NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)

Patients must be 1-30 years at the time of the biopsy that established the diagnosis of NRSTS.

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.

Diagnosis

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.

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.

Patient must have adequate organ function in the organs that will be within the radiotherapy field.

Adequate renal function defined as:

Creatinine clearance or radioisotope GFR \> 70 mL/min/1.73 m2, or

A normal serum creatinine based on age/gender as follows

Age Maximum Serum Creatinine (mg/dL) Male Female 2 to \< 6 years 0.8 0.8 6 to \< 10 years 1 1 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.4 \> 16 years 1.5 1.4

Adequate liver function defined as:

Total bilirubin \< 1.5 x upper limit of normal (ULN) for age

SGOT (AST) or SGPT (ALT) \< 2.5 x ULN for age

Adequate cardiac function defined as:

Ejection fraction of \> 55% by echocardiogram or cardiac MRI

QTc \< 480 msec

Adequate pulmonary function defined as:

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.

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.

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

Organ Function

Adequate bone marrow function defined as:

Absolute neutrophil count \> 1000/µL

Platelet count \> 100,000/µL

Hemoglobin \> 8 g/dL for patients \< 16 years of age

Hemoglobin \> 9 g/dL for patients \> 16 years of age

Note: No transfusions are permitted 7 days prior to laboratory studies to determine eligibility.

Adequate renal function defined as:

Creatinine clearance or radioisotope GFR \> 70 mL/min/1.73 m2, or

A normal serum creatinine based on age/gender as follows

Age Maximum Serum Creatinine (mg/dL) Male Female 2 to \< 6 years 0.8 0.8 6 to \< 10 years 1 1 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.4 \> 16 years 1.5 1.4

Adequate liver function defined as:

Total bilirubin \< 1.5 x upper limit of normal (ULN) for age

SGOT (AST) or SGPT (ALT) \< 2.5 x ULN for age

Adequate cardiac function defined as:

Ejection fraction of \> 55% by echocardiogram or cardiac MRI

QTc \< 480 msec

Adequate pulmonary function defined as:

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.

Anticoagulation

Patients on low molecular weight heparin, warfarin (with a stable INR), or direct oral anticoagulants (DOAC) who have been on a stable dose of 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.

Life Expectancy

Patient must have a life expectancy of at least 3 months with appropriate therapy.

3.4.13 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.

3.4.14 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.

What this study is about