This phase III trial compares higher dose chemotherapy, with vincristine, dactinomycin and cyclophosphamide, over a shorter amount of time to lower dose chemotherapy plus maintenance, with vincristine, dactinomycin, cyclophosphamide, irinotecan and vinorelbine, over a longer amount of time, along with standard of care surgery and radiation, in patients with newly diagnosed intermediate risk rhabdomyosarcoma. Vincristine and vinorelbine are in a class of medications called vinca alkaloids. They work by stopping tumor cells from growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only used in cancer chemotherapy (antineoplastic antibiotic). It works by damaging the cell's DNA and may kill tumor cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells. It may also lower the body's immune response. Irinotecan is in a class of antineoplastic medications called topoisomerase I inhibitors. It blocks a certain enzyme needed for cell division and DNA repair and may kill tumor cells. It is not yet known if the higher dose chemotherapy over a shorter amount of time or the lower dose chemotherapy with maintenance over a longer amount of time is more effective in the treatment of patient with newly diagnosed, intermediate risk rhabdomyosarcoma.
Patient must be ≤ 50 years of age at the time of enrollment
Patients with newly diagnosed soft tissue RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification, are eligible to enroll on the study based upon FOXO1 fusion status, Stage, Intergroup Rhabdomyosarcoma Study (IRS) group, and age, as below. FOXO1 fusion status must be determined prior to enrollment. RMS types included under embryonal rhabdomyosarcoma (ERMS) include those which are reclassified in the 2020 World Health Organization (WHO) classification as ERMS (typical, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Classification of alveolar Rhabdomyosarcoma (ARMS) in the 2020 WHO Classification is the same as in the International Classification of Rhabdomyosarcoma (ICR) and includes classic and solid variants.
FOXO1 fusion negative (FN)
Stage 2/3, Group III
Patients with evidence of uncontrolled infection are not eligible
Previous or concurrent cancer(s) that is/was being treated with chemotherapy and/or radiation.
Note: Surgical resection alone of previous or concurrent cancer(s) is allowed
Malignant cells detected in cerebrospinal fluid
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood and cerebrospinal fluid sample collection
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Bone Scan
Procedure/SurgeryUndergo bone scan
Computed Tomography
Procedure/SurgeryUndergo CT scan
Cyclophosphamide
DrugGiven IV and PO
Dactinomycin
Biological/VaccineGiven IV
Irinotecan Hydrochloride
DrugGiven IV
Lumbar Puncture
Procedure/SurgeryUndergo lumbar puncture
Lymph Node Biopsy
Procedure/SurgeryUndergo lymph node biopsy
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Positron Emission Tomography
Procedure/SurgeryUndergo FDG PET scan
Radiation Therapy
RadiationUndergo radiation therapy
Resection
Procedure/SurgeryUndergo resection surgery
Survey Administration
Other interventionAncillary studies
Vincristine Sulfate
DrugGiven IV
Vinorelbine Tartrate
DrugGiven IV
Event free survival (EFS)
Will be estimated using the Kaplan-Meier method and will be compared between the randomized treatment groups using the stratified log-rank test.
Overall survival (OS)
Will be estimated using the Kaplan-Meier method and will be compared between the randomized treatment groups using the stratified log-rank test.
Clinician-reported adverse events (AEs)
Clinician-reported treatment-related grade 3 or higher AEs will be reported using Common Terminology Criteria for Adverse Events version 5.0. Comparison of toxicities will be conducted using Fisher's exact test. The maximum grade for each toxicity will be recorded for each patient. Averages and confidence intervals for these toxicity frequencies will be provided.
Proportion of patients who successfully undergo real-time review of delayed primary excision (DPE)
Assessing the feasibility of real-time central review of DPE. The proportion of patients who successfully undergo real-time review by the time of local control will be evaluated to determine feasibility. If 80% or greater of the eligible cases reviewed have a determination of DPE-eligible or DPE-ineligible by the time of local control (by Week 12), then DPE eligibility assessment will be deemed feasible. The percentage of DPE-eligible patients who underwent DPE/all DPE-eligible patients will be calculated.
Local failure rate for patients deemed eligible for DPE
Cumulative incidence curves will be used to present the local failure rates over time.
Somatic molecular featuresTP53 mutation
Binary (1 = Mutation present, 0 = Mutation absent) no unit. Assessed via MCI to determine association with EFS and OS. EFS and OS will be estimated using KM method. The distribution will be compared by molecular features using log-rank test
Somatic molecular features MYCN amplification TP53 mutation
Binary (1 = Amplified, 0 = Not amplified) no unit. Assessed via MCI to determine association with EFS and OS. EFS and OS will be estimated using KM method. The distribution will be compared by molecular features using log-rank test.
Somatic molecular features MYOD1 mutation
Binary (1 = Mutation present, 0 = Mutation absent) no unit. Assessed via MCI to determine association with EFS and OS. EFS and OS will be estimated using KM method. The distribution will be compared by molecular features using log-rank test.
Somatic molecular features CDK4 amplification
Binary (1 = Not amplified, 0 = Amplified) no unit. Assessed via MCI to determine association with EFS and OS. EFS and OS will be estimated using KM method. The distribution will be compared by molecular features using log-rank test.
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