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 that isappropriate for ifosfamide therapy. Patients must be planning to undergo treatmentwith 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.

• 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 ≥ 10 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

• 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 by Cockcroft-Gault

• 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 become pregnant or suspect she is pregnant whileparticipating in this study, she must inform her treating physician immediately.Highly effective methods of birth control are defined as those that results in a lowfailure rate (that is, <1% per year) when used consistently and correctly, such asimplants, injectables, combined oral contraceptives, some intrauterine contraceptivedevices (IUDs), sexual abstinence, or a vasectomized partner. Exceptions: Femalesnot of child-bearing potential due to surgical sterilization (at least 6 weeksfollowing tubal ligation, hysterectomy, or surgical bilateral oophorectomy with orwithout hysterectomy) confirmed by medical history; or postmenopausal female. Apostmenopausal female is a female with spontaneous amenorrhea for at least 12months, not induced by a medical condition such as anorexia nervosa and not takingmedications during the amenorrhea that induced the amenorrhea (for example, oralcontraceptives, hormones, gonadotropin releasing hormone, antiestrogens, selectiveestrogen receptor modulators [SERMs], or chemotherapy).

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

Exclusion Criteria:

• Well-differentiated liposarcoma or other low grade STS, Kaposi sarcoma, bonesarcomas, cartilage sarcomas, and 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 warfarin,factor Xa inhibitors, and direct thrombin inhibitors unless these medications can besafely discontinued 14 days prior to ADI-PEG 20 and ifosfamide administration. Note:Low molecular weight heparin and prophylactic low dose warfarin are permitted.PT/PTT must meet the inclusion criteria. Subjects taking warfarin must have theirINR followed closely.

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

• All herbal medicines (e.g., St. John's wort), and supplements, within the 10days prior to C1D-7. Standard adult multi-vitamin is allowed.

• CYP2C8 substrates with a narrow therapeutic window within the 14 days prior toC1D-7.

• Medications known to cause QTc interval prolongation within 7 days prior toC1D-7. Ondansetron is permitted for treatment of nausea and vomiting at thediscretion of the treating physician.

• No live vaccines within 2 weeks of C1D-7.

• Patients with active infection requiring IV antibiotics within 2 weeks of the firstdose of ADI-PEG 20.

• The patient has a serious cardiac condition, such as congestive heart failure; NewYork Heart Association Class II/ III/IV heart disease; unstable angina pectoris,cardiac stenting within 6 months of C1D-7; myocardial infarction within the 6 monthsof 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 negativeserum pregnancy test within 7 days of C1D-7.

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