NCT07466316

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

• Status: Not Yet Recruiting
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 342 (estimated)
• Sponsor: Children's Oncology Group · Network
• Sex: All
• Age: 50 Years
• Healthy volunteers: Not accepted

Summary

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.

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.

Conditions

• Rhabdomyosarcoma

Interventions

Type	Name	Description
PROCEDURE	Biospecimen Collection	Undergo blood and cerebrospinal fluid sample collection
PROCEDURE	Bone Marrow Aspiration	Undergo bone marrow aspiration
PROCEDURE	Bone Marrow Biopsy	Undergo bone marrow biopsy
PROCEDURE	Bone Scan	Undergo bone scan
PROCEDURE	Computed Tomography	Undergo CT scan
DRUG	Cyclophosphamide	Given IV and PO
BIOLOGICAL	Dactinomycin	Given IV
DRUG	Irinotecan Hydrochloride	Given IV
PROCEDURE	Lumbar Puncture	Undergo lumbar puncture
PROCEDURE	Lymph Node Biopsy	Undergo lymph node biopsy
PROCEDURE	Magnetic Resonance Imaging	Undergo MRI
PROCEDURE	Positron Emission Tomography	Undergo FDG PET scan
RADIATION	Radiation Therapy	Undergo radiation therapy
PROCEDURE	Resection	Undergo resection surgery
OTHER	Survey Administration	Ancillary studies
DRUG	Vincristine Sulfate	Given IV
DRUG	Vinorelbine Tartrate	Given IV

Timeline

• Start date: 2026-06-22
• Primary completion: 2031-03-31
• Completion: 2031-03-31
• First posted: 2026-03-12
• Last updated: 2026-03-12

Regulatory

• FDA-regulated drug study