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
3 other identifiers
interventional
342
1 country
65
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Jul 2026
Longer than P75 for phase_3
65 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
January 28, 2026
CompletedFirst Posted
Study publicly available on registry
March 12, 2026
CompletedStudy Start
First participant enrolled
July 14, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 31, 2031
ExpectedStudy Completion
Last participant's last visit for all outcomes
March 31, 2031
July 30, 2026
July 1, 2026
4.7 years
January 28, 2026
July 29, 2026
Conditions
Outcome Measures
Primary Outcomes (1)
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, assessed up to 5 years
Secondary Outcomes (5)
Overall survival (OS)
From randomization to death from any cause, assessed up to 4 years
Clinician-reported adverse events (AEs)
Up to 5 years
Proportion of patients undergoing delayed primary excision (DPE) among patients deemed to be DPE eligible on retrospective central review
Up to week 12 of treatment
Local failure rate for patients deemed eligible for DPE
Up to 5 years
Percentage of molecular biomarker testing that is resulted within the 6-week timeframe
Up to cycle 3 (each cycle is 21 days)
Other Outcomes (14)
Somatic molecular features TP53 mutation
Up to 5 years
Somatic molecular features MYCN amplification
Up to 5 years
Somatic molecular features MYOD1 mutation
Up to 5 years
- +11 more other outcomes
Study Arms (2)
Regimen A (Higher cyclophosphamide dose regimen
EXPERIMENTALSee Detailed Description for Regimen A.
Regimen B (Lower cyclophosphamide dose, maintenance)
EXPERIMENTALSee Detailed Description for Regimen B.
Interventions
Undergo bone marrow biopsy
Undergo bone scan
Given IV and PO
Given IV
Given IV
Undergo lumbar puncture
Undergo lymph node biopsy
Undergo MRI
Undergo FDG PET scan
Undergo radiation therapy
Undergo resection surgery
Ancillary studies
Given IV
Given IV
Undergo blood and cerebrospinal fluid sample collection
Undergo bone marrow aspiration
Undergo CT scan
Eligibility Criteria
You may qualify if:
- 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.)
- +23 more criteria
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (65)
Mattel Children's Hospital UCLA
Los Angeles, California, 90095, United States
Valley Children's Hospital
Madera, California, 93636, United States
Kaiser Permanente-Oakland
Oakland, California, 94611, United States
Children's Hospital of Orange County
Orange, California, 92868, United States
Children's Hospital Colorado
Aurora, Colorado, 80045, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver, Colorado, 80218, United States
Connecticut Children's Medical Center
Hartford, Connecticut, 06106, United States
Alfred I duPont Hospital for Children
Wilmington, Delaware, 19803, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
Hollywood, Florida, 33021, United States
Nemours Children's Clinic-Jacksonville
Jacksonville, Florida, 32207, United States
Nemours Children's Hospital
Orlando, Florida, 32827, United States
Nemours Children's Clinic - Pensacola
Pensacola, Florida, 32504, United States
Saint Mary's Medical Center
West Palm Beach, Florida, 33407, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
Atlanta, Georgia, 30329, United States
Wesley Medical Center
Wichita, Kansas, 67214, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536, United States
MaineHealth Coastal Cancer Treatment Center
Bath, Maine, 04530, United States
MaineHealth Maine Medical Center - Portland
Portland, Maine, 04102, United States
MaineHealth Cancer Care Center of York County
Sanford, Maine, 04073, United States
Maine Children's Cancer Program
Scarborough, Maine, 04074, United States
MaineHealth Maine Medical Center- Scarborough
Scarborough, Maine, 04074, United States
Sinai Hospital of Baltimore
Baltimore, Maryland, 21215, United States
UMass Memorial Medical Center - University Campus
Worcester, Massachusetts, 01655, United States
Bronson Battle Creek
Battle Creek, Michigan, 49017, United States
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
Grand Rapids, Michigan, 49503, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
Grand Rapids, Michigan, 49503, United States
Trinity Health Grand Rapids Hospital
Grand Rapids, Michigan, 49503, United States
Bronson Methodist Hospital
Kalamazoo, Michigan, 49007, United States
West Michigan Cancer Center
Kalamazoo, Michigan, 49007, United States
Beacon Kalamazoo
Kalamazoo, Michigan, 49048, United States
Trinity Health Muskegon Hospital
Muskegon, Michigan, 49444, United States
Corewell Health Lakeland Hospitals - Niles Hospital
Niles, Michigan, 49120, United States
Cancer and Hematology Centers of Western Michigan - Norton Shores
Norton Shores, Michigan, 49444, United States
Corewell Health Reed City Hospital
Reed City, Michigan, 49677, United States
Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center
Saint Joseph, Michigan, 49085, United States
Corewell Health Lakeland Hospitals - Saint Joseph Hospital
Saint Joseph, Michigan, 49085, United States
Munson Medical Center
Traverse City, Michigan, 49684, United States
University of Michigan Health - West
Wyoming, Michigan, 49519, United States
University of Mississippi Medical Center
Jackson, Mississippi, 39216, United States
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, 64108, United States
Renown Regional Medical Center
Reno, Nevada, 89502, United States
Albany Medical Center
Albany, New York, 12208, United States
University of Rochester
Rochester, New York, 14642, United States
Montefiore Medical Center - Moses Campus
The Bronx, New York, 10467, United States
Mission Hospital
Asheville, North Carolina, 28801, United States
Children's Hospital Medical Center of Akron
Akron, Ohio, 44308, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
Toledo, Ohio, 43606, United States
Legacy Emanuel Children's Hospital
Portland, Oregon, 97227, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104, United States
Saint Christopher's Hospital for Children
Philadelphia, Pennsylvania, 19134, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, 15224, United States
Rhode Island Hospital
Providence, Rhode Island, 02903, United States
East Tennessee Childrens Hospital
Knoxville, Tennessee, 37916, United States
The Children's Hospital at TriStar Centennial
Nashville, Tennessee, 37203, United States
Driscoll Children's Hospital
Corpus Christi, Texas, 78411, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390, United States
Methodist Children's Hospital of South Texas
San Antonio, Texas, 78229, United States
University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78229, United States
Primary Children's Hospital
Salt Lake City, Utah, 84113, United States
University of Virginia Cancer Center
Charlottesville, Virginia, 22908, United States
Inova Fairfax Hospital
Falls Church, Virginia, 22042, United States
Mary Bridge Children's Hospital and Health Center
Tacoma, Washington, 98405, United States
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Madison, Wisconsin, 53718, United States
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792, United States
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, 53226, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Christine M Heske
Children's Oncology Group
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NETWORK
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
January 28, 2026
First Posted
March 12, 2026
Study Start
July 14, 2026
Primary Completion (Estimated)
March 31, 2031
Study Completion (Estimated)
March 31, 2031
Last Updated
July 30, 2026
Record last verified: 2026-07