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

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.