Treatment of Newly Diagnosed Rhabdomyosarcoma Using Molecular Risk Stratification and Liposomal Irinotecan Based Therapy in Children With Intermediate and High Risk Disease

Phase 2

Recruiting

• Conditions: Rhabdomyosarcoma
• Interventions: Drug: Vincristine; Drug: Dactinomycin; Drug: Cyclophosphamide; Procedure: Surgical Resection; Procedure: Proton beam radiation or external beam radiation or brachytherapy; Drug: Liposomal irinotecan; Drug: Vinorelbine; Drug: Temozolomide; Drug: Filgrastim, peg-filgrastim

• Registration Number: NCT06023641
• Lead Sponsor: St. Jude Children's Research Hospital

Brief Summary

This is a phase II study to determine safety and efficacy of combining liposomal irinotecan with vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan with temozolomide and vincristine alternating with VAC in high-risk patients and the chemotherapy combinations when given with concomitant radiation therapy in intermediate and high risk patients.

Primary Objective

* Estimate event-free survival for intermediate-risk participants treated with VAC and vincristine and liposomal irinotecan (VLI) with the addition of maintenance therapy with vinorelbine and cyclophosphamide.

* Estimate the event-free survival for high-risk patients treated with VAC and vincristine, liposomal irinotecan, and temozolomide with the addition of maintenance therapy with vinorelbine and cyclophosphamide.

Secondary Objectives

* To assess the relation between pharmacogenetic variation in CEP72 genotype and vinca alkaloid (vincristine; vinorelbine) disposition in children with rhabdomyosarcoma.

* To assess the relation between the pharmacogenetic variation in drug metabolizing enzymes and drug transporters, and the pharmacokinetics of vinca alkaloids, liposomal irinotecan, and cyclophosphamide in children with rhabdomyosarcoma.

* To assess the extent of inter-patient variability in the pharmacokinetics of vinca alkaloids, liposomal irinotecan, and cyclophosphamide in children with rhabdomyosarcoma, and explore possible associations between drug disposition and patient specific covariates (e.g., age, sex, race, weight).

* Estimate the cumulative incidence of local recurrence and overall 3-year event-free survival in patients with low-risk disease, intermediate-risk disease or high-risk disease treated with either no adjuvant radiation or minimal volume radiation and compare these outcomes with the outcomes achieved on RMS13.

Detailed Description

This is a phase II study to determine safety and efficacy of combining liposomal irinotecan with vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan with temozolomide and vincristine alternating with VAC in high-risk patients and the chemotherapy combinations when given with concomitant radiation therapy in intermediate and high risk patients. The dose of liposomal irinotecan for intermediate and high risk patients will be 160/mg/m2 on Day 1 based on the results and recommended phase 2 dose of the Phase I trial ONITT trial. The primary objective is to assess event-free survival (EFS). The sample size is determined based on a 2-year EFS estimate for each risk group, with a total study duration of 4 years for enrollment and 2 years of follow-up per patient.

The study employs a single-arm adaptive Phase II design, with an estimated 46 patients in the intermediate-risk group and 34 patients in the high-risk group, ensuring 80% power and a 5% Type I error rate. The trial will conclude once the last enrolled patient has completed 2 years of follow-up.

Study Timeline

• Study First Submitted: 2023-08-27
• Study First Submitted QC: 2023-08-27
• Study First Posted: 2023-09-05
• Study Start: 2024-03-13
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-13
• Last Update Posted: 2025-05-18
• Primary Completion: 2034-10
• Study Completion: 2037-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 135

Inclusion Criteria

• Newly diagnosed participants with the diagnosis of rhabdomyosarcoma (RMS) of any subtype. This includes embryonal rhabdomyosarcoma (fusion negative), alveolar rhabdomyosarcoma (fusion positive), as well as spindle cell and sclerosing

• Must have either low-, intermediate-risk or high-risk disease, defined as:

1. Low-risk: TP53 and MYOD1 negative AND

   • Embryonal, congenital/infantile spindle cell, or spindle cell/sclerosing FOXO1 fusion negative histology

   • Stage 1 Group I, Group II
   • Stage 1 Group III orbital only
   • Stage 2 Group I, Group II

2. Intermediate-risk: MYOD1 and TP53 negative AND

   • Embryonal, congenital/infantile spindle cell, or spindle cell/sclerosing FOXO1 fusion negative histology o Stage 1 Group III non orbit o Stage 3 Group I/II

   o Stage 2/3 Group III

   • Stage 4 Group IV and Oberlin 0-1

     • Alveolar, spindle cell/sclerosing FOXO1 fusion positive histology

   • Stage 1-3, Group I-III N0

3. High-risk: All MYOD1 and TP53 mutant tumors regardless of stage and Group AND/OR

   • Embryonal, congenital/infantile spindle cell or spindle cell/sclerosing FOXO1 fusion negative o Group IV ≥ 10 year of age and Oberlin ≥ 2

   • Alveolar, spindle cell/sclerosing FOXO1 fusion positive

     • N1
     • Stage 4 Group IV

   See Appendices I and II for Staging and Clinical Grouping.

   Age < 22 years (eligible for enrollment until 22nd birthday)

   • Performance level corresponding to ECOG score of 0, 1, or 2. The Lansky performance score should be used for participants < 16 years (see Appendix VII).

   • Participant has received no prior radiotherapy or chemotherapy for rhabdomyosarcoma (excluding steroids) unless an emergency situation requires local tumor treatment (discuss with PI).
   • Initiation of chemotherapy is planned within 6 weeks (42 days) of the definitive biopsy or surgical resection.
   • Adequate bone marrow function defined as:
   • Peripheral absolute neutrophil count (ANC) ≥ 750/μL
   • Platelet count ≥ 75,000/μL (transfusion independent)
   • Adequate liver function defined as total bilirubin < 1.5 x upper limit of normal (ULN) for age. Participants with biliary or hepatic primaries with bilirubin values greater than 1.5 x ULN may be enrolled on study if all other eligibility criteria are met.

   Adequate renal function defined as:

   Creatinine clearance or radioisotope GFR > 70 mL/min/1.732 or serum creatinine based on age as follows:

   Age Maximum serum creatinine (mg/dL) Male Female

   1 month to < 6 months 0.4 0.4 6 months to < 1 year 0.5 0.5 Age Maximum serum creatinine (mg/dL)

   1. to < 2 years 0.6 0.6
   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 1.7 1.4

   The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR25 utilizing child length and stature. Data published by the CDC.

   Participants with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract.

   • Adequate pulmonary function defined as: no evidence of dyspnea at rest and a pulse oximetry > 94% if there is a clinical indication for determination. Pulmonary function tests are not required.

   • Patients requiring emergency radiation therapy are eligible for enrollment on this trial. See Section 4.11 for radiation therapy guidelines.

   • No evidence of active, uncontrolled infection.

   All participants and/or their parents or legal guardians must sign a written informed consent.

Exclusion Criteria

• Patients who have received any chemotherapy (excluding steroids).

• Patients who have received prior full course RT at the primary site of disease. This does not exclude patients that received emergent radiation.

• Ongoing or history of non-infectious interstitial lung disease requiring significant medical intervention.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for at least 3 months after treatment is completed.
• Female patients who are pregnant are not eligible since fetal toxicities or teratogenic effects have been noted for several of the study drugs. Female participants > 10 years of age or post-menarchal must have a negative serum or urine pregnancy test within 24 hours prior to beginning treatment.
• Lactating females who are or plan to breastfeed their infants are not eligible.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
High-risk	Filgrastim, peg-filgrastim	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
Intermediate-risk	Vincristine	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
High-risk	Surgical Resection	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
Intermediate-risk	Dactinomycin	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
Low -risk	Surgical Resection	The participant will receive 12 weeks (4 cycles) of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks (4 cycles) of VA chemotherapy (vincristine, dactinomycin). Each cycle of VAC/VA chemotherapy will last for 3 weeks, for a total of 12 weeks (VAC or VA will be given in Week 1 of each cycle and vincristine will be given Weeks 2 and 3). At week 12, the participant will have scans and tests to reevaluate your tumor's response to the treatment. After surgery and radiation, the participant will receive an additional 12 weeks (4 cycles) of the same chemotherapy without cyclophosphamide. Vincristine and dactinomycin, also called "VA". After 4 cycles of VA, The investigator will re-evaluate the tumor again at week 24 and the patient will not get any more chemotherapy, but will be closely watched for any signs of tumor recurrence.
Intermediate-risk	Filgrastim, peg-filgrastim	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
Low -risk	Proton beam radiation or external beam radiation or brachytherapy	The participant will receive 12 weeks (4 cycles) of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks (4 cycles) of VA chemotherapy (vincristine, dactinomycin). Each cycle of VAC/VA chemotherapy will last for 3 weeks, for a total of 12 weeks (VAC or VA will be given in Week 1 of each cycle and vincristine will be given Weeks 2 and 3). At week 12, the participant will have scans and tests to reevaluate your tumor's response to the treatment. After surgery and radiation, the participant will receive an additional 12 weeks (4 cycles) of the same chemotherapy without cyclophosphamide. Vincristine and dactinomycin, also called "VA". After 4 cycles of VA, The investigator will re-evaluate the tumor again at week 24 and the patient will not get any more chemotherapy, but will be closely watched for any signs of tumor recurrence.
Intermediate-risk	Surgical Resection	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
Intermediate-risk	Proton beam radiation or external beam radiation or brachytherapy	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
Intermediate-risk	Liposomal irinotecan	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
High-risk	Liposomal irinotecan	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
High-risk	Proton beam radiation or external beam radiation or brachytherapy	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
Low -risk	Vincristine	The participant will receive 12 weeks (4 cycles) of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks (4 cycles) of VA chemotherapy (vincristine, dactinomycin). Each cycle of VAC/VA chemotherapy will last for 3 weeks, for a total of 12 weeks (VAC or VA will be given in Week 1 of each cycle and vincristine will be given Weeks 2 and 3). At week 12, the participant will have scans and tests to reevaluate your tumor's response to the treatment. After surgery and radiation, the participant will receive an additional 12 weeks (4 cycles) of the same chemotherapy without cyclophosphamide. Vincristine and dactinomycin, also called "VA". After 4 cycles of VA, The investigator will re-evaluate the tumor again at week 24 and the patient will not get any more chemotherapy, but will be closely watched for any signs of tumor recurrence.
Low -risk	Dactinomycin	The participant will receive 12 weeks (4 cycles) of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks (4 cycles) of VA chemotherapy (vincristine, dactinomycin). Each cycle of VAC/VA chemotherapy will last for 3 weeks, for a total of 12 weeks (VAC or VA will be given in Week 1 of each cycle and vincristine will be given Weeks 2 and 3). At week 12, the participant will have scans and tests to reevaluate your tumor's response to the treatment. After surgery and radiation, the participant will receive an additional 12 weeks (4 cycles) of the same chemotherapy without cyclophosphamide. Vincristine and dactinomycin, also called "VA". After 4 cycles of VA, The investigator will re-evaluate the tumor again at week 24 and the patient will not get any more chemotherapy, but will be closely watched for any signs of tumor recurrence.
Low -risk	Cyclophosphamide	The participant will receive 12 weeks (4 cycles) of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks (4 cycles) of VA chemotherapy (vincristine, dactinomycin). Each cycle of VAC/VA chemotherapy will last for 3 weeks, for a total of 12 weeks (VAC or VA will be given in Week 1 of each cycle and vincristine will be given Weeks 2 and 3). At week 12, the participant will have scans and tests to reevaluate your tumor's response to the treatment. After surgery and radiation, the participant will receive an additional 12 weeks (4 cycles) of the same chemotherapy without cyclophosphamide. Vincristine and dactinomycin, also called "VA". After 4 cycles of VA, The investigator will re-evaluate the tumor again at week 24 and the patient will not get any more chemotherapy, but will be closely watched for any signs of tumor recurrence.
Intermediate-risk	Cyclophosphamide	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
Intermediate-risk	Vinorelbine	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
High-risk	Vincristine	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
High-risk	Cyclophosphamide	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
High-risk	Dactinomycin	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
High-risk	Temozolomide	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
High-risk	Vinorelbine	The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.

Primary Outcome Measures

Name	Time	Method
Event-free survival (EFS)	2 years post, off therapy	We will estimate the 2-year event-free survival for intermediate-risk and high-risk patients, which is the estimated probability of a patient not having any events within the 2-year follow-up. If an event, including local failure, distant failure, death or loss to follow-up occurs for a patient within 2-year, we call it failure, otherwise call it response.
Local recurrence rate (LRR)	2 years	LRR is defined as a binary endpoint in the study. The local recurrence-free survival (LRFS) is defined as time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. The distant failure will be considered to be the competing risk, patients for whom follow-up ended without clinical improvement will be censored. The goal of the local recurrence rate endpoint is to evaluate the 2-year LRR by comparing the administration of 59.4 GyRBE and 68 GyRBE for patients (pooled intermediate- and high-risk groups) with tumor size greater than or equal to 5cm meeting the eligibility criteria for randomization (no biliary tree or specific extremity cases).; .
Maximum tolerated doses (MTDs)	4 years	MTD is defined in the study as the highest treatment dose that would deliver desirable treatment effects without resulting in a target toxicity rate greater than 0.3. For each of three groups (intermediate-risk, high-risk, and intermediate-and-high-risk-with-early-radiation), we will employ the Bayesian optimal interval (BOIN) design to find the MTD.

Trial Locations

Locations (3)

Cook Children's Medical Center; 🇺🇸 Fort Worth, Texas, United States

Sanford University; 🇺🇸 Palo Alto, California, United States

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States