Neoadjuvant ADI-PEG 20 + Ifosfamide + Radiotherapy in Soft Tissue Sarcoma

Inclusion Criteria:

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

• Patients with sufficient tumor tissue for correlative analyses. Patients withoutsufficient tissue may be allowed to enroll on a case-by-case basis with permissionof sponsor-investigator.

• Staging workup shows no definitive evidence of distant metastasis and there isplanned 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, whomust 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 thisreason and because chemotherapeutics are known to be teratogenic, women ofchildbearing potential and men must agree to use adequate contraception prior tostudy entry, for the duration of study participation, and 12 months after completionof the study. Should a woman or female partner become pregnant or suspect she ispregnant while participating in this study, she must inform her treating physicianimmediately. Highly effective methods of birth control are defined as those thatresults in a low failure rate (that is, <1% per year) when used consistently andcorrectly, such as implants, injectables, combined oral contraceptives, someintrauterine contraceptive devices (IUDs), partner or a vasectomized partner. Sexualabstinence is considered a highly effective method only if defined as refrainingfrom heterosexual intercourse during the entire period of risk associated with thestudy intervention. The reliability of sexual abstinence needs to be evaluated inrelation to the duration of the study and the preferred and usual lifestyle of theparticipant. Exceptions: Exceptions: Females not of child-bearing potential due tosurgical sterilization (at least 6 weeks following tubal ligation, hysterectomy, orsurgical bilateral oophorectomy with or without hysterectomy) confirmed by medicalhistory; or postmenopausal female. A postmenopausal female is a female meetingeither of the following criteria: Spontaneous amenorrhea for at least 12 months, notinduced by a medical condition such as anorexia nervosa and not taking medicationsduring the amenorrhea that induced the amenorrhea (for example, oral contraceptives,hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen receptormodulators [SERMs], or chemotherapy). Spontaneous amenorrhea for 6 to 12 months anda follicle-stimulating hormone (FSH) level >40 IUnits/L

• Ability to understand and willingness to sign an IRB approved written informedconsent 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 lungnodules less than 5 mm are acceptable.

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

• Currently receiving any other investigational agents.

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

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

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

• Clinically significant bleeding within 4 weeks of C1D-7, current use of directthrombin inhibitors unless these medications can be safely discontinued 14 daysprior to C1D-7. Note: Low molecular weight heparin and factor Xa inhibitors arepermitted.

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

• All herbal medicines (e.g., St. John's wort), and supplements, within the 6days prior to C1D-7. Standard adult multi-vitamin is allowed.

• CYP2C8 substrates with a narrow therapeutic window within the 6 days prior toC1D-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; NewYork Heart Association Class III/IV heart disease; unstable angina pectoris, cardiacstenting within 6 months of C1D-7; myocardial infarction within 6 months of C1D-7;valvulopathy that is severe, moderate, and deemed clinically significant; orarrhythmias that are symptomatic or require treatment.

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

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