In this study, patients with soft tissue sarcoma (STS) will receive ADI-PEG 20 and ifosfamide in combination with radiation as neoadjuvant therapy. In phase I of the study, up to 5 dose levels will be tested to find the recommended phase II dose (RP2D), after which patients enrolling to phase II will be treated at that dose level to assess efficacy.

Inclusion Criteria:

• Patients with pathologically proven diagnosis of grade 2-3 (intermediate or high grade) soft tissue sarcoma of the trunk or extremities with size ≥5 cm by clinical or radiographic assessment that is appropriate for ifosfamide therapy. Patients must be planning to undergo treatment with curative intent.

• Patients with sufficient tumor tissue for correlative analyses. Patients without sufficient tissue may be allowed to enroll on a case-by-case basis with permission of sponsor-investigator.

• Staging workup shows no definitive evidence of distant metastasis and there is planned definitive surgical resection of the primary tumor.

• At least 18 years of age at time of consent.

• ECOG performance status ≤ 1

• Adequate bone marrow, coagulation, and organ function as defined below:

  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm
  • Hemoglobin ≥ 9 g/dL (no transfusions within 7 days of C1D-7)
  • International Normalized Ratio (INR) ≤ 1.5 x IULN or prothrombin time (PT) ≤ 1.5 x IULN, and partial thromboplastin time (aPTT or PTT) ≤ 1.5 x IULN (inclusion only applicable to subjects not using anticoagulation).
  • Total bilirubin ≤ 1.5 x IULN (except for patients with Gilbert's Syndrome, who must have a total bilirubin <3 mg/dL)
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
  • Creatinine clearance ≥ 60 mL/min/1.73^2 by MDRD

• The effects of the study therapy on the developing human fetus are unknown. For this reason and because chemotherapeutics are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and 12 months after completion of the study. Should a woman or female partner become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Highly effective methods of birth control are defined as those that results in a low failure rate (that is, <1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), partner or a vasectomized partner. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. Exceptions: Exceptions: Females not of child-bearing potential due to surgical sterilization (at least 6 weeks following tubal ligation, hysterectomy, or surgical bilateral oophorectomy with or without hysterectomy) confirmed by medical history; or postmenopausal female. A postmenopausal female is a female meeting either of the following criteria: Spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as anorexia nervosa and not taking medications during the amenorrhea that induced the amenorrhea (for example, oral contraceptives, hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen receptor modulators [SERMs], or chemotherapy). Spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH) level >40 IUnits/L

• Ability to understand and willingness to sign an IRB approved written informed consent document.

Exclusion Criteria:

• Pure well-differentiated liposarcoma, low grade STS, Kaposi sarcoma, bone sarcomas, cartilage sarcomas, or GIST.

• Definitive clinical or radiologic evidence of metastatic disease; indeterminate lung nodules less than 5 mm are acceptable.

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• Currently receiving any other investigational agents.

• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to ADI-PEG 20, ifosfamide, PEGylated compounds, or other agents used in the study.

• Prior systemic chemotherapy for the study cancer (sarcoma); note that prior chemotherapy for a different cancer (including a different sarcoma) is allowable if given greater than three years prior. However, unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia (Grade 2 or 3 toxicities from prior antitumor therapy that are considered irreversible [defined as having been present and stable for > 6 months] may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by the sponsor-investigator.

• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.

• Clinically significant bleeding within 4 weeks of C1D-7, current use of direct thrombin inhibitors unless these medications can be safely discontinued 14 days prior to C1D-7. Note: Low molecular weight heparin and factor Xa inhibitors are permitted.

• Concomitant use of the below medications is restricted during the study:

  • All herbal medicines (e.g., St. John's wort), and supplements, within the 6 days prior to C1D-7. Standard adult multi-vitamin is allowed.
  • CYP2C8 substrates with a narrow therapeutic window within the 6 days prior to C1D-7.
  • No live vaccines within 6 days of C1D-7.

• Patients with active infection requiring IV antibiotics within 2 weeks of C1D-7

• The patient has a serious cardiac condition, such as congestive heart failure; New York Heart Association Class III/IV heart disease; unstable angina pectoris, cardiac stenting within 6 months of C1D-7; myocardial infarction within 6 months of C1D-7; valvulopathy that is severe, moderate, and deemed clinically significant; or arrhythmias that are symptomatic or require treatment.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 7 days of C1D-7.

• Patients with known active Hepatitis B or C or HIV.