NRSTS2021: A Risk Adapted Study Using Pazopanib, Radiation Therapy, and Selinexor for Non-Rhabdomyosarcoma Soft Tissue Sarcoma

NRSTS2021 is a phase 1/2 clinical trial that seeks to improve outcomes for newly diagnosed patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS). Our objectives are to improve outcomes in patients with intermediate- and high-risk diseases while reducing side effects in patients who fare well. Patients will be stratified by disease risk and therapy will be tailored accordingly.

Patients with low-risk disease will be part of an exploratory cohort and receive therapy consisting of surgery +/- dose modified radiation therapy (RT). Patients with intermediate-risk disease will participate in the phase 2 component of the study, which will assess the impact of the addition of maintenance pazopanib and risk-adapted, dose-modified RT on survival. Patients with high-risk diseases fare poorly, and new treatment strategies are needed.

Selinexor is a selective inhibitor of nuclear export (SINE) that leads to nuclear accumulation and functional reactivation of tumor suppressor proteins, such as p53. Selinexor may potentiate the action of agents that cause significant DNA damage. It has produced favorable responses when combined with doxorubicin in adults with NRSTS. Therefore, patients with high-risk disease will comprise a separate phase 1 component of the study, which will determine the safety and tolerability of the addition of selinexor to ifosfamide, doxorubicin, and pazopanib followed by maintenance pazopanib. An expansion cohort is planned.

Primary Objectives

For intermediate-risk patients:

• Estimate the 3-year, event-free survival for treatment with ifosfamide, doxorubicin, pazopanib, surgery, and maintenance pazopanib, with or without RT.
• Characterize the pharmacokinetics of pazopanib and doxorubicin in combination with ifosfamide in intermediate-risk participants and explore the associations between clinical effects and pazopanib and doxorubicin pharmacokinetics.

For high-risk patients:

• 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.
• Assess the objective response rate (ORR) of selinexor in combination with ifosfamide, doxorubicin, pazopanib, and maintenance pazopanib in high-risk participants.
• Characterize the pharmacokinetics of selinexor, pazopanib, and doxorubicin in combination with ifosfamide in high-risk participants and explore the associations between clinical effects and selinexor, pazopanib, and doxorubicin pharmacokinetics.

Eligibility Criteria

Inclusion criteria include:

• Newly diagnosed non-rhabdomyosarcoma soft tissue sarcoma
• Up to 30 years old

Exclusion criteria include:

• Previous chemotherapy or radiation therapy (previous surgery acceptable if in the required timeframe)
• Poor organ function
• Pregnant or lactating females
• Active bleeding or new thrombus
• Uncontrolled hypertension

Study Sites

St. Jude Children’s Research Hospital
Memphis, Tennessee

About this study

Non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) consists of a group of tumors (cancers) that occur in the soft tissues of the body, such as the muscles. The treatment for this cancer is based on how abnormal the tumor cells look (tumor grade), how big the tumor is, if it can be surgically removed, and if it has spread to other parts of the body (metastasized).

Using this information, NRSTS patients are usually classified into 3 groups. These groups are based on the patient’s risk of cancer returning after treatment. These groups are low-, intermediate-, and high-risk. While most NRSTS in low-risk patients can be cured with surgery with or without radiation therapy, better treatments with fewer side effects are needed for those in the intermediate- and high-risk groups.

Purpose of this clinical trial

In this clinical trial, we hope to find better treatments for NRSTS patients who are intermediate- and high-risk. Our goal is to lower the risk of the tumor coming back after treatment, while using treatments with fewer risks of long-term side effects.

Patients in this study will receive treatment based on their risk:

• Low-risk patients will be treated with surgery to remove the tumor and, if needed, radiation therapy (protons or X-rays) to kill cancer cells.
• Intermediate-risk patients will receive standard chemotherapy with anti-cancer drugs, surgery, and radiation therapy (protons or X-rays). As part of their treatment, these patients will also receive a new chemotherapy drug called pazopanib. This drug was approved by the United States Food and Drug Administration (FDA) for adult patients with other cancer and was recently shown to be safely tolerated in children and young adults with NRSTS.
• High-risk patients will receive standard chemotherapy with anti-cancer drugs, surgery, and radiation therapy (protons or X-rays). As part of their treatment, these patients will also receive pazopanib and a new chemotherapy drug, selinexor. We want to find the safest dose of selinexor to use and better treat children with high-risk NRSTS.

Eligibility overview

To take part in this study, you must be:

• Newly diagnosed non-rhabdomyosarcoma soft tissue sarcoma
• Up to 30 years old