A Study Comparing Higher Dose Chemotherapy Over a Shorter Amount of Time to Lower Dose Chemotherapy Plus Maintenance Over a Longer Amount of Time in Patients With Newly Diagnosed Intermediate-Risk Rhabdomyosarcoma (IR RMS)

A Randomized Phase 3 Study to Compare VAC (Higher Cyclophosphamide Dose and Intensity) Versus VAC/VI (Lower Cyclophosphamide Dose and Intensity) Plus Maintenance Therapy in Patients With Newly Diagnosed Intermediate-Risk Rhabdomyosarcoma

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Rhabdomyosarcoma
• Intervention / Treatment: Procedure: Lumbar Puncture; Procedure: Magnetic Resonance Imaging; Drug: Vincristine Sulfate; Other: Survey Administration; Radiation: Radiation Therapy; Procedure: Computed Tomography; Drug: Irinotecan Hydrochloride; Procedure: Bone Marrow Aspiration; Biological: Dactinomycin; Procedure: Lymph Node Biopsy; Drug: Vinorelbine Tartrate; Procedure: Bone Marrow Biopsy; Drug: Cyclophosphamide; Procedure: Bone Scan; Procedure: Positron Emission Tomography; Procedure: Biospecimen Collection; Procedure: Resection

Detailed Description

PRIMARY OBJECTIVE:

I. To determine if the event free survival (EFS) of patients with intermediate risk rhabdomyosarcoma (IR RMS) treated with surgery, radiotherapy, and vincristine, dactinomycin, cyclophosphamide (VAC) (2.2 g/m^2/cycle cyclophosphamide) chemotherapy (regimen A) is better than that of patients treated with surgery, radiotherapy, and VAC alternating with vincristine, irinotecan (VI) (VAC/VI) (1.2 g/m^2/cycle cyclophosphamide) chemotherapy plus 24 weeks of maintenance chemotherapy with vinorelbine and cyclophosphamide (regimen B).

SECONDARY OBJECTIVES:

I. To determine if the overall survival (OS) of patients with IR RMS treated with surgery and/or radiotherapy, and VAC (2.2 g/m^2/cycle cyclophosphamide) chemotherapy (regimen A) is better than the OS of patients treated with surgery, radiotherapy, and VAC alternating with VI (VAC/VI) (1.2 g/m^2/cycle cyclophosphamide) plus 24 weeks of maintenance chemotherapy with vinorelbine and cyclophosphamide (regimen B).

II. To compare clinician-reported treatment-related adverse event (AE) rates between two regimens.

III. To assess the feasibility of real-time central surgical review conducted by the study team radiologists, surgeons, and radiation oncologists to determine eligibility for delayed primary excision (DPE) after week 9 imaging, and to then determine the proportion of patients deemed eligible for DPE on central review who undergo DPE.

IV. To compare the 4-year local failure (LF) rate of patients deemed DPE-eligible by central surgical review who undergo DPE with the 4-year LF rate of patients deemed DPE-eligible by central surgical review who do not undergo DPE.

V. To determine the feasibility of reporting diagnostic tumor molecular features identified via the Molecular Characterization Initiative (MCI) within 6 weeks of treatment initiation for clinical group III patients.

EXPLORATORY OBJECTIVES:

I. To prospectively evaluate the following somatic molecular features (PAX3 or PAX7 and FOXO1 fusion, MYCN amplification, TP53 mutation, MYOD1 mutation, CDK4 amplification) via MCI and determine their association with EFS and OS.

II. To explore the relationship between methylation patterns in IR RMS and EFS and OS.

III. To test the use of digital pathology/artificial intelligence to refine the diagnosis of IR RMS.

IV. To assess the differential impact of regimen intensity on gonadal toxicity experienced by patients.

V. To determine the proportion of patients having fertility discussions and fertility preservation procedures prior to starting treatment.

VI. To collect biospecimens for patient-derived xenograft (PDX) RMS model generation.

VII. To bank biospecimens for future research. VIII. To evaluate the association between Household Material Hardship (HMH) measures and EFS and OS.

OUTLINE: Patients are randomized to 1 of 2 regimens.

REGIMEN A:

CYCLES 1-4, 8, 12: Patients receive vincristine intravenously (IV) on days 1, 8 and 15 of each cycle, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 1-6 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

CYCLES 5, 9, 10, 13, 14: Patients receive vincristine IV on day 1 of each cycle, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 1-6 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

CYCLE 6: Patients receive vincristine IV on day 1 and cyclophosphamide IV over 1-6 hours on day 1. Cycle 6 continues for 21 days in the absence of disease progression or unacceptable toxicity.

CYCLE 7: Patients receive vincristine IV on days 1, 8 and 15 and cyclophosphamide IV over 1-6 hours on day 1. Cycle 7 continues for 21 days in the absence of disease progression or unacceptable toxicity.

Patients may undergo surgical resection during cycle 4 (week 12), radiation to the primary site during cycle 5 and 6 and/or radiation to distant metastatic sites during cycle 14. Patients do not receive dactinomycin during radiation. Patients undergo computed tomography (CT) scan and/or magnetic resonance imaging (MRI) and blood sample collection throughout the study. Patients may undergo lymph node biopsy during screening and/or fludeoxyglucose (FDG) positron emission tomography (PET) scan, bone scan, bone marrow biopsy and aspiration, lumbar puncture with cerebrospinal fluid sample collection throughout the study.

REGIMEN B:

CYCLES 1, 3, 8: Patients receive vincristine IV on days 1, 8 and 15 of each cycle, dactinomycin IV over 15 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 1-6 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

CYCLES 2, 4, 11: Patients receive vincristine IV on days 1, 8 and 15 of each cycle and irinotecan IV over 90 minutes on days 1-5 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

CYCLES 5, 10, 12, 14: Patients receive vincristine IV on day 1 of each cycle, dactinomycin IV over 15 or 10-15 minutes on day 1 of each cycle, and cyclophosphamide IV over 1-6 hours on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

CYCLES 6, 7, 9, 13: Patients receive vincristine IV on days 1 and 8 of each cycle and irinotecan IV over 90 minutes on days 1-5 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients may undergo surgical resection during cycle 4 (week 12), radiation to the primary site during cycle 5 and 6 and/or radiation to distant metastatic sites during cycle 14. Patients do not receive dactinomycin during radiation.

MAINTENANCE: Patients receive vinorelbine IV over 6-10 minutes on days 1, 8 and 15 of each cycle and cyclophosphamide orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients undergo CT scan and/or MRI and blood sample collection throughout the study. Patients may undergo lymph node biopsy during screening and/or FDG PET scan, bone scan, bone marrow biopsy and aspiration, lumbar puncture with cerebrospinal fluid sample collection throughout the study.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for years 2 and 3 then every 6 months for year 4 and 5.

• Study Type: Interventional
• Enrollment (Estimated): 342
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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
    • Stage 4, Group IV, < 10 years old

  • FOXO1 fusion positive (FP)

    • Stages 1-3, Groups I-III
  • Disease/staging imaging studies, if applicable, must be obtained within 21 days prior to enrollment and start of protocol therapy (repeat if necessary)
• FOXO1 status results must be available to enroll. All patients will undergo institutional pathology review and institutional FOXO1 fusion determination regardless of histology prior to enrollment. FOXO1 status may confirmed by cytogenetic, fluorescence in situ hybridization (FISH), or next generation sequencing techniques. FOXO1 fusion results should be SUBMITTED as an upload to RAVE at study enrollment because this information is required for randomization.

Please note the following:

• Institutional PAX3 versus (vs.) PAX7 determination is not required but should be submitted if available. Institutional FOXO1 testing may be performed at a contract or commercial lab as long as reports can be submitted and uploaded to RAVE. Additional molecular pathology reports, including the MCI report, are not required but should be submitted if available.

• Patients who are < 10 years old with distant metastatic disease (Stage 4) who have institutional molecular testing indicating fusion negative (FN) RMS but are later found to have fusion positive (FP) RMS by MCI or other testing will be considered to have metastatic FP disease and will go off study

  • Appropriate lymph node sampling based on primary site of disease is required
  • Patients must have a performance status of Lansky performance status score ≥ 50 for patients ≤ 16 years of age or Karnofsky performance status score ≥ 50 for patients > 16 years of age
  • Peripheral absolute neutrophil count (ANC) ≥ 750/μL (All laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Laboratory studies must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment. Laboratory tests need not be repeated if therapy starts within seven (7) days of their most recent prior assessment. If the result of a laboratory study that is repeated at any time post-enrollment and prior to the start of protocol therapy is outside the limits for eligibility, then the evaluation must be rechecked within 48 hours prior to initiating protocol therapy. The results of the recheck must be within the limits for eligibility to proceed. If the result of the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.)
  • Platelet count ≥ 75,000/μL (All laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Laboratory studies must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment. Laboratory tests need not be repeated if therapy starts within seven (7) days of their most recent prior assessment. If the result of a laboratory study that is repeated at any time post-enrollment and prior to the start of protocol therapy is outside the limits for eligibility, then the evaluation must be rechecked within 48 hours prior to initiating protocol therapy. The results of the recheck must be within the limits for eligibility to proceed. If the result of the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.)
  • For pediatric patients < 18 years of age:

• A serum creatinine based on age/sex as follows:

  • 1 month to < 6 months: Maximum serum creatinine 0.4 mg/dL (male), 0.4 mg/dL (female)
  • 6 months to < 1 year: Maximum serum creatinine 0.5 mg/dL (male), 0.5 mg/dL (female)
  • 1 to < 2 years: Maximum serum creatinine 0.6 mg/dL (male), 0.6 mg/dL (female)
  • 2 to < 6 years: Maximum serum creatinine 0.8 mg/dL (male), 0.8 mg/dL (female)
  • 6 to < 10 years: Maximum serum creatinine 1 mg/dL (male), 1 mg/dL (female)
  • 10 to < 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female)
  • 13 to < 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
  • ≥ 16 years: Maximum serum creatinine 1.7 mg/dL (male),1.4 mg/dL (female)
• OR a 24-hour urine Creatinine clearance ≥ 50 mL/min/1.73 m^2

• OR a glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).

  • Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
• Patients with an elevated serum creatinine due to obstructive hydronephrosis secondary to tumor are still eligible. However, patients with urinary tract obstruction by tumor must have unimpeded urinary flow established via diversion (ie, percutaneous nephrostomies or ureteric stents) of the urinary tract.

For adult patients (aged 18 years or older):

• Creatinine clearance ≥ 50 mL/min, as estimated by the Cockcroft and Gault formula or as a 24-hour urine collection. Estimated creatinine clearance is based on actual body weight.

(All laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Laboratory studies must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment. Laboratory tests need not be repeated if therapy starts within seven (7) days of their most recent prior assessment. If the result of a laboratory study that is repeated at any time post-enrollment and prior to the start of protocol therapy is outside the limits for eligibility, then the evaluation must be rechecked within 48 hours prior to initiating protocol therapy. The results of the recheck must be within the limits for eligibility to proceed. If the result of the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.)

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (All laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Laboratory studies must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment. Laboratory tests need not be repeated if therapy starts within seven (7) days of their most recent prior assessment. If the result of a laboratory study that is repeated at any time post-enrollment and prior to the start of protocol therapy is outside the limits for eligibility, then the evaluation must be rechecked within 48 hours prior to initiating protocol therapy. The results of the recheck must be within the limits for eligibility to proceed. If the result of the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.)

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

• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 135 U/L (All laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Laboratory studies must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment. Laboratory tests need not be repeated if therapy starts within seven (7) days of their most recent prior assessment. If the result of a laboratory study that is repeated at any time post-enrollment and prior to the start of protocol therapy is outside the limits for eligibility, then the evaluation must be rechecked within 48 hours prior to initiating protocol therapy. The results of the recheck must be within the limits for eligibility to proceed. If the result of the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.)

  • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L.
• Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

Exclusion Criteria:

• 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

• Patients with central nervous system involvement of RMS as defined below:

  • Malignant cells detected in cerebrospinal fluid
  • Intra-parenchymal brain metastases separate and distinct from primary tumor (i.e., direct extension from parameningeal primary tumors is allowed)
  • Diffuse leptomeningeal disease
• Patients with known Charcot-Marie-Tooth disease

• Patients who have received any chemotherapy (excluding steroids) and/or radiation therapy for RMS prior to enrollment. Note: the following exception:

  • Patients requiring emergency radiation therapy for life-threatening complications of tumor burden due to RMS. These patients are eligible, provided they are consented to ARST2531 prior to administration of radiation.
  • Note: Patients who have received or are receiving chemotherapy or radiation for non-malignant conditions (eg, autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regimen A (Higher cyclophosphamide dose regimen; See Detailed Description for Regimen A.	Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Drug: Vincristine Sulfate; Given IV; Other Names: Oncovin; Kyocristine; Leurocristine Sulfate; Leurocristine, sulfate; Vincasar; Vincosid; Vincrex; Vincristine, sulfate; Other: Survey Administration; Ancillary studies; Radiation: Radiation Therapy; Undergo radiation therapy; Other Names: Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Energy Type; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Biological: Dactinomycin; Given IV; Other Names: Cosmegen; Actinomycin A IV; Actinomycin C1; Actinomycin I1; Actinomycin IV; Actinomycin X 1; Actinomycin-[thr-val-pro-sar-meval]; DACT; Dactinomycine; Lyovac Cosmegen; Meractinomycin; Actinomycin D; Procedure: Lymph Node Biopsy; Undergo lymph node biopsy; Other Names: Biopsy of Lymph Node; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Drug: Cyclophosphamide; Given IV and PO; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Asta B 518; B-518; WR-138719; B 518; B518; WR 138719; WR138719; Procedure: Bone Scan; Undergo bone scan; Other Names: Bone Scintigraphy; Procedure: Positron Emission Tomography; Undergo FDG PET scan; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Procedure: Biospecimen Collection; Undergo blood and cerebrospinal fluid sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Resection; Undergo resection surgery; Other Names: Surgical Resection
Experimental: Regimen B (Lower cyclophosphamide dose, maintenance); See Detailed Description for Regimen B.	Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Drug: Vincristine Sulfate; Given IV; Other Names: Oncovin; Kyocristine; Leurocristine Sulfate; Leurocristine, sulfate; Vincasar; Vincosid; Vincrex; Vincristine, sulfate; Other: Survey Administration; Ancillary studies; Radiation: Radiation Therapy; Undergo radiation therapy; Other Names: Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Energy Type; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Campto; Camptosar; U-101440E; CPT-11; Camptothecin 11; Camptothecin-11; CPT 11; Irinomedac; Irinotecan Hydrochloride Trihydrate; Irinotecan Monohydrochloride Trihydrate; CPT11; U 101440E; U101440E; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Biological: Dactinomycin; Given IV; Other Names: Cosmegen; Actinomycin A IV; Actinomycin C1; Actinomycin I1; Actinomycin IV; Actinomycin X 1; Actinomycin-[thr-val-pro-sar-meval]; DACT; Dactinomycine; Lyovac Cosmegen; Meractinomycin; Actinomycin D; Procedure: Lymph Node Biopsy; Undergo lymph node biopsy; Other Names: Biopsy of Lymph Node; Drug: Vinorelbine Tartrate; Given IV; Other Names: Navelbine; Eunades; NVB; Biovelbin; KW-2307; Navelbine Ditartrate; Vinorelbine Ditartrate; KW 2307; KW2307; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Drug: Cyclophosphamide; Given IV and PO; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Asta B 518; B-518; WR-138719; B 518; B518; WR 138719; WR138719; Procedure: Bone Scan; Undergo bone scan; Other Names: Bone Scintigraphy; Procedure: Positron Emission Tomography; Undergo FDG PET scan; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Procedure: Biospecimen Collection; Undergo blood and cerebrospinal fluid sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Resection; Undergo resection surgery; Other Names: Surgical Resection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization until the first occurrence of progression or relapse, second malignancy, or death, up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization to death from any cause, up to 5 years
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.	Up to 5 years
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.	Up to week 12 of treatment
Local failure rate for patients deemed eligible for DPE	Cumulative incidence curves will be used to present the local failure rates over time.	Up to 5 years
Percentage of molecular biomarker testing that is resulted within the 6-week timeframe	Assessing the feasibility of reporting diagnostic tumor molecular features in patients with clinical group III intermediate risk rhabdomyosarcoma via the molecular characterization initiative (MCI) among the first 50 Clinical Group III patients who initiated treatment and consent to MCI. If 14 or more patients cannot have diagnostic tumor molecular features identified via MCI within 6 weeks of treatment, this aim will be considered not feasible.	Up to cycle 3 (each cycle is 21 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Up to 5 years
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.	Up to 5 years
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.	Up to 5 years
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.	Up to 5 years
Methylation patterns: EFS	Deoxyribonucleic acid (DNA) methylation data from rhabdomyosarcoma tumors collected during the conduct of ARST2531 will be analyzed. This data will be collected by array-based methods as part of MCI. The clinical significance of the rhabdomyosarcoma subsets determined in our DNA methylation studies will be analyzed. The association of DNA methylation subsets to EFS will be analyzed using the log-rank test and Cox model.	Up to 5 years
Methylation patterns: OS	Deoxyribonucleic acid (DNA) methylation data from rhabdomyosarcoma tumors collected during the conduct of ARST2531 will be analyzed. This data will be collected by array-based methods as part of MCI. The clinical significance of the rhabdomyosarcoma subsets determined in our DNA methylation studies will be analyzed. The association of DNA methylation subsets to OS will be analyzed using the log-rank test and Cox model.	Up to 5 years
Use of digital pathology/artificial intelligence: Risk Predictions compared to EFS	Risk predictions will be recorded and ultimately compared to clinical outcomes, specifically 4-year EFS.	4 years from study enrollment
Use of digital pathology/artificial intelligence: Risk Predictions compared to OS	Risk predictions will be recorded and ultimately compared to clinical outcomes, specifically 4-year OS.	4 years from study enrollment
Impact of regimen intensity on gonadal toxicity	Anti-mullerian hormone (AMH) levels and follicle stimulating hormone (FSH) levels will be converted to z scores based on age using mean and standard deviation data. AMH, FSH and Inhibin A z-score will be summarized by treatment arms before initiation, end of the therapy and one year post-therapy stratified by sex. Comparison will be made at one year post therapy using t-test.	Up to 5 years
Clinical practices of fertility discussions	Fertility consultation information (risk assessment, available fertility preservation options) will be collected and summarized to determine the frequency of fertility discussions	Up to 5 years
Clinical practices of fertility procedures	Fertility consultation information (risk assessment, available fertility preservation options) will be collected and summarized to determine the fraction of patients who undergo a fertility preservation procedure before or during the study therapy.	Up to 5 years
Patient derived xenograft rhabdomyosarcoma model generation	Will viably collect tumor samples for generation of patient-derived xenograft models that can be used in future research studies to advance the understanding of rhabdomyosarcoma biology.	Pre-treatment and cycle 3 (each cycle is 21 days)
Household material hardship (HMH)	HMH will be analyzed first as a binary variable (present/absent) and then as an ordinal (0-4) variable. Cox proportional hazard model will be used to assess the association between variable EFS and OS. Then association between the ordinal measure and EFS and OS will be assessed using COX model.	At time of survey completion, from enrollment until start of cycle 3 (each cycle is 21 days)
EFS by treatment arm within racial subgroups	Will be estimated using the Kaplan-Meier method. The corresponding 95% confidence interval (CI) will be estimated using Peto-peto method.	Up to 5 years
EFS by treatment arm within ethnicity subgroups	Will be estimated using the Kaplan-Meier method. The corresponding 95% CI will be estimated using Peto-peto method.	Up to 5 years
EFS by treatment arm within sex subgroups	Will be estimated using the Kaplan-Meier method. The corresponding 95% CI will be estimated using Peto-peto method.	Up to 5 years

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Investigators: Principal Investigator: Christine M Heske, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start (Estimated): June 22, 2026
• Primary Completion (Estimated): March 31, 2031
• Study Completion (Estimated): March 31, 2031

Study Registration Dates

• First Submitted: January 28, 2026
• First Submitted That Met QC Criteria: March 11, 2026
• First Posted (Actual): March 12, 2026

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms, Muscle Tissue; Myosarcoma; Rhabdomyosarcoma; Peptides; Amino Acids, Peptides, and Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Hydrocarbons; Physical Phenomena; Camptothecin; Alkaloids; Polycyclic Compounds; Indoles; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Spectrum Analysis; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Macrocyclic Compounds; Peptides, Cyclic; Diagnostic Techniques, Neurological; Heterocyclic Compounds, 3-Ring; Lymph Node Excision; Irinotecan; Vinorelbine; Cyclophosphamide; Vincristine; Dactinomycin; Radiotherapy; Radiation; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; Spinal Puncture; Sentinel Lymph Node Biopsy
• Other Study ID Numbers: ARST2531 (Other Identifier: CTEP); U10CA180886 (U.S. NIH Grant/Contract); NCI-2026-00319 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes