NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
The study participant has been diagnosed with non-rhabdomyosarcoma (NRSTS). Primary Objectives Intermediate-Risk * To estimate the 3-year event-free survival for intermediate-risk patients treated with ifosfamide, doxorubicin, pazopanib, surgery, and maintenance pazopanib, with or without RT. * To characterize the pharmacokinetics of pazopanib and doxorubicin in combination with ifosfamide in intermediate-risk participants, to assess potential covariates to explain the inter- and intra-individual pharmacokinetic variability, and to explore associations between clinical effects and pazopanib and doxorubicin pharmacokinetics. High-Risk * To estimate the maximum tolerated dose (MTD) and/or the recommended phase 2 dosage (RP2D) of selinexor in combination with ifosfamide, doxorubicin, pazopanib, and maintenance pazopanib in high-risk participants. * To characterize the pharmacokinetics of selinexor, pazopanib and doxorubicin in combination with ifosfamide in high-risk participants, to assess potential covariates to explain the inter- and intra-individual pharmacokinetic variability, and to explore associations between clinical effects and selinexor, pazopanib and doxorubicin pharmacokinetics. Secondary Objectives * To estimate the cumulative incidence of primary site local failure and distant metastasis-free, disease-free, event-free, and overall survival in participants treated on the risk-based treatment strategy defined in this protocol. * To define and describe the CTCAE Grade 3 or higher toxicities, and specific grade 1-2 toxicities, in low- and intermediate-risk participants. * To study the association between radiation dosimetry in participants receiving radiation therapy and the incidence and type of dosimetric local failure, normal adjacent tissue exposure, and musculoskeletal toxicity. * To evaluate the objective response rate (complete and partial response) after 3 cycles for high-risk patients receiving the combination of selinexor with ifosfamide, doxorubicin, pazopanib, and maintenance pazopanib. * To assess the relationship between the pharmacogenetic variation in drug-metabolizing enzymes or drug transporters and the pharmacokinetics of selinexor, pazopanib, and doxorubicin in intermediate- or high-risk patients. Exploratory Objectives * To explore the correlation between radiographic response, pathologic response, survival, and toxicity, and tumor molecular characteristics, as assessed through next-generation sequencing (NGS), including whole genome sequencing (WGS), whole exome sequencing (WES), and RNA sequencing (RNAseq). * To explore the feasibility of determining DNA mutational signatures and homologous repair deficiency status in primary tumor samples and to explore the correlation between these molecular findings and the radiographic response, survival, and toxicity of patients treated on this protocol. * To explore the feasibility of obtaining DNA methylation profiling on pretreatment, post-induction chemotherapy, and recurrent (if possible) tumor material, and to assess the correlation with this and pathologic diagnosis, tumor control, and survival outcomes where feasible. * To explore the feasibility of obtaining high resolution single-cell RNA sequencing of pretreatment, post-induction chemotherapy, and recurrent (if possible) tumor material, and to characterize the longitudinal changes in tumor heterogeneity and tumor microenvironment. * To explore the feasibility of identifying characteristic alterations in non-rhabdomyosarcoma soft tissue sarcoma in cell-free DNA (cfDNA) in blood as a non-invasive method of detecting and tracking changes during therapy, and to assess the correlation of cfDNA and mutations in tumor samples. * To describe cardiovascular and musculoskeletal health, cardiopulmonary fitness among children and young adults with NRSTS treated on this protocol. * To investigate the potential prognostic value of serum cardiac biomarkers (high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro B-type natriuretic peptide (NT-Pro-BNP), serial electrocardiograms (EKGs), and serial echocardiograms in patients receiving ifosfamide, doxorubicin, and pazopanib, with or without selinexor. * To define the rates of near-complete pathologic response (\>90% necrosis) and change in FDG PET maximum standard uptake value (SUVmax) from baseline to week 13 in intermediate risk patients with initially unresectable tumors treated with induction pazopanib, ifosfamide, and doxorubicin, and to correlate this change with tumor control and survival outcomes. * To determine the number of high-risk patients initially judged unresectable at diagnosis that are able to undergo primary tumor resection after treatment with ifosfamide, doxorubicin, selinexor, and pazopanib. * To identify the frequency with which assessment of volumes of interest (VOIs) of target lesions would alter RECIST response assessment compared with standard linear measurements.
• 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 28 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.
⁃ 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
⁃ 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.