Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor for the Treatment of Non-rhabdomyosarcoma Soft Tissue Sarcoma

Inclusion Criteria

• Patients must be ≤ 30 years at the time of the biopsy that established the diagnosis of NRSTS
• Surgical resection: Patients who had an upfront resection prior to enrollment will be eligible if they are able to begin therapy within 42 days of resection assuming other eligibility criteria are met. Delayed resection is preferred for all patients with intermediate and high-risk disease
• Lansky performance status score ≥ 60 for patients ≤ 16 years of age. Karnofsky performance status score ≥ 60 for patients > 16 years of age. Note patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Newly diagnosed NRSTS of the following histologic types: * “Intermediate (rarely metastasizing)” or “malignant” tumors listed below, as defined in the World Health Organization (WHO) Classification of Soft Tissue Tumors ** Adipocytic tumors – Liposarcoma (well-differentiated, dedifferentiated, myxoid/round cell, pleomorphic, myxoid pleomorphic, not otherwise specified) ** Fibroblastic/myofibroblastic tumors – Solitary fibrous tumor, low grade myofibroblastic sarcoma, myxoinflammatory fibroblastic sarcoma, adult fibrosarcoma, myxofibrosarcoma, low grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma ** So-called fibrohistiocytic tumors – plexiform fibrohistiocytic tumor, giant cell tumor of soft tissue, malignant tenosynovial giant cell tumor ** Smooth muscle tumors – Leiomyosarcoma ** Pericytic (perivascular) tumors – Malignant glomus tumor ** Vascular tumors – Retiform hemangioendothelioma, papillary intralymphatic angioendothelioma, composite hemangioendothelioma, Kaposi sarcoma, pseudomyogenic hemangioendothelioma, epithelioid hemangioendothelioma, angiosarcoma of soft tissue ** Chondro-osseous tumors – mesenchymal chondrosarcoma, extraskeletal osteosarcoma ** Tumors of uncertain differentiation – Atypical fibroxanthoma, angiomatoid fibrous histiocytoma, ossifying fibromyxoid tumor, myoepithelioma, myoepithelial carcinoma, malignant phosphaturic mesenchymal tumor, synovial sarcoma, epithelioid sarcoma, clear cell sarcoma of soft tissue, extraskeletal myxoid chondrosarcoma, malignant perivascular epithelioid tumor, malignant ossifying fibromyxoid tumor, intimal sarcoma ** Malignant peripheral nerve sheath tumor ** Dermatofibrosarcoma protuberans – Only tumors that are both non-metastatic and grossly resected. Patients with non-metastatic unresected and metastatic dermatofibrosarcoma protuberans are NOT eligible ** Embryonal sarcoma of the liver ** Unclassified soft tissue sarcomas that are too undifferentiated to be placed in a specific pathologic category in the WHO classification (often called “undifferentiated soft tissue sarcoma” or “soft tissue sarcoma NOS”) * Patients with CIC-DUX 4 rearranged sarcomas will be enrolled on the high-risk stratum only, regardless of presence of metastasis, size, or resection status * Note that tumors arising in bone (with the exception of mesenchymal chondrosarcoma) are NOT eligible for this study. If there is a question of whether the tumor arose from bone or soft tissues, eligibility will be determined by the histology and its expected sites of origin
• LOW-RISK PARTICIPANTS: Patient has low-risk disease if the patient has a: * Low-grade tumor of any size where R0 or R1 surgical margins are anticipated or achieved * High-grade tumors that are ≤ 5 cm where R0 or R1 resection margins are anticipated or achieved
• LOW-RISK PARTICIPANTS: Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2, or a normal serum creatinine based on age/gender as follows: * Age 2 to < 6 years: Male 0.8 mg/dL, female 0.8 mg/dL * Age 6 to < 10 years: Male 1 mg/dL, female 1 mg/dL * Age 10 to < 13 years: Male 1.2 mg/dL, female 1.2 mg/dL * Age 13 to < 16 years: Male 1.5 mg/dL, female 1.4 mg/dL * Age ≥ 16 years: Male 1.5 mg/dL, female 1.4 mg/dL
• LOW-RISK PARTICIPANTS: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age
• LOW-RISK PARTICIPANTS: Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x ULN for age
• LOW-RISK PARTICIPANTS: Ejection fraction of ≥ 55% by echocardiogram or cardiac MRI
• LOW-RISK PARTICIPANTS: Corrected QT interval (QTc) < 480 msec
• LOW-RISK PARTICIPANTS: No evidence of dyspnea at rest, no exercise intolerance, and a resting pulse oximetry reading > 94% on room air if there is clinical indication for determination
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Patient has intermediate-risk if the patient has a: * Low-grade non-metastatic initially unresectable disease at study enrollment where delayed resection is planned * High-grade ≤ 5 cm non-metastatic initially unresectable disease at study enrollment where delayed resection is planned. Of note, patients enrolled on the low-risk arm who were unable to achieve gross total resection where delayed re-resection is planned are eligible for this arm * High-grade tumor > 5 cm that is potentially resectable
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Patient high-risk if the patient has: * Metastatic disease at presentation * Unresectable disease at study enrollment where delayed resection is not anticipated. Of note, patients enrolled on the low-risk arm who were unable to achieve gross total resection where delayed re-resection is not-planned are eligible for this arm * CIC-DUX4 rearranged sarcoma
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Absolute neutrophil count ≥ 1000/uL. (Note: No transfusions are permitted 7 days prior to laboratory studies to determine eligibility)
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Platelet count ≥ 100,000/uL. (Note: No transfusions are permitted 7 days prior to laboratory studies to determine eligibility)
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Hemoglobin ≥ 8 g/dL for patients ≤ 16 years of age. (Note: No transfusions are permitted 7 days prior to laboratory studies to determine eligibility)
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Hemoglobin ≥ 9 g/dL for patients > 16 years of age. (Note: No transfusions are permitted 7 days prior to laboratory studies to determine eligibility)
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m^2, or a normal serum creatinine based on age/gender as follows: * Age 2 to < 6 years: Male 0.8 mg/dL, female 0.8 mg/dL * Age 6 to < 10 years: Male 1 mg/dL, female 1 mg/dL * Age 10 to < 13 years: Male 1.2 mg/dL, female 1.2 mg/dL * Age 13 to < 16 years: Male 1.5 mg/dL, female 1.4 mg/dL * Age ≥ 16 years: Male 1.5 mg/dL, female 1.4 mg/dL
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: SGOT (AST) or SGPT (ALT) < 2.5 x ULN for age
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Ejection fraction of ≥ 55% by echocardiogram or cardiac MRI
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: QTc < 480 msec
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: No evidence of dyspnea at rest, no exercise intolerance, and a resting pulse oximetry reading > 94% on room air if there is clinical indication for determination
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Patients on low molecular weight heparin, warfarin (with a stable international normalized ratio [INR]), or direct oral anticoagulants (DOAC) who have been on a stable dose are eligible. Patients being treated for a pulmonary embolism or deep venous thrombosis (DVT) must have been treated for a minimum of 6 weeks prior to starting therapy treatment
• INTERMEDIATE AND HIGH-RISK PARTICIPANTS: Patient must have a life expectancy of at least 3 months with appropriate therapy

Exclusion Criteria

• Patients with known primary central nervous system (CNS) sarcoma or CNS metastases are not eligible. Note: Brain imaging is not an eligibility requirement. Tumors with intracranial extension will be allowed
• Patients with the following histologic diagnosis are not eligible: intermediate locally aggressive tumors as defined by WHO, malignant rhabdoid tumor, alveolar soft part sarcoma, infantile fibrosarcoma, unresectable/metastatic dermatofibrosarcoma protuberans, inflammatory myofibroblastic tumor, desmoid fibromatosis, rhabdomyosarcoma, desmoplastic small round cell tumor, BCOR-CCNB3 fusion positive sarcoma
• Bleeding diathesis: Patients with evidence of active bleeding or bleeding diathesis will be excluded (Note: Patients aged > 17 years with excess of 2.5 mL of hemoptysis are not eligible)
• Uncontrolled hypertension: Patients with uncontrolled hypertension (CTCAE version [v]5 grade ≥ 2) are ineligible. Hypertension must be well controlled on stable doses of medication for at least two weeks
• Prior therapy * Patients must have had no prior systemic therapy for the treatment of the NRSTS * Patients must have had no prior anthracycline or ifosfamide chemotherapy * Patients must have had no prior use of pazopanib or similar multi-targeted tyrosine kinase inhibitor (TKI)
• Patients must have had no prior radiotherapy to tumor-involved sites. Note: Patients previously treated for a non-NRSTS cancer are eligible provided they meet the prior therapy requirements. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier are excluded
• CYP3A4 substrates with narrow therapeutic indices: Patients chronically receiving medications known to be metabolized by CYP3A4 and with narrow therapeutic indices within 7 days prior to study enrollment, including but not limited to pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible. Note: the use of fentanyl is permitted
• CYP3A4 inhibitors: Patients chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to itraconazole, clarithromycin, erythromycin, many non-nucleoside reverse transcriptase inhibitors (NNRTIs), diltiazem, verapamil, and grapefruit juice are not eligible
• CYP3A4 Inducers: Patients chronically receiving drugs that are known potent CYP3A4 inducers within 14 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifampin, and St. John’s wort are not eligible (with the exception of glucocorticoids)
• Certain medications that are associated with a risk for QTc prolongation and/or Torsade’s de Pointes, although not prohibited, should be avoided or replaced with medications that do not carry these risks, if possible
• Subjects with any condition that may impair the ability to absorb oral medications/investigational product including: * Prior surgical procedures affecting absorption including, but not limited to major resection of stomach or small bowel * Active peptic ulcer disease * Malabsorption syndrome
• Thyroid replacement therapy: Patients who require thyroid replacement therapy are not eligible if they have not been receiving a stable replacement dose for at least 4 weeks prior to study enrollment
• Subjects with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including: * Active peptic ulcer disease * Known intraluminal metastatic lesions * Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other gastrointestinal conditions which increase the risk of perforation * History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to beginning study treatment
• Pulmonary embolism or DVT. Patients must not have experienced: * An untreated pulmonary embolism or DVT in last 6 months or * Treated pulmonary embolism or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks * Arterial thrombosis in last 12 months
• History of serious or non-healing wound, ulcer, or bone fracture
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pazopanib. In addition, these subjects are at increased risk of lethal infections when treated with marrow-suppressive therapy
• Patients who are receiving any other investigational agent(s)
• Pregnancy and breast feeding * Pregnancy and breast-feeding female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies * Lactating females are not eligible unless they have agreed not to breastfeed their infants during treatment and for a period of 1 month following completion of treatment * Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained * Unwillingness to use an effective contraceptive method for the duration of their study participation and for at least 1 month after treatment is completed if sexually active with reproductive potential