Table 2.
Review of clinical trials assessing the therapeutic effectiveness of ADI-PEG 20 in cancer treatment.
| Title | Status | Conditions | Interventions | Phases | Start Date | Enrollment | Outcome | NCT | Ref |
|---|---|---|---|---|---|---|---|---|---|
| ADI-PEG in Patients with Metastatic Melanoma | Completed | Melanoma | ADI-PEG 20 | Phase I | 2001/9/1 | 15 | NA | NCT00029900 | |
| Testing of ADI-PEG in Hepatocellular Carcinoma | Completed | HCC | ADI-PEG 20 | Phase II | 2002/9/1 | 34 | NA | NCT00056992 | |
| Pegylated Arginine Deiminase in Treating Patients with Metastatic Melanoma That Cannot Be Removed by Surgery | Completed | Melanoma | ADI-PEG 20 | Phase II | 2004/6/1 | 38 | 38 subjects were enrolled, 10 were ASS1 positive, and 17 were ASS1 negative. Median OS was 9.3 vs. 14.6 months for ASS1 positive vs. ASS1 negative, respectively. Median TTP was 1.8 vs. 3.6 months for ASS1 positive vs. ASS1 negative, respectively. 11 subjects who declined pre-treatment biopsies were not assessed. | NCT00450372 | [106] |
| Study of ADI-PEG 20 in Patients with Advanced Melanoma | Completed | Melanoma | ADI PEG 20 | Phase I/II | 2007/7/1 | 31 | No objective responses were seen, but 9 patients had SD. Pharmacodynamic analysis showed complete plasma arginine depletion in 30 of 31 patients. | NCT00520299 | [107] |
| Study of ADI-PEG 20 in Patients with Relapsed Sensitive or Refractory Small Cell Lung Cancer | Terminated | SCLC | ADI-PEG 20 | Phase II | 2011/1/1 | 22 | 20 evaluable patients were included in two cohorts: 8 with “sensitive” disease and 12 with “refractory” disease. 2 out of 8 had SD in the “sensitive” cohort and 2 out of 12 had SD in the “refractory” cohort. Pharmacodynamic analysis showed complete plasma arginine depletion in 21 out of 22 patients. | NCT01266018 | |
| A Clinical Trial of ADI-PEG 20TM in Patients with Malignant Pleural Mesothelioma | Unknown | MPM | ADI-PEG 20 | Phase II | 2011/1/1 | 70 | 68 patients were evaluated, with a median PFS of 3.2 vs. 2.0 months (p = 0.03) in the ADI-PEG 20 group vs. best supportive care group. There were no significant differences between groups in response rate, OS, and adverse event rate. The best response observed was SD. | NCT01279967 | [111] |
| Ph 3 ADI-PEG 20 Versus Placebo in Subjects with Advanced Hepatocellular Carcinoma Who Have Failed Prior Systemic Therapy | Completed | HCC | ADI-PEG 20 | Phase III | 2011/7/1 | 636 | 635 patients were evaluated, with 70% progressing on sorafenib. Median OS was 7.8 months for ADI-PEG 20 and 7.4 months for placebo (p = 0.88, HR = 1.02), while median PFS was 2.6 months for both (p = 0.07, HR = 1.17). The death rate within 30 days of the end of treatment was 15.2% on ADI-PEG 20 and 10.4% on placebo, with none related to therapy. A trend towards improved OS was observed in patients with more prolonged arginine depletion. | NCT01287585 | [103] |
| Ph 1 Trial of ADI-PEG 20 Plus Docetaxel in Solid Tumors with Emphasis on Prostate Cancer and Non-Small Cell Lung Cancer | Completed | Solid Tumors and Prostate Cancer | ADI-PEG 20 | Phase I | 2011/9/6 | 43 | NA | NCT01497925 | |
| Ph 1 Trial of ADI-PEG 20 Plus Cisplatin in Patients with Metastatic Melanoma | Completed | Melanoma and OC | ADI-PEG 20 | Phase I | 2012/9/1 | 8 | NA | NCT01665183 | |
| PH 2 ADI-PEG 20 Study in Non-Hodgkin’s Lymphoma Subjects Who Have Failed Prior Systemic Therapy | Completed | NHL | ADI-PEG 20 | Phase II | 2013/12/6 | 18 | NA | NCT01910025 | |
| Ph 1 ADI-PEG 20 Plus Doxorubicin; Patients with HER2 Negative Metastatic Breast Cancer | Completed | HER2(-ve) Breast Cancer | ADI-PEG 20 | Phase I | 2014/4/1 | 15 | NA | NCT01948843 | |
| Ph 1 Study in Subjects with Tumors Requiring Arginine to Assess ADI-PEG 20 With Pemetrexed and Cisplatin | Terminated | MPM, NSCLC, Melanoma, HCC, Glioma, and Sarcoma | ADI-PEG 20 | Phase I | 2014/4/23 | 85 | Results were reported in 3 studies. In the first study, 7 patients had SD with a median PFS of 3.0 months and a median OS of 11.5 months. In the second study, the DCR was 85.7% with a PR rate of 47.6%. Median PFS and OS were 4.2 and 7.2 months, respectively. In the third study, treatment was well tolerated with a best overall response of SD in 8 patients. Median PFS was 5.2 months and OS was 6.3 months. | NCT02029690 | [92,96,110] |
| Ph 2 Trial of ADI PEG 20 Plus Concurrent Transarterial Chemoembolization (TACE) vs. TACE Alone in Patients with Unresectable Hepatocellular Carcinoma | Completed | Unresectable HCC | ADI-PEG 20 + TACE | Phase II | 2014/10/15 | 30 | NA | NCT02006030 | |
| Ph 1-2 Study ADI-PEG 20 Plus FOLFOX in Subjects with Advanced GI Malignancies Focusing on Hepatocellular Carcinoma | Terminated | Advanced GI cancer | ADI-PEG 20 + mFOLFOX6 | Phase I/II | 2014/11/1 | 140 | In the phase 1 trial, 27 patients were enrolled (23 with advanced HCC and 4 with other GI tumors). No dose-limiting toxicities were observed in cohort 1 or 2, and the recommended phase 2 dose for ADI-PEG 20 was 36 mg/m2 weekly with mFOLFOX6. The ORR was 21% (95% CI 7.5–43.7), with a median PFS and OS of 7.3 and 14.5 months, respectively. Arginine levels were depleted despite low levels of anti-ADI-PEG 20 antibodies, but there was no correlation between arginine depletion at 4 and 8 weeks and archival tumoral ASS1 levels with response | NCT02102022 | [102] |
| Ph 1 Trial of ADI PEG 20 Plus Sorafenib to Treat Patients with Liver Cancer | Completed | HCC | ADI-PEG 20 | Phase I | 2014/11/1 | 8 | NA | NCT02101593 | |
| Ph 1B Trial With ADI-PEG 20 Plus Nab-Paclitaxel and Gemcitabine in Subjects with Pancreatic Cancer | Completed | Pancreatic Cancer | ADI-PEG 20 | Phase I | 2014/11/17 | 21 | NA | NCT02101580 | |
| PH 2 ADI-PEG 20 Acute Myeloid Leukemia | Completed | AML | ADI-PEG 20 | Phase II | 2015/1/6 | 43 | Among 21 evaluated patients, 2 (9.5%) achieved CR and 7 (33.3%) had stable disease, resulting in a DCR of 42.9%. The duration of response for the two CR patients was 7.5 and 8.8 months. DCR was associated with arginine depletion to ≤10 μM for a median of 8 weeks. | NCT01910012 | [113] |
| Ph 1 Study of ADI-PEG 20 Plus Low Dose Cytarabine in Older Patients With AML | Terminated | AML | ADI-PEG 20 + Cytarabine | Phase I | 2017/1/20 | 23 | 23 patients were given low-dose cytarabine subcutaneously twice daily for 10 days every 28 days and ADI-PEG20 at 18 or 36 mg/m2 (dose levels 1 and 2) intramuscularly weekly. 18 evaluable patients had a 44.4% ORR and median OS of 8.0 (4.5-not reached) months. In 7 treatment-naïve patients, the ORR was 71.4% with 57.1% complete remission rate. No dose-limiting toxicities were reported, and the combination was well-tolerated. | NCT02875093 | [114] |
| Study ADI-PEG 20 Plus Pembrolizumab in Advanced Solid Cancers | Terminated | Advanced Solid Cancers | ADI PEG 20 + Pembrolizumab | Phase I | 2017/7/14 | 33 | 25 patients were evaluated; 9 in the dose-escalation cohort and 16 in the expansion cohort. Mean arginine levels were suppressed for 1–3 weeks but gradually increased. CD3+ T cells increased in 10 of 12 subjects (83.3%) after ADI-PEG 20 treatment, including 3 PR (p = 0.02). PD-L1 expression was low and increased in 3 of 10 subjects (30%). 6 of 25 heavily pretreated patients had PR, including both ASS1 proficient and deficient subjects, for a response rate of 24%. | NCT03254732 | [117] |
| Ph 2/3 Study in Subjects with MPM to Assess ADI-PEG 20 With Pemetrexed and Cisplatin | Completed | MPM | ADI-PEG 20 + Pemetrexed + Cisplatin | Phase II/III | 2017/8/1 | 249 | The plasma arginine decreased while citrulline increased and was maintained over 18 weeks of ADIPemCis therapy. In 31 pilot evaluable patients, the DCR was 93.5% (n = 29/31; 95% CI: 78.6–99.2%), with a PR rate of 35.5% (n = 11/31; 95% CI: 19.2–54.6%). The median PFS and OS were 5.6 (4.0–6.0) and 10.1 (6.1–11.1) months, respectively. The treatment was well tolerated. | NCT02709512 | [112,118] |
| ADI-PEG 20 in Combination with Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma, Osteosarcoma, Ewing’s Sarcoma, and Small Cell Lung Cancer | Completed | Sarcoma | ADI-PEG 20 + Gemcitabine + Docetaxel | Phase II | 2018/5/9 | 98 | 75 patients were evaluated with PFS/OS (months) results of 6.0/N.D. for the 600 mg/m2 group (n = 31), 7.2/22.5 for leiomyosarcoma (LMS) (n = 33), 5.1/17.4 for liposarcoma, and 2.8/15.0 for other (n = 36). Out of 75 patients, 8% (6/75) had CR (3 LMS, 1 synovial, and 2 angiosarcoma), 17% (13/75) had PR, and 43% (32/75) had SD, leading to an ORR of 25% (19/75) and a clinical benefit rate of 68% (51/75). There was a tendency for ASS1 negative tumors to benefit more than ASS1 positive tumors. | NCT03449901 | [119] |
| Study in Patients With Tumours Requiring Arginine to Assess ADI-PEG 20 With Atezolizumab, Pemetrexed and Carboplatin | Withdrawn | NSCLC | Atezolizumab + Pemetrexed + Carboplatin + ADI PEG 20 | Phase I | 2018/6/1 | 0 | NA | NCT03498222 | |
| Study of Immunotherapy Plus ADI-PEG 20 for the Treatment of Advanced Uveal Melanoma | Completed | Melanoma | ADI PEG 20 + Nivolumab + Ipilimumab | Phase I | 2019/4/16 | 9 | NA | NCT03922880 | |
| ADI-PEG 20 Plus Radiotherapy and Temozolomide in Subjects with Glioblastoma Multiforme | Recruiting | GBM | ADI-PEG 20 + Temozolomide | Phase I | 2020/9/14 | Estimated 32 | NA | NCT04587830 | |
| Study of ADI-PEG 20 Versus Placebo in Subjects with Genotype WWOX-GG, Unresectable HCC | Recruiting | HCC | ADI-PEG 20 | Phase III | 2022/3/14 | Estimated 150 | NA | NCT05317819 | |
| Study of ADI-PEG 20, Venetoclax and Azacitidine in Acute Myeloid Leukemia | Recruiting | AML | ADI-PEG 20 | Phase I | 2022/4/5 | Estimated 60 | NA | NCT05001828 | |
| Nivolumab and ADI-PEG 20 Before Surgery for the Treatment of Resectable Liver Cancer | Withdrawn | Resectable HCC | Nivolumab + ADI-PEG 20 + Resection | Phase II | 2022/4/13 | 0 | NA | NCT04965714 | |
| ADI-PEG 20 in Combination with Gemcitabine and Docetaxel After Progression on Frontline Therapy in Non-small Cell and Small Cell Lung Cancers | Not yet recruiting | NSCLC and SCLC | ADI-PEG 20 + Gemcitabine + Docetaxel | Phase I/II | 2023/3/31 | Estimated 108 | NA | NCT05616624 | |
| Study of ADI-PEG 20 or Placebo Plus Gem and Doc in Previously Treated Subjects with Leiomyosarcoma (ARGSARC) | Not yet recruiting | Sarcoma | ADI PEG 20 | Phase III | 2023/6/15 | Estimated 300 | NA | NCT05712694 |
Abbreviation: HCC, hepatocellular carcinoma; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; MPM, malignant pleural mesothelioma; OC, ovarian cancer; NHL, non-Hodgkin’s lymphoma; AML, acute myeloid leukemia; GBM, glioblastoma multiforme; GI cancer, gastrointestinal cancer; TACE, transarterial chemoembolization; mFOLFOX6, modified FOLFOX6; OS, overall survival; PFS, progression-free survival; TTP, time-to-tumor progression; SD, stable disease; DCR, disease control rate; ORR, overall response rate; PR, partial response; CR, complete response.