RMS2021: Treatment of Intermediate- and High-risk Pediatric Rhabdomyosarcoma Using Molecular Risk Stratification and Liposomal Irinotecan

The standard therapy for newly diagnosed rhabdomyosarcoma in children consists of chemotherapy, surgery, and radiation therapy. The current treatment approach also uses risk-based stratification systems to guide treatment plans.

Recent findings from genomic studies of rhabdomyosarcoma have led us to identify three rhabdomyosarcoma patient groups: low-risk, intermediate-risk, and high-risk.

In this phase 1-2 study, we will determine the safety and efficacy of:

• Treatment with VLI (vincristine, liposomal irinotecan) alternating with VAC chemotherapy (vincristine, dactinomycin, cyclophosphamide) in intermediate-risk patients
• Treatment with VLIT (vincristine, liposomal irinotecan with temozolomide) alternating with VAC in high-risk patients
• Chemotherapy combinations when given with concomitant radiation therapy in intermediate and high-risk patients

Phase 1 is a dose-escalation study for patients in the intermediate-risk, high-risk, and intermediate-and-high-risk-with early-radiation treatment groups. We will find the maximum tolerated dose and recommended dose to use in phase 2.

In Phase 2, we will determine the sample size needed to assess the efficacy and evaluate the local recurrence rate (LRR) of patients with tumor size ≥5cm.

Primary Objectives

• Phase 1 will estimate the maximum tolerated doses (MTDs) and recommended Phase 2 doses (RP2Ds) of: (1) combining liposomal irinotecan with vincristine alternating with VAC in intermediate-risk patients; (2) liposomal irinotecan with temozolomide and vincristine alternating with VAC in high-risk patients; and (3) chemotherapy combinations when given with concomitant radiation therapy in intermediate and high-risk patients.
• Estimate event-free survival for intermediate-risk participants treated with VAC and vincristine and liposomal irinotecan (VLI) adding maintenance therapy using vinorelbine and cyclophosphamide.
  
• Estimate the event-free survival for high-risk patients treated with VAC and vincristine, liposomal irinotecan, and temozolomide adding maintenance therapy using vinorelbine and cyclophosphamide.
  
• Estimate the local recurrence rate for unresected intermediate- and high-risk patients with initial tumor size with ≥ 5 cm randomized to various total proton radiation doses while receiving VAC/VLI (intermediate-risk) or VAC/VLI plus temozolomide (high-risk) and maintenance therapy.

Eligibility Criteria

Inclusion criteria include:

• Newly diagnosed with rhabdomyosarcoma (RMS) of any subtype
• Low-risk, intermediate-risk, or high-risk disease, as defined in the research protocol
• Up to 21 years old
• No prior radiotherapy or chemotherapy
• No active infection

Exclusion criteria include:

• Received chemotherapy
• Received a full course of radiation therapy
• Non-infectious interstitial lung disease
• Sexually active patients
• Pregnant patients and lactating females

Study Sites

St. Jude Children’s Research Hospital, Memphis, Tennessee

Cook Children’s Medical Center, Fort Worth, Texas

About this study

Rhabdomyosarcoma (RMS) is a type of cancerous tumor found in soft tissue, such as muscles. The standard treatment for newly diagnosed rhabdomyosarcoma is chemotherapy, surgery, and radiation therapy (the use of high-dose x-rays to kill cancer cells).

A patient’s prognosis can vary depending on what kind of changes (mutations) they have to the DNA of their cancer cells. Based on these mutations found in rhabdomyosarcoma patients, we have identified 3 groups of patients. These groups are based on the risk of their cancer returning after treatment:

• Low-risk
• Intermediate-risk
• High-risk

Purpose of this clinical trial

We hope to find the most effective treatment for each risk group of rhabdomyosarcoma patients. The treatment they will receive is based on the risk of their cancer returning. The risk groups include:

• Low-risk rhabdomyosarcoma: these patients will receive the standard of care treatment (vincristine, dactinomycin and cyclophosphamide, known as “VAC”), along with surgery and radiation therapy.
• Intermediate-risk rhabdomyosarcoma: find out if adding a drug called liposomal irinotecan (also called Onivyde), along with the standard (VAC) chemotherapy/radiation/surgery, will be more effective than standard therapy alone. We also want to find the best radiation dose to give to patients who have large tumors.
• High-risk rhabdomyosarcoma: find out if alternating standard (VAC) chemotherapy with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide), along with surgery and radiation therapy, will be more effective. We also want to find the best radiation dose to give to these patients who have large tumors.

Eligibility overview

To take part in this study, you must be one of the following:

• Newly diagnosed with rhabdomyosarcoma (RMS)
• Low-risk, intermediate-risk, or high-risk disease, as defined in the research protocol
• Up to 21 years old
• No prior radiotherapy or chemotherapy
• No active infection