.nih.gov)

Melanoma and other solid tumors
- Phase 1 of ADI‑PEG 20 + cisplatin (n=99; ASS1‑deficient cohorts): ORR 5%, disease control 41%, median PFS 3.6 months, OS 8.1 months, with some durable control in uveal melanoma. (pmc.ncbi.nlm.nih.gov)
- Earlier melanoma monotherapy studies largely showed disease stabilization without objective responses at tested doses. (pmc.ncbi.nlm.nih.gov)

Soft‑tissue sarcoma (combination, nonrandomized)
- Phase 2 (gemcitabine+docetaxel+ADI‑PEG 20; n=75): ORR 25% (including 8% complete responses); clinical benefit rate 68%; signals greater in ASS1‑negative tumors. Doses of G/D required reduction for cytopenias; randomized trials were proposed. (ascopubs.org)

Safety

In ATOMIC‑meso, grade ≥3 treatment‑related AEs occurred in 28.8% with pegargiminase‑chemotherapy vs 16.9% with placebo‑chemotherapy; events were mainly hematologic from the backbone chemotherapy. Hypersensitivity (including rare anaphylaxis) and skin reactions were uncommon but more frequent with pegargiminase. (pmc.ncbi.nlm.nih.gov)
With monotherapy in HCC, common mostly grade 1–2 events included hypersensitivity rash, injection‑site reactions, hyperuricemia, pruritus, fatigue, and occasional hyperammonemia; severe hypersensitivity was rare. (pmc.ncbi.nlm.nih.gov)
Across combination studies, tolerability has generally been acceptable; cytopenias reflect partner chemotherapy, and immunogenicity (anti‑ADI‑PEG 20 antibodies) is common and may limit exposure duration. (pmc.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 versus placebo plus gemcitabine/docetaxel in previously treated advanced or metastatic leiomyosarcoma, and to compare overall response, overall survival, and safety between arms.

Patients: Adults (>18 years) with histologically or cytologically confirmed grade 2–3 leiomyosarcoma, uterine or non‑uterine, measurable by RECIST 1.1, previously treated with up to two prior systemic regimens including at least one doxorubicin‑containing regimen. ECOG 0–1 required with adequate marrow, hepatic, and renal function. Key exclusions include prior ADI‑PEG 20, prior pelvic radiation, prior gemcitabine/docetaxel within the last year (adjuvant/neoadjuvant >1 year allowed), known brain metastases, significant uncontrolled comorbidities, grade ≥2 neuropathy, active HIV on antiretrovirals, pregnancy or breastfeeding, and hypersensitivity to study agents or excipients.

Design: Global, multicenter, randomized, double‑blind, placebo‑controlled, parallel‑group phase 3 trial. Allocation is randomized with blinded independent central review for efficacy assessments. Planned enrollment is 300 in the second‑ or third‑line setting.

Treatments: Experimental arm: ADI‑PEG 20 at 36 mg/m2 on Day −7 of Cycle 1 and on 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 and targets tumors with loss of ASS1, rendering them arginine‑auxotrophic. The agent has shown improved survival when combined with platinum–pemetrexed in nonepithelioid malignant pleural mesothelioma in a randomized phase 2/3 study, while monotherapy in hepatocellular carcinoma did not improve overall survival; activity in sarcomas has been suggested in combination with gemcitabine/docetaxel in nonrandomized studies. Mechanistically, sustained arginine depletion may sensitize ASS1‑deficient tumors to chemotherapy, though anti‑drug antibodies can emerge and potentially limit durability of depletion.

Outcomes: Primary endpoint: progression‑free survival by RECIST 1.1 assessed by blinded independent central review. Secondary endpoints: objective response rate (CR+PR) by RECIST 1.1, overall survival, and safety/tolerability graded by NCI CTCAE v5. Time on therapy consists of 21‑day cycles with triplet treatment; subjects tolerating chemotherapy may continue beyond 8 cycles and up to approximately 104 weeks, with weekly monotherapy ADI‑PEG 20 or placebo after chemotherapy discontinuation per protocol.

Burden on patient: Moderate. The regimen requires frequent clinic visits inherent to gemcitabine/docetaxel (Days 1 and 8 each 21‑day cycle) plus additional weekly injections of ADI‑PEG 20 or placebo, including a Day −7 lead‑in, increasing visit frequency relative to standard gemcitabine/docetaxel alone. Routine safety labs and imaging at typical RECIST intervals are expected, without extensive pharmacokinetic sampling or protocol‑mandated biopsies. Toxicities are primarily those of gemcitabine/docetaxel (myelosuppression, fatigue) with potential for hypersensitivity or injection‑site reactions from ADI‑PEG 20. Travel and time commitment are higher than standard doublet due to weekly dosing but align with standard phase 3 chemotherapy‑based care without extraordinary procedures.

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