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.

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.

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.

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request

Data will be made available at the time of article publication.

Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.