Clinical Trials /

Risk-Adapted Focal Proton Beam Radiation and/or Surgery in Patients With Low, Intermediate and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy

NCT01871766

Description:

This study will treat participants with newly diagnosed, low, intermediate and high risk rhabdomyosarcoma (RMS) using multi-modality risk-adapted therapy with standard or intensified dose chemotherapy, radiation and surgical resection. Intermediate and high risk participants will receive an additional 12 weeks (4 cycles) of maintenance therapy with anti-angiogenic chemotherapy. 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.

Related Conditions:
  • Rhabdomyosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Risk-Adapted Focal Proton Beam Radiation and/or Surgery in Patients With Low, Intermediate and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy
  • Official Title: Risk-Adapted Focal Proton Beam Radiation and/or Surgery in Patients With Low, Intermediate and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: RMS13
  • SECONDARY ID: NCI-2013-00913
  • NCT ID: NCT01871766

Conditions

  • Rhabdomyosarcoma

Interventions

DrugSynonymsArms
VincristineOncovin®Low-Risk, Subset 1
DactinomycinActinomycin-D, Cosmegen®Low-Risk, Subset 1
CyclophosphamideCytoxan(R)Low-Risk, Subset 1
BevacizumabrhuMab, VEGF, Avastin®Intermediate-Risk
SorafenibNexavar®Intermediate-Risk
Myeloid Growth FactorG-CSF, Filgrastim, PegfilgrastimLow-Risk, Subset 1
IrinotecanCamptosar ®High-Risk
IfosfamideIfex ®High-Risk
EtoposideVP-16, Vepesid®High-Risk
Etoposide PhosphateEtopophos®High-Risk
DoxorubicinAdriamycin®High-Risk
DexrazoxaneZinecardHigh-Risk
^1^1C-methionineContrast MediaLow-Risk, Subset 1

Purpose

This study will treat participants with newly diagnosed, low, intermediate and high risk rhabdomyosarcoma (RMS) using multi-modality risk-adapted therapy with standard or intensified dose chemotherapy, radiation and surgical resection. Intermediate and high risk participants will receive an additional 12 weeks (4 cycles) of maintenance therapy with anti-angiogenic chemotherapy. 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

      Participants will be stratified based on both a pretreatment staging system and a
      post-surgery surgico/pathologic clinical grouping system. Treatment for low-risk (subset 1)
      participants will consist of chemotherapy and radiation. Low-risk (subset 2) and
      intermediate-risk participants will receive chemotherapy and radiation and/or undergo surgery
      to destroy/remove the tumor. Intermediate-risk participants will also receive 16 weeks of
      maintenance chemotherapy. High-risk participants will receive chemotherapy and radiation
      therapy. High-risk participants will also receive additional maintenance therapy with
      anti-angiogenic chemotherapy.
    

Trial Arms

NameTypeDescriptionInterventions
Low-Risk, Subset 1ExperimentalLymph 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
  • Dactinomycin
  • Cyclophosphamide
  • Myeloid Growth Factor
  • ^1^1C-methionine
Low-Risk, Subset 2ExperimentalLymph 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
  • Dactinomycin
  • Cyclophosphamide
  • Myeloid Growth Factor
  • ^1^1C-methionine
Intermediate-RiskExperimentalLymph 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
  • Dactinomycin
  • Cyclophosphamide
  • Bevacizumab
  • Sorafenib
  • Myeloid Growth Factor
  • ^1^1C-methionine
High-RiskExperimentalLymph 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
  • Dactinomycin
  • Cyclophosphamide
  • Bevacizumab
  • Sorafenib
  • Myeloid Growth Factor
  • Irinotecan
  • Ifosfamide
  • Etoposide
  • Etoposide Phosphate
  • Doxorubicin
  • Dexrazoxane
  • ^1^1C-methionine

Eligibility Criteria

        Inclusion Criteria:

          -  Newly diagnosed participants with localized rhabdomyosarcoma (RMS).

          -  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.

        Exclusion Criteria:

          -  Participants who fail to meet one or more of the inclusion criteria will be excluded.

        Inclusion Criteria for Contrast-Enhanced Ultrasound (CEUS) Sub-Study:

          -  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 Criterial for CEUS Sub-Study:

          -  Undergoing upfront surgical resection of the primary tumor.

          -  History of allergy to Optison(TM) contrast agent or blood products.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (intermediate risk arm)
Time Frame:2 years after last intermediate risk arm enrollment
Safety Issue:
Description:To estimate event-free survival for intermediate risk participants treated by vincristine-dactinomycin-cyclophosphamide (VAC) with the addition of maintenance anti-angiogenic therapy

Secondary Outcome Measures

Measure:Event-free survival (high risk arm)
Time Frame:5 years after last high-risk arm enrollment
Safety Issue:
Description:To estimate event-free survival for high risk participants.
Measure:Rate of false negative and false positive the sentinel lymph node procedure (low and intermediate risk arms)
Time Frame:2 years after last low or intermediate arm enrollment
Safety Issue:
Description:Estimate the false negative rate and incidence of additional positive lymph nodes in participants undergoing sentinel lymph node biopsy followed by limited nodal dissection.
Measure:Rate of false negative and false positive the sentinel lymph node procedure (high risk arm)
Time Frame:5 years after last high risk arm enrollment
Safety Issue:
Description:Estimate the false negative rate and incidence of additional positive lymph nodes in participants undergoing sentinel lymph node biopsy followed by limited nodal dissection.
Measure:Local failure rate (low and intermediate risk arms)
Time Frame:2 years after last low or intermediate risk arm enrollment
Safety Issue:
Description:Maintain a high local control rate in participants treated with surgery and / or limited volume proton and photon radiation without dose escalation
Measure:Local failure rate (high risk arm)
Time Frame:5 years after last high risk arm enrollment
Safety Issue:
Description:Maintain a high local control rate in participants treated with surgery and / or limited volume proton and photon radiation without dose escalation
Measure:Patterns of failure (low and intermediate risk arms)
Time Frame:2 years after last low or intermediate risk arm enrollment
Safety Issue:
Description:Define the incidence and type of failure in participants who receive risk-adapted local therapy relative to the primary tumor volume
Measure:Patterns of failure (high risk arm)
Time Frame:5 years after last high risk arm enrollment
Safety Issue:
Description:Define the incidence and type of failure in participants who receive risk-adapted local therapy relative to the primary tumor volume
Measure:Number of patients that complete all cycles of maintenance chemotherapy (intermediate risk arm)
Time Frame:2 years after last low or intermediate risk arm enrollment
Safety Issue:
Description:Establish the feasibility of delivering 4 cycles of maintenance antiangiogenic chemotherapy (bevacizumab / sorafenib / low dose cyclophosphamide) in intermediate risk patients following standard chemotherapy.
Measure:Number of patients that complete all cycles of maintenance chemotherapy (high risk arm)
Time Frame:5 years after last high risk arm enrollment
Safety Issue:
Description:Establish the feasibility of delivering 4 cycles of maintenance antiangiogenic chemotherapy (bevacizumab / sorafenib / low dose cyclophosphamide) in high risk patients following standard chemotherapy.
Measure:Incidence of CTC grade 3 and higher toxicities related to proton bream therapy (low and intermediate and high risk arms)
Time Frame:2 years after last enrollment
Safety Issue:
Description:Define the incidence of CTC grade 3 and higher toxicities (and specific grade 1-2 toxicities) related to proton beam therapy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

Trial Keywords

  • Rhabdomyosarcoma
  • Radiation therapy
  • Proton beam

Last Updated

August 19, 2019