Study of ADI-PEG 20 or Placebo Plus Gem and Doc in Previously Treated Subjects with Leiomyosarcoma (ARGSARC)

Inclusion Criteria:

• A subject will be eligible for study participation if he/she meets the followingcriteria:

1. Histologically or cytologically confirmed, grade 2 or 3, LMS STS that would bestandardly 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 beaccurately 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 byclinical exam.

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

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

6. Age >18 years.

7. Eastern Cooperative Oncology Group (ECOG) performance status of < 1 atenrollment (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'sDisease)

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 foradult 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 fromintercourse for the duration of the study and for 35 days after the last doseof ADI-PEG 20 or for at least 3 months (male subjects) or 6 months (femalesubjects) 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 theexclusion criteria:

1. Subjects with history of another primary cancer, including co-existent secondmalignancy, with the exception of: a) curatively resected non-melanoma skincancer; b) curatively treated cervical carcinoma in situ; or c) other primarysolid tumor with no known active disease present in the opinion of theInvestigator will not affect subject outcome in the setting of currentdiagnosis.

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

3. Prior treatment with ADI-PEG 20, Gem or Doc. Patients treated > one year ago inthe 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 becauseof their poor prognosis and because they often develop progressive neurologicdysfunction that would confound the evaluation of neurologic and other adverseevents.

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

7. Uncontrolled intercurrent illness including, but not limited to, ongoing oractive infection, symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia, or psychiatric illness/social situations thatwould 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 anegative pregnancy test within 14 days of study entry.

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

12. Currently receiving other immunosuppressive agents.

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