ARST2032: Very Low-Risk and Low-Risk Rhabdomyosarcoma Study

Previous clinical trials (D9602 and ARST0331) of patients treated for low-risk rhabdomyosarcoma (LR-RMS) have shown excellent outcomes, with 4-year event-free survival rates of about 90%. New, adverse fusion-negative RMS mutations (TP53 or MYOD1) were recently identified. These new mutations have not been included in prospective clinical trials.

In this study, we will reclassify patients with TP53 or MYOD1 mutations to determine if this will enrich the LR-RMS patient group for a more favorable prognosis. We will subdivide the molecularly defined LR cohort into 2 newly defined risk groups:

• Very low-risk rhabodmyosarcoma (VLR-RMS): Patients with fusion negative (FN), stage 1/CG I disease with MYOD1/TP53 wildtype (WT) tumors
• Low-risk rhabodmyosarcoma (LR-RMS): Patients with stage 1/CG II, or stage 2/CG I/II or CG III (orbit only) disease with MYOD1 or TP53 WT tumors

Patients with VLR-RMS will be treated for 24 weeks with VA (vincristine and dactinomycin) therapy, which is a reduced therapy duration compared to that used in the D9602 trial. It also eliminates any alkylating agent (cyclophosphamide) used in the ARST0331 trial.

Patients with LR-RMS will be treated with 12 weeks of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks of VA therapy. The goal is to achieve better outcomes in this now-enriched population of patients (MYOD1/TP53 WT).

Patients with VLR or LR disease whose tumors contain adverse fusion negative MYOD1 or TP53 mutations will receive VAC therapy escalated to 42 weeks.

Primary Objectives

• To evaluate the failure-free survival (FFS) of patients with VLR-RMS (fusion negative, stage 1, clinical group I, MYOD1 WT, TP53 WT when treated with 24 weeks of VA therapy
• To evaluate the FFS of patients with LR-RMS (fusion negative, stage 1, clinical group II, or stage 2 clinical group I/II or clinical group III (orbit only), MYOD1 WT, TP53 WT) when treated with 12 weeks of VAC followed by 12 weeks of VA.

Eligibility Criteria

Inclusion criteria include:

• Enrollment on APEC14B1 and consent to molecular characterization before enrollment and treatment on ARST2032
• Up to 21 years old
• Newly diagnosed ERMS, RMS, or FOXO1 fusion negative ARMS (Institutional FOXO1 fusion results are acceptable.)

Exclusion criteria include:

• Previous chemotherapy and/or radiation therapy  
• Received drugs that are moderate-to-strong CYP3A4 inhibitors and inducers within 7 days of enrollment
• Unable to undergo radiation therapy
• Uncontrolled infections
• Pregnant or lactating females who plan to breastfeed their infants

Study Site

St. Jude Children’s Research Hospital, Memphis, Tennessee
Other collaborating sites

About this study

Rhabdomyosarcoma (RMS) is a type of cancerous tumor found in soft tissue, such as muscles. Cancers can happen when there is a change in the genes (DNA) of a person’s cells. A patient’s prognosis can vary, depending on what kind of changes (mutations) they have. Some mutations increase a person’s risk for cancer.

Past clinical trials of patients with low-risk rhabdomyosarcoma (LR-RMS) showed that 90% of them survived for 4 years without a significant health event. But recently, scientists found new mutations for RMS. Patients with these mutations have a greater risk of a poor outcome. These new mutations are known as MYOD and TP53. Because they are newly discovered, researchers did not look for them in past RMS studies.

In this study, we will reclassify RMS patients and look for MYOD1 or TP53 mutations in tumor tissue samples. We will find out who has these changes and who does not.

Based on lab results, we will put RMS patients without these mutations into 2 groups:

1. Very low-risk (VLR)-RMS patients. These patients will be treated for 24 weeks with VA (vincristine and dactinomycin) chemotherapy. Because they are lower risk, they will not be treated as long, and will not get the chemotherapy drug cyclophosphamide, as used in other trials.
2. Low-risk (LR)-RMS patients. These patients will be treated with 12 weeks of VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy, followed by 12 weeks of VA chemotherapy. We want to see how well these patients do.

For patients who do have the MYOD1 or TP53 mutations, and have VLR or LR disease, we will treat them with VAC therapy for 42 weeks to see if they would benefit from getting therapy longer than normal to fight their disease.

Purpose of this clinical trial

• Compare the effects of giving less chemotherapy drugs to people with VLR-RMS, who do not have the MYOD1 or TP53 mutation, to find out which is better.
• To find out how well people with LR-RMS, without MYOD1 or TP53 mutations, respond to standard chemotherapy.  
• See the effects of giving chemotherapy drugs for a longer amount of time. We want to see if patients with RMS and the MYOD1 or TP53 mutation benefit from longer therapy than the shorter treatment we give to VLR or LR patients.

Eligibility overview

To take part in this study, you must:

• Be already enrolled in the APEC14B1 clinical trial
• Consent to DNA testing before being enrolled and treated on the ARST2032 trial
• Up to 21 years old
• Have newly diagnosed embryonal rhabdomyosarcoma, spindle cell/sclerosing RMS, or FOXO1 fusion negative alveolar rhabdomyosarcoma (ARMS)