Chemotherapy for the Treatment of Patients With Newly Diagnosed Very Low-Risk and Low Risk Fusion Negative Rhabdomyosarcoma

Inclusion Criteria:

• All patients must be enrolled on APEC14B1 (NCT02402244) and consented to theMolecular Characterization Initiative (Part A) prior to enrollment and treatment onARST2032 (this trial).

• Patients must be =< 21 years at the time of enrollment.

• Patients must have newly diagnosed embryonal rhabdomyosarcoma (ERMS), spindlecell/sclerosing RMS, or FOXO1 fusion negative alveolar rhabdomyosarcoma (ARMS) (institutional FOXO1 fusion results are acceptable). RMS types included under ERMSinclude those classified in the 1995 International Classification ofRhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), whichare reclassified in the 2020 World Health Organization (WHO) classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassingthe historical spindle cell ERMS variant and the newly recognized sclerosing RMSvariant). Enrollment in APEC14B1 is required for all patients.

• All patients will be evaluated for stage and clinical group. Note that clinicalgroup designation assigned at the time of enrollment on study remains unchangedregardless of any second-look operation that may be performed.

• Patients will be eligible for the very low-risk stratum (Regimen VA) ifthey have Stage 1, CG I disease.

• Patients will be eligible for the low-risk stratum (Regimen VAC/VA) ifthey have Stage 1, CG II disease, Stage 2, CG I or II disease, or Stage 1,CG III (orbit only) disease.

• Paratesticular Tumors: Staging ipsilateral retroperitoneal lymph node sampling (SIRLNS) is required for all patients >= 10 years of age with paratesticulartumors who do not have gross nodal involvement on imaging.

• Extremity Tumors: Regional lymph node sampling is required for histologicevaluation in patients with extremity tumors.

• Clinically or radiographically enlarged nodes must be sampled for histologicevaluation.

• Patients must have a Lansky (for patients =< 16 years of age) or Karnofsky (forpatients > 16 years of age) performance status score of >= 50. Patients who areunable to walk because of paralysis, but who are up in a wheelchair, will beconsidered ambulatory for the purpose of assessing performance score.

• Peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior toenrollment).

• Platelet count >= 75,000/uL (transfusion independent) (within 7 days prior toenrollment).

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 or a serum creatinine (within 7 days prior to enrollment) based onage/gender as follows:

• Age: 1 month to < 6 months; Maximum serum creatinine (mg/dL): 0.4 (male) : 0.4 (female)

• Age: 6 months to < 1 year; Maximum serum creatinine (mg/dL): 0.5 (male) : 0.5 (female)

• Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male) : 0.6 (female)

• Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male) : 0.8 (female)

• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male) : 1 (female)

• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male) : 1.2 (female)

• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male) : 1.4 (female)

• Age >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male) : 1.4 (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior toenrollment), and

• If there is evidence of biliary obstruction by the tumor, then the totalbilirubin must be < 3 x ULN for age.

• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to thevalue of 45 U/L.

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135U/L

• If there is evidence of biliary obstruction by the tumor, then the totalbilirubin must be < 3 x ULN for age

• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to thevalue of 45 U/L

• All patients and/or their parents or legal guardians must sign a written informedconsent.

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

Exclusion Criteria:

• Patients who have received prior chemotherapy and/or radiation therapy for cancerprior to enrollment. Surgical resection alone of previous cancer(s) is permitted.

• Patients who have received chemotherapy or radiation for non-malignant conditions (e.g., autoimmune diseases) are eligible. Patients must discontinue chemotherapy fornon-malignant conditions prior to starting protocol therapy.

• Vincristine is sensitive substrate of the CYP450 3A4 isozyme. Patients must not havereceived drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7days prior to study enrollment.

• Patients unable to undergo radiation therapy, if necessary, as specified in theprotocol.

• Evidence of uncontrolled infection.

• Female patients who are pregnant since fetal toxicities and teratogenic effects havebeen noted for several of the study drugs. A pregnancy test is required for femalepatients of childbearing potential.

• Lactating females who plan to breastfeed their infants.

• Sexually active patients of reproductive potential who have not agreed to use aneffective contraceptive method for the duration of their study participation.