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

Conditions

• Adipocytic Neoplasm
• Angiomatoid Fibrous Histiocytoma
• Angiosarcoma
• Atypical Fibroxanthoma
• Fibrosarcoma NOS
• Liposarcoma
• Myoepithelioma
• Myxofibrosarcoma
• Osteosarcoma, Extraskeletal

Eligibility Criteria

Sex

ALL

Age

N/A - 30 Years

Healthy Volunteers

Not accepted

Interventions

• Surgical resection — PROCEDURE
  Low, Intermediate and High-risk Surgery to remove tumor (standard of care)
• Proton beam radiation therapy — RADIATION
  Low, Intermediate and High-risk Radiation therapy is considered standard of care for patients with NRSTS who have positive tumor margins. However, the dose that will be given in this study is higher than what is usually given, therefore, the dose of radiation in this study is research. Radiation will start about 3 to 6 weeks after your surgery, depending on how quickly you recover from surgery. Radiation will be given daily (Monday through Friday) for about 5 to 6 weeks.
• Pazopanib — DRUG
  Intermediate and High-risk By mouth, either by tablet or a liquid suspension, 7 doses, days 1 to 7
• Ifosfamide — DRUG
  Intermediate and High-risk Ifosfamide is a structural analogue of cyclophosphamide. Into the vein (IV) over about 3 hours, 3 doses, days 1, 2, and 3
• Doxorubicin — DRUG
  Intermediate and High-risk An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. Intermediate, High-risk Into the vein (IV) over about 1 hour, 2 doses, days 1 and 2
• Selinexor — DRUG
  High-risk Dosage and route of administration: Selinexor tablets for oral administration should be taken at approximately the same time each day without regards to meals. Selinexor is a selective inhibitor of nuclear export (SINE). Selinexor specifically blocks XPO1-mediated nuclear export by forming a slowly reversible covalent bond with the nuclear export protein XPO1 By mouth, either by tablet or a liquid suspension, 1 dose and day 3

Study Details

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.

Key Dates

Start date

Mar 27, 2024

Status verified

Jun 2026

Primary completion

Jun 30, 2034

Completion

Jun 30, 2037

Study Design

Enrollment

139 participants (estimated)

Allocation

NON_RANDOMIZED

Intervention model

FACTORIAL

Primary purpose

TREATMENT

Arms

• Experimental: Low-Risk Subset A
  Participants with low grade tumors of any size, or high-grade tumors \< 5 cm that have been (or are expected to be) completely removed by surgery. When the pathologist reviews the tumor specimen, the tissue around the tumor (margins) must be negative for cancer cells, meaning all of the cancer has been removed. These participants will have surgery to remove the tumor, followed by close observation. There will no further therapy after surgery, just monitoring for tumor recurrence and any side effects from surgery.
• Experimental: Low-Risk Subset B
  Participants with high-grade tumors that are \< 5 cm with positive margins. This means that the pathologist finds cancer cells at the edge of the tissue, suggesting that all of the cancer has not been removed. These participants will have surgery followed by radiation therapy for about 5-6 weeks.
• Experimental: Intermediate-Risk Subset A (participants with low grade tumors):
  * If your tumor is completely removed at surgery \[meaning the tissue around the tumor (margins) is negative for tumor cells\], you will receive no further therapy and you will be closely observed for any signs of tumor recurrence. * If your tumor cannot be completely removed at surgery \[meaning the tissue around the tumor (margins) is positive for tumor cells\] and the tumor is low-grade, you will get consolidation therapy with additional chemotherapy and radiation therapy, followed by 6 months of maintenance therapy with pazopanib.
• Experimental: Intermediate-Risk Subset B (participants with high-grade tumors between 5 and 10 cm in size
  * If your tumor is completely removed at surgery \[meaning the tissue around the tumor (margins) is negative for tumor cells\] you will continue with consolidation chemotherapy with additional chemotherapy without radiation therapy, followed by 6 months of maintenance therapy with pazopanib. * If your tumor cannot be completely removed at surgery \[meaning the tissue around the tumor (margins) is positive for tumor cells\], you will get consolidation therapy with additional chemotherapy and radiation therapy, followed by 6 months of maintenance therapy with pazopanib.
• Experimental: Intermediate-Risk Subset C (participants with high-grade tumors > 10 cm):
  * After 3 cycles of induction chemotherapy, your doctor may decide to give an additional 4th cycle if he/she thinks it would be beneficial before surgery. * You will get consolidation therapy with additional chemotherapy and radiation therapy, followed by 6 months of maintenance therapy with pazopanib. The dose of radiation that you receive will be higher if your tumor cannot be completely removed at surgery (positive margins).
• Experimental: High-Risk - 2 groups
  * If you have a low-grade tumor that has spread to other parts of the body AND the surgeon was able to completely remove all tumors from all parts of your body, you will have no further therapy after surgery. You will be closely followed to monitor you for any signs of tumor recurrence. * If you have a high-grade tumor OR a tumor that cannot be completely removed by surgery OR you have the CIC-DUX4 mutation, you will get consolidation chemotherapy and radiation therapy, followed by 6 months of maintenance therapy with pazopanib.

Primary Outcome Measure

Event-free survival (EFS) [ Time Frame: 9 years (6 years of accrual and 3 year follow-up after enrollment of last patient ]

Central Contacts

• Jessica Gartrell, MD
  888-226-4343
  [email protected]

Locations (7)

Find similar trials in Atlanta, GA

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