Risk-Adapted Focal Proton Beam Radiation and/or Surgery in Patients With Low, Intermediate and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy
NCT ID: NCT01871766
Last Updated: 2025-12-17
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ACTIVE_NOT_RECRUITING
PHASE2
115 participants
INTERVENTIONAL
2013-12-04
2030-06-30
Brief Summary
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PRIMARY OBJECTIVE:
* Estimate event-free survival for intermediate risk participants treated with vincristine, dactinomycin and cyclophosphamide with the addition of maintenance anti-angiogenic therapy.
SECONDARY OBJECTIVES:
* Estimate the false negative rate and incidence of additional positive lymph nodes in participants undergoing sentinel lymph node biopsy followed by limited nodal dissection.
* Maintain a high local control rate in participants treated with surgery and/or limited volume proton and photon radiation without dose escalation.
* Define the incidence and type of failure in participants who receive risk-adapted local therapy relative to the primary tumor volume.
* Establish the feasibility of delivering 4 cycles of maintenance anti-angiogenic chemotherapy in intermediate and high risk patients following standard chemotherapy.
* Estimate the event free survival for high risk patients receiving interval dose compressed therapy and maintenance anti-angiogenic therapy.
* Define the incidence of CTC grade 3 and higher toxicities (and specific grade 1-2 toxicities) related to proton beam therapy.
Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Low-Risk, Subset 1
Lymph node sampling will take place pretreatment and pre-surgery. Participants receive 12 weeks of chemotherapy (vincristine, dactinomycin and cyclophosphamide). They are then evaluated to determine how the tumor responded to treatment. Twelve additional weeks of chemotherapy (vincristine and dactinomycin) is given, followed by evaluation for tumor response. No further treatment is given, and participants are observed closely. Myeloid growth factor is given if needed.
Participants also receive \^1\^1C-methionine as described in the intervention section.
Vincristine
Dosage and route of administration:
* \< 1 year of age=0.025 mg/kg intravenously (IV)
* \> 1 year and \< 3 years= 0.05 mg/kg IV
* ≥ 3 years=1.5 mg/m\^2 IV. Maximum dose 2 mg in all participants.
Dactinomycin
Dosage and route of administration:
* \< 1 year=0.025 mg/kg IV push
* ≥ 1 year=0.045 mg/kg IV push over 1 to 5 minutes.
Cyclophosphamide
Dosage and route of administration:
During VAC chemotherapy:
* \< 3 years of age = 40 mg/kg IV
* ≥ 3 years of age = 1200 mg/m\^2 IV, with MESNA.
During maintenance for intermediate-risk participants:
* oral cyclophosphamide 50 mg/m\^2/dose/day (liquid or tablet)
Surgical Resection
Surgery will be performed for the primary site tumor with the goal of removing tumor cells while maintaining function in the organ or adjacent organs involved.
Radiation
Radiation therapy will be delivered at approximately week 13 (intermediate risk) or week 19 (high risk) after initiation of chemotherapy. Certain patients will receive radiation at week 4.
Myeloid Growth Factor
If a participant's chemotherapy has been delayed or modified for hematologic toxicity, or if participant experiences a significant life-threatening toxicity due to bone marrow suppression, myeloid growth factor (either filgrastim or peg-filgrastim) will be given per institutional practice.
High Risk participants receive filgrastim 5 micrograms/kg/day (maximum 300 micrograms) subcutaneously beginning 24-36 hours after the last dose of chemotherapy. Continue at least 7 days, or until the ANC ≥750/µL whichever comes last. Sargramostim or peg-filgrastim may not be used.
Lymph Node Sampling
Clinical and/or imaging evaluation of regional lymph nodes will be conducted pretreatment and preoperatively as part of staging. This will aid in determining the efficacy of this procedure in defining involved lymphatics in "at risk" patients.
^1^1C-methionine
Participants receive \^1\^1C-methionine to relate the distribution, intensity and change in \^1\^1C-methionine CTPET imaging of the primary site to tumor control and patient outcome.
Low-Risk, Subset 2
Lymph node sampling will take place pretreatment and pre-surgery. Participants receive 12 weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide). The tumor is evaluated to determine how it responded to treatment. Radiation therapy and/or surgical resection is performed to destroy or remove the remaining tumor. Twelve additional weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide) is given, followed by evaluation for tumor response. If delayed for medical reasons, radiation therapy and/or surgical resection is done at this time. Participants then receive 16 weeks of additional chemotherapy (vincristine, dactinomycin and cyclophosphamide). No further treatment is given, and participants are observed closely. Myeloid growth factor will be given if needed.
Participants also receive \^1\^1C-methionine as described in the intervention section.
Vincristine
Dosage and route of administration:
* \< 1 year of age=0.025 mg/kg intravenously (IV)
* \> 1 year and \< 3 years= 0.05 mg/kg IV
* ≥ 3 years=1.5 mg/m\^2 IV. Maximum dose 2 mg in all participants.
Dactinomycin
Dosage and route of administration:
* \< 1 year=0.025 mg/kg IV push
* ≥ 1 year=0.045 mg/kg IV push over 1 to 5 minutes.
Cyclophosphamide
Dosage and route of administration:
During VAC chemotherapy:
* \< 3 years of age = 40 mg/kg IV
* ≥ 3 years of age = 1200 mg/m\^2 IV, with MESNA.
During maintenance for intermediate-risk participants:
* oral cyclophosphamide 50 mg/m\^2/dose/day (liquid or tablet)
Radiation
Radiation therapy will be delivered at approximately week 13 (intermediate risk) or week 19 (high risk) after initiation of chemotherapy. Certain patients will receive radiation at week 4.
Myeloid Growth Factor
If a participant's chemotherapy has been delayed or modified for hematologic toxicity, or if participant experiences a significant life-threatening toxicity due to bone marrow suppression, myeloid growth factor (either filgrastim or peg-filgrastim) will be given per institutional practice.
High Risk participants receive filgrastim 5 micrograms/kg/day (maximum 300 micrograms) subcutaneously beginning 24-36 hours after the last dose of chemotherapy. Continue at least 7 days, or until the ANC ≥750/µL whichever comes last. Sargramostim or peg-filgrastim may not be used.
Lymph Node Sampling
Clinical and/or imaging evaluation of regional lymph nodes will be conducted pretreatment and preoperatively as part of staging. This will aid in determining the efficacy of this procedure in defining involved lymphatics in "at risk" patients.
^1^1C-methionine
Participants receive \^1\^1C-methionine to relate the distribution, intensity and change in \^1\^1C-methionine CTPET imaging of the primary site to tumor control and patient outcome.
Intermediate-Risk
Lymph node sampling takes place pretreatment and pre-surgery. Participants receive 12 weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide). The tumor is evaluated for treatment response. Radiation therapy and/or surgical resection is done. Twelve weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide) is followed by evaluation for tumor response. If delayed for medical reasons, radiation therapy and/or surgical resection is done at this time. Participants receive 16 weeks of chemotherapy (vincristine, dactinomycin, cyclophosphamide) followed by 12 weeks of maintenance treatment (bevacizumab, sorafenib, oral cyclophosphamide). No further treatment is given, and participants are observed closely. Myeloid growth factor is given if needed.
Participants also receive \^1\^1C-methionine as described in the intervention section.
Vincristine
Dosage and route of administration:
* \< 1 year of age=0.025 mg/kg intravenously (IV)
* \> 1 year and \< 3 years= 0.05 mg/kg IV
* ≥ 3 years=1.5 mg/m\^2 IV. Maximum dose 2 mg in all participants.
Dactinomycin
Dosage and route of administration:
* \< 1 year=0.025 mg/kg IV push
* ≥ 1 year=0.045 mg/kg IV push over 1 to 5 minutes.
Cyclophosphamide
Dosage and route of administration:
During VAC chemotherapy:
* \< 3 years of age = 40 mg/kg IV
* ≥ 3 years of age = 1200 mg/m\^2 IV, with MESNA.
During maintenance for intermediate-risk participants:
* oral cyclophosphamide 50 mg/m\^2/dose/day (liquid or tablet)
Surgical Resection
Surgery will be performed for the primary site tumor with the goal of removing tumor cells while maintaining function in the organ or adjacent organs involved.
Radiation
Radiation therapy will be delivered at approximately week 13 (intermediate risk) or week 19 (high risk) after initiation of chemotherapy. Certain patients will receive radiation at week 4.
Bevacizumab
Dosage and route of administration: 15 mg/kg/dose/day IV.
Sorafenib
Dosage and route of administration: 90 mg/m\^2/dose twice daily.
Myeloid Growth Factor
If a participant's chemotherapy has been delayed or modified for hematologic toxicity, or if participant experiences a significant life-threatening toxicity due to bone marrow suppression, myeloid growth factor (either filgrastim or peg-filgrastim) will be given per institutional practice.
High Risk participants receive filgrastim 5 micrograms/kg/day (maximum 300 micrograms) subcutaneously beginning 24-36 hours after the last dose of chemotherapy. Continue at least 7 days, or until the ANC ≥750/µL whichever comes last. Sargramostim or peg-filgrastim may not be used.
Lymph Node Sampling
Clinical and/or imaging evaluation of regional lymph nodes will be conducted pretreatment and preoperatively as part of staging. This will aid in determining the efficacy of this procedure in defining involved lymphatics in "at risk" patients.
^1^1C-methionine
Participants receive \^1\^1C-methionine to relate the distribution, intensity and change in \^1\^1C-methionine CTPET imaging of the primary site to tumor control and patient outcome.
High-Risk
Lymph node sampling takes place pretreatment and pre-surgery. Participants receive 6 weeks (2 cycles) chemotherapy (vincristine and irinotecan). The tumor is evaluated for treatment response. 3 cycles of chemotherapy \[vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide (or etoposide phosphate) (VDC/IE)\] are given. Dexrazoxane is given prior to each dose of doxorubicin. Radiation therapy begins at week 4 or 20 (depending on tumor location) while receiving vincristine and irinotecan. 2 cycles of VDC/IE, 4 cycles of modified vincristine, dactinomycin, cyclophosphamide (VAC), then 2 cycles of modified vincristine/irinotecan (total of 54 weeks). High risk participants also receive additional maintenance therapy beginning week 55 with anti-angiogenic chemotherapy (bevacizumab, sorafenib, cyclophosphamide). Myeloid growth factor is given as needed.
Participants also receive \^1\^1C-methionine as described in the intervention section.
Vincristine
Dosage and route of administration:
* \< 1 year of age=0.025 mg/kg intravenously (IV)
* \> 1 year and \< 3 years= 0.05 mg/kg IV
* ≥ 3 years=1.5 mg/m\^2 IV. Maximum dose 2 mg in all participants.
Dactinomycin
Dosage and route of administration:
* \< 1 year=0.025 mg/kg IV push
* ≥ 1 year=0.045 mg/kg IV push over 1 to 5 minutes.
Cyclophosphamide
Dosage and route of administration:
During VAC chemotherapy:
* \< 3 years of age = 40 mg/kg IV
* ≥ 3 years of age = 1200 mg/m\^2 IV, with MESNA.
During maintenance for intermediate-risk participants:
* oral cyclophosphamide 50 mg/m\^2/dose/day (liquid or tablet)
Surgical Resection
Surgery will be performed for the primary site tumor with the goal of removing tumor cells while maintaining function in the organ or adjacent organs involved.
Radiation
Radiation therapy will be delivered at approximately week 13 (intermediate risk) or week 19 (high risk) after initiation of chemotherapy. Certain patients will receive radiation at week 4.
Bevacizumab
Dosage and route of administration: 15 mg/kg/dose/day IV.
Sorafenib
Dosage and route of administration: 90 mg/m\^2/dose twice daily.
Myeloid Growth Factor
If a participant's chemotherapy has been delayed or modified for hematologic toxicity, or if participant experiences a significant life-threatening toxicity due to bone marrow suppression, myeloid growth factor (either filgrastim or peg-filgrastim) will be given per institutional practice.
High Risk participants receive filgrastim 5 micrograms/kg/day (maximum 300 micrograms) subcutaneously beginning 24-36 hours after the last dose of chemotherapy. Continue at least 7 days, or until the ANC ≥750/µL whichever comes last. Sargramostim or peg-filgrastim may not be used.
Lymph Node Sampling
Clinical and/or imaging evaluation of regional lymph nodes will be conducted pretreatment and preoperatively as part of staging. This will aid in determining the efficacy of this procedure in defining involved lymphatics in "at risk" patients.
Irinotecan
Dosage and Route Administration: During interval compressed therapy - irinotecan 50mg/m\^2 IV (maximum dose 100 mg/day) daily x 5.
Ifosfamide
Dosage and Route of Administration: During interval compressed therapy - Age \> 1 year: 1800 mg/m\^2/day IV x 5 Age \<1 year: treat with 50% doses calculated on a m\^2 basis.
Etoposide
Dosage and Route of Administration:
Age \>1 year 100 mg/m\^2/day IV x 5 Age \< 1 year treat with 50% doses calculated on a m\^2 basis
Etoposide Phosphate
Dosage and Route of Administration: Used in substitution for etoposide in participants who experience allergic reaction. It will be administered 100 mg/m\^2/day IV.
Doxorubicin
Dosage and route of Administration:
Age ≥1 year, 37.5 mg/m\^2 IV over 1 hour x 2 days Age \<1 year, 18.75 mg/m\^2 (i.e., a 50% dose reduction) IV over 1 hour x 2 days.
Dexrazoxane
Dosage and Route of Administration: Dexrazoxane dose should be 10x that of doxorubicin.
Age ≥1 year, 375 mg/m\^2 IV over 15-30 minutes Age \<1 year, 187l.5 mg/m\^2 (i.e., a 50% dose reduction) IV over 15-30 minutes.
^1^1C-methionine
Participants receive \^1\^1C-methionine to relate the distribution, intensity and change in \^1\^1C-methionine CTPET imaging of the primary site to tumor control and patient outcome.
Interventions
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Vincristine
Dosage and route of administration:
* \< 1 year of age=0.025 mg/kg intravenously (IV)
* \> 1 year and \< 3 years= 0.05 mg/kg IV
* ≥ 3 years=1.5 mg/m\^2 IV. Maximum dose 2 mg in all participants.
Dactinomycin
Dosage and route of administration:
* \< 1 year=0.025 mg/kg IV push
* ≥ 1 year=0.045 mg/kg IV push over 1 to 5 minutes.
Cyclophosphamide
Dosage and route of administration:
During VAC chemotherapy:
* \< 3 years of age = 40 mg/kg IV
* ≥ 3 years of age = 1200 mg/m\^2 IV, with MESNA.
During maintenance for intermediate-risk participants:
* oral cyclophosphamide 50 mg/m\^2/dose/day (liquid or tablet)
Surgical Resection
Surgery will be performed for the primary site tumor with the goal of removing tumor cells while maintaining function in the organ or adjacent organs involved.
Radiation
Radiation therapy will be delivered at approximately week 13 (intermediate risk) or week 19 (high risk) after initiation of chemotherapy. Certain patients will receive radiation at week 4.
Bevacizumab
Dosage and route of administration: 15 mg/kg/dose/day IV.
Sorafenib
Dosage and route of administration: 90 mg/m\^2/dose twice daily.
Myeloid Growth Factor
If a participant's chemotherapy has been delayed or modified for hematologic toxicity, or if participant experiences a significant life-threatening toxicity due to bone marrow suppression, myeloid growth factor (either filgrastim or peg-filgrastim) will be given per institutional practice.
High Risk participants receive filgrastim 5 micrograms/kg/day (maximum 300 micrograms) subcutaneously beginning 24-36 hours after the last dose of chemotherapy. Continue at least 7 days, or until the ANC ≥750/µL whichever comes last. Sargramostim or peg-filgrastim may not be used.
Lymph Node Sampling
Clinical and/or imaging evaluation of regional lymph nodes will be conducted pretreatment and preoperatively as part of staging. This will aid in determining the efficacy of this procedure in defining involved lymphatics in "at risk" patients.
Irinotecan
Dosage and Route Administration: During interval compressed therapy - irinotecan 50mg/m\^2 IV (maximum dose 100 mg/day) daily x 5.
Ifosfamide
Dosage and Route of Administration: During interval compressed therapy - Age \> 1 year: 1800 mg/m\^2/day IV x 5 Age \<1 year: treat with 50% doses calculated on a m\^2 basis.
Etoposide
Dosage and Route of Administration:
Age \>1 year 100 mg/m\^2/day IV x 5 Age \< 1 year treat with 50% doses calculated on a m\^2 basis
Etoposide Phosphate
Dosage and Route of Administration: Used in substitution for etoposide in participants who experience allergic reaction. It will be administered 100 mg/m\^2/day IV.
Doxorubicin
Dosage and route of Administration:
Age ≥1 year, 37.5 mg/m\^2 IV over 1 hour x 2 days Age \<1 year, 18.75 mg/m\^2 (i.e., a 50% dose reduction) IV over 1 hour x 2 days.
Dexrazoxane
Dosage and Route of Administration: Dexrazoxane dose should be 10x that of doxorubicin.
Age ≥1 year, 375 mg/m\^2 IV over 15-30 minutes Age \<1 year, 187l.5 mg/m\^2 (i.e., a 50% dose reduction) IV over 15-30 minutes.
^1^1C-methionine
Participants receive \^1\^1C-methionine to relate the distribution, intensity and change in \^1\^1C-methionine CTPET imaging of the primary site to tumor control and patient outcome.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Must have either low-, intermediate-, or high-risk disease, defined as:
* Low-risk: Embryonal, botryoid, spindle cell tumors only (Subset 1: Stage 1, Group I; Stage 1 Group I; Stage 1 Group III orbital only; Stage 2 Group I; Stage 2 Group II) (Subset 2: Stage 1 Group III non orbit; Stage 3 Group I, II)
* Intermediate-risk: Embryonal, botryoid, or spindle cell RMS Stage 2 or 3 and Group III; Alveolar, undifferentiated, or anaplastic RMS: Stage 1-3, group I-I; I)
* High-risk: Embryonal, botryoid, spindle cell, alveolar, undifferentiated, or anaplastic RMS with metastatic disease at diagnosis (stage 4).
* Participants treated on this protocol in the low or intermediate risk arm who experience disease progression prior to week 13 will transfer to the high risk arm and proceed with high risk chemotherapy starting at week 1 of the protocol.
* Age \< 22 years (eligible until 22nd birthday)
* Performance level corresponding to ECOG score of 0, 1, or 2. The Lansky performance score should be used for participants \< 16 years
* Participant has received no prior radiotherapy or chemotherapy for rhabdomyosarcoma (excluding steroids) unless an emergency situation requires local tumor treatment. Prior biopsy, surgical resection and lymph node sampling is allowed.
* Initiation of chemotherapy is planned within 6 weeks (42 days) of the definitive biopsy or surgical resection.
* Adequate bone marrow function defined as:
* Peripheral absolute neutrophil count (ANC) ≥ 750/μL
* Platelet count ≥ 75,000/μL (transfusion independent)
* Adequate liver function defined as total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. Participants with biliary or hepatic primaries with bilirubin values greater than 1.5 x ULN may be enrolled on study if all other eligibility criteria are met.
* Adequate renal function defined as:
* Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.732 or
* Serum creatinine based on age and gender
* Participants with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract.
* Patients requiring emergency radiation therapy are eligible for enrollment on this study.
* Females of child-bearing potential cannot be pregnant or breast-feeding. Female participants ≥ 10 years of age or post-menarchal must have a negative serum or urine pregnancy test within 24 hours prior to beginning treatment. Female participants who are breast feeding must agree to stop breast feeding.
* Sexually active patients of childbearing potential must be willing to use effective contraception during therapy and for at least 1 month after treatment is completed.
* No evidence of active, uncontrolled infection.
* All participants and/or their parents or legal guardians must sign a written informed consent.
* Newly diagnosis or suspected diagnosis of previously untreated participants with rhabdomyosarcoma (RMS). NOTE: Patients with suspected diagnosis of RMS may enroll on screening part of study but must have histologic diagnosis to enroll on treatment part of study.
* Must have either intermediate-risk or high risk disease.
* 0-21 years of age.
Exclusion Criteria
* History of allergy to Optison(TM) contrast agent or blood products.
21 Years
ALL
No
Sponsors
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St. Jude Children's Research Hospital
OTHER
Responsible Party
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Principal Investigators
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Matthew J. Krasin, MD
Role: PRINCIPAL_INVESTIGATOR
St. Jude Children's Research Hospital
Locations
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University of Florida Proton Therapy Institute
Jacksonville, Florida, United States
Nemours Children's Clinic
Jacksonville, Florida, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
Cook Children's Medical Center
Fort Worth, Texas, United States
Countries
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References
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Patel AG, Chen X, Huang X, Clay MR, Komorova N, Krasin MJ, Pappo A, Tillman H, Orr BA, McEvoy J, Gordon B, Blankenship K, Reilly C, Zhou X, Norrie JL, Karlstrom A, Yu J, Wodarz D, Stewart E, Dyer MA. The myogenesis program drives clonal selection and drug resistance in rhabdomyosarcoma. Dev Cell. 2022 May 23;57(10):1226-1240.e8. doi: 10.1016/j.devcel.2022.04.003. Epub 2022 Apr 27.
Related Links
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St. Jude Children's Research Hospital
Clinical Trials Open at St. Jude
Other Identifiers
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NCI-2013-00913
Identifier Type: REGISTRY
Identifier Source: secondary_id
RMS13
Identifier Type: -
Identifier Source: org_study_id