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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I/II Trial of Neoadjuvant ADI-PEG 20 in Combination With Ifosfamide and Radiotherapy in Soft Tissue Sarcoma (STS)

Conditions
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Soft Tissue Sarcoma, Sts, Sarcoma,Soft Tissue

Intervention / Treatment
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* Drug: ADI PEG20
* Drug: Ifosfamide
* Radiation: Radiotherapy
* Drug: Mesna


Participation Criteria
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Eligibility Criteria
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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. Patients must be planning to undergo treatment with curative intent. Patients must be able to provide tumor tissue for correlative analyses at baseline. Patients without tissue may be allowed to enroll with permission of sponsor-investigator. Staging workup shows no distant metastasis and there is planned definitive surgical resection of the primary tumor. At least 18 years of age. ECOG performance status ≤ 1 Normal 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, who must 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 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 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), sexual abstinence, or a vasectomized partner. 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); OR 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: Well-differentiated liposarcoma or other low grade STS, Kaposi sarcoma, bone sarcomas, cartilage sarcomas, and 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 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 screening, current use of warfarin, factor Xa inhibitors, and direct thrombin inhibitors unless these medications can be safely 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 their INR 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 10 days prior to C1D-7. Standard adult multi-vitamin is allowed. CYP2C8 substrates with a narrow therapeutic window within the 14 days prior to C1D-7. Medications known to cause QTc interval prolongation within 7 days prior to C1D-7. Ondansetron is permitted for treatment of nausea and vomiting at the discretion 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 first dose of ADI-PEG 20. The patient has a serious cardiac condition, such as congestive heart failure; New York Heart Association Class II/ III/IV heart disease; unstable angina pectoris, cardiac stenting within 6 months of enrollment; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or 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 the first dose of ADI-PEG 20. Patients with known active Hepatitis B or C or HIV.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: ADI-PEG 20 + ifosfamide + radiotherapy<br>Patients will receive ADI-PEG 20 on Day -7 of Cycle 1 and Days 1, 8, and 15 of each of three 21-day cycles, and ifosfamide per dose escalation/de-escalation schedule on days 1 through 5 of each cycle. Mesna will be given on days 1 through 5 with ifosfamide as supportive care. Patients will also receive radiotherapy (XRT) starting on Week 4. | Drug: ADI PEG20<br>* ADI-PEG 20 will be given on an outpatient basis at a dose of 36 mg/m^2 via intramuscular injection into either the deltoid or gluteal muscle.<br>* Other names: PEGylated arginine deiminase;Drug: Ifosfamide<br>* Ifosfamide will be administered intravenously per package insert and institutional practice on Days 1 through 5 of all 3 cycles.<br>* Other names: ifex;Radiation: Radiotherapy<br>* Radiotherapy will begin on C2D1 and will continue as per institutional practice.<br>Drug: Mesna<br>* Mesna will be administered for supportive care either intravenously or by mouth per package insert and institutional practice on Days 1 through 5 of all 3 cycles.<br>* Other names: sodium 2-mercaptoethane sulfonate;|
| Experimental: Phase II: ADI-PEG 20 + ifosfamide + radiotherapy<br>Patients will receive ADI-PEG 20 on Day -7 of Cycle 1 and Days 1, 8, and 15 of each of three 21-day cycles, and ifosfamide per the RP2D determined in Phase I of the study on days 1 through 5 of each cycle. Mesna will be given on days 1 through 5 with ifosfamide as supportive care. Patients will also receive radiotherapy (XRT) starting on Week 4. | Drug: ADI PEG20<br>* ADI-PEG 20 will be given on an outpatient basis at a dose of 36 mg/m^2 via intramuscular injection into either the deltoid or gluteal muscle.<br>* Other names: PEGylated arginine deiminase;Drug: Ifosfamide<br>* Ifosfamide will be administered intravenously per package insert and institutional practice on Days 1 through 5 of all 3 cycles.<br>* Other names: ifex;Radiation: Radiotherapy<br>* Radiotherapy will begin on C2D1 and will continue as per institutional practice.<br>Drug: Mesna<br>* Mesna will be administered for supportive care either intravenously or by mouth per package insert and institutional practice on Days 1 through 5 of all 3 cycles.<br>* Other names: sodium 2-mercaptoethane sulfonate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related serious adverse event (SAE) rate | An adverse event is considered serious if, in the view of the investigator, it results in any of the following: Death A life threatening adverse event Inpatient hospitalization or prolongation of existing hospitalization A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect Any other important medical event that does not fit the criteria above but, based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above | From start of study treatment through 30 days after the last dose (estimated to be 14 weeks) | 
| Recommended Phase II dose (Phase I only) | The MTD is defined as the highest dose level at which no more than 1 out of 6 patients experienced DLT at the end of Cycle 2. Dose escalations will proceed until the MTD has been reached or until Dose Level 3, and this dose level will then be defined as the Recommended Phase 2 Dose (RP2D). | From start of study treatment through 2 cycles of treatment (estimated to be 7 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent necrosis in final surgical specimen | Defined as the proportion of patients with a necrosis in the final surgical specimen. | At time of surgical resection (estimated to be 16 weeks) | 
| Pathologic complete response (pCR) in final surgical specimen | Defined as the proportion of patients with a pCR confirmed in the final surgical specimen. | At time of surgical resection (estimated to be 16 weeks) | 
| Percent local failure (%LF) | Defined as the proportion of patients with a local failure, which is either local tumor recurrence or local tumor progression. | At 2 years from surgical resection (estimated to be 120 weeks) | 
| Disease free survival (DFS) | Defined as the time from start of treatment to time of recurrence or death, whichever occurs first. | At 2 years from surgical resection (estimated to be 120 weeks) | 
| Overall survival (OS) | Defined as the time from start of treatment to death from any cause. | At 2 years from surgical resection (estimated to be 120 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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arginine starvation, ADI-PEG20, ifosfamide, radiotherapy, radiation therapy, ASS1 expression