Combination Chemotherapy in Treating Young Patients With Nonmetastatic Rhabdomyosarcoma

August 9, 2013 updated by: European Paediatric Soft Tissue Sarcoma Study Group

A Protocol For Nonmetastatic Rhabdomyosarcoma [RMS-2005]

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective in treating rhabdomyosarcoma.

PURPOSE: This randomized phase III trial is studying different combination chemotherapy regimens to compare how well they work in treating young patients with nonmetastatic rhabdomyosarcoma.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

  • Improve the outcome in pediatric patients with low-risk rhabdomyosarcoma (RMS) treated with vincristine and dactinomycin alone.
  • Evaluate whether the outcome for older patients with standard-risk RMS with favorable features may be improved/maintained by administering a treatment with limited intensity.
  • Evaluate whether chemotherapy intensity for patients with standard-risk RMS can be reduced, by lowering the cumulative dose of ifosfamide.
  • Evaluate whether treatment can be reduced in a subgroup of patients with standard-risk RMS arising in an unfavorable site (e.g., parameningeal or other site) but with favorable site and age.
  • Compare the value of standard chemotherapy comprising ifosfamide, vincristine, and dactinomycin with vs without doxorubicin (as early intensification in the initial part of treatment) in patients with high-risk RMS.
  • Determine the role of low-dose maintenance chemotherapy comprising 6 months of cyclophosphamide and vinorelbine in patients with high-risk RMS.
  • Improve the results in patients with poor prognosis (very high-risk) RMS treated with more intensive ifosfamide, vincristine, dactinomycin, and doxorubicin followed by maintenance chemotherapy.

OUTLINE: This is a non-blinded, randomized, prospective, multicenter study. Patients are stratified according to risk group (low risk vs standard risk vs high risk vs very high risk) and participating country.

  • Stratum 1 (low-risk group): Patients receive vincristine IV on day 1 in weeks 1-4, 7-10, 13-16, and 19-22 and dactinomycin IV on day 1 in weeks 1, 4, 7, 10, 13, 16, 19, and 22.

  • Stratum 2 (standard-risk group): Patients are assigned to 1 of 3 treatment groups according to their standard-risk subgroup.

    • Subgroup B: Patients receive ifosfamide IV over 3 hours on days 1 and 2 in weeks 1, 4, 7, and 10; vincristine IV on day 1 in weeks 1-7, 10, 13, 16, 19, 22, and 25; and dactinomycin IV on day 1 in weeks 1, 4, 7, 10, 13, 16, 19, 22, and 25.
    • Subgroup C: Patients receive ifosfamide IV over 3 hours on days 1 and 2 in weeks 1, 4, and 7; vincristine IV on day 1 in weeks 1-7; and dactinomycin IV on day 1 in weeks 1, 4, and 7. Patients are evaluated for tumor response in week 9. Patients in complete remission (CR) with favorable age and tumor size continue to receive ifosfamide, vincristine, and dactinomycin as above in weeks 10, 13, 16*, 19, 22, and 25. Patients may also undergo radiotherapy beginning in week 13 and continuing for 5-6 weeks. Patients in CR with unfavorable age or tumor size OR in partial remission (PR) (i.e., > 1/3 tumor volume reduction) continue to receive ifosfamide as above in weeks 10 and 16 and vincristine and dactinomycin as above in weeks 10, 13, 16*, 19, 22, and 25. These patients also undergo radiotherapy beginning in week 13 and continuing for 5-6 weeks. Patients with stable or progressive disease in week 9 proceed to second-line therapy and radiotherapy. Patients with residual disease after completion of chemotherapy in week 10 undergo surgical resection followed by ifosfamide, vincristine, and dactinomycin (with or without radiotherapy) as above in weeks 13, 16*, 19, 22, and 25.
    • Subgroup D: Patients receive ifosfamide IV over 3 hours on days 1 and 2 in weeks 1, 4, and 7; vincristine IV on day 1 in weeks 1-7; and dactinomycin IV on day 1 in weeks 1, 4, and 7. Patients are evaluated for tumor response in week 9. Patients in CR or PR continue to receive ifosfamide, vincristine, and dactinomycin as above in weeks 10, 13, 16*, 19, 22, and 25. Patients may also undergo radiotherapy beginning in week 13 and continuing for 5-6 weeks. Patients with stable or progressive disease in week 9 proceed to second-line therapy and radiotherapy. Patients with residual disease after completion of chemotherapy in week 10 undergo surgical resection followed by ifosfamide, vincristine, and dactinomycin (with or without radiotherapy) as above in weeks 13, 16*, 19, 22, and 25.

NOTE: *Dactinomycin may be omitted during radiotherapy in week 16.

  • Stratum 3 (high-risk group): Patients are randomized to 1 of 2 treatment arms.

    • Arm I: Patients receive ifosfamide, vincristine, and dactinomycin as in subgroups C and D of stratum 2. Patients are evaluated for tumor response in week 9. Patients in CR or PR continue to receive ifosfamide, vincristine, and dactinomycin as in subgroups C and D of stratum 2. Patients may also undergo radiotherapy beginning in week 13 and continuing for 5-6 weeks. Patients with stable or progressive disease in week 9 proceed to second-line therapy and radiotherapy. Patients with residual disease after completion of chemotherapy in week 10 undergo surgical resection followed by ifosfamide, vincristine, and dactinomycin (with or without radiotherapy) as above in weeks 13, 16*, 19, 22, and 25.
    • Arm II: Patients receive ifosfamide, vincristine, and dactinomycin as in subgroups C and D of stratum 2. Patients also receive doxorubicin IV over 4 hours on days 1 and 2 in weeks 1, 4, and 7. Patients are evaluated for tumor response in week 9. Patients in CR or PR continue to receive ifosfamide, vincristine, dactinomycin, and doxorubicin as above in week 10 and then ifosfamide, vincristine, and dactinomycin as above in weeks 13, 16*, 19, 22, and 25. Patients may also undergo radiotherapy beginning in week 13 and continuing for 5-6 weeks. Patients with stable or progressive disease in week 9 proceed to second-line therapy and radiotherapy. Patients with residual disease after completion of chemotherapy in week 10 undergo surgical resection followed by ifosfamide, vincristine, and dactinomycin (with or without radiotherapy) as above in weeks 13, 16*, 19, 22, and 25.

NOTE: *Dactinomycin may be omitted during radiotherapy in week 16.

  • Maintenance chemotherapy: Patients who remain in CR or with minimal abnormalities on imaging studies after completion of therapy according to their randomized arm (as above) undergo a second randomization. Randomization occurs within 6 weeks after administration of the last course of chemotherapy on arm I or II.

    • Arm I: Patients receive no maintenance chemotherapy.

    • Arm II: Patients receive vinorelbine IV over 5-10 minutes on days 1, 8, and 15 and oral cyclophosphamide once daily on days 1-28. Treatment repeats every 28 days for up to 6 courses.

      • Stratum 4 (very high-risk group): Patients receive ifosfamide, vincristine, and dactinomycin as in subgroups C and D of stratum 2. Patients also receive doxorubicin as in arm II of stratum 3. Patients are evaluated for tumor response in week 9. Patients in CR or PR continue to receive ifosfamide, vincristine, dactinomycin, and doxorubicin as in arm II of stratum 3. Patients may also undergo radiotherapy beginning in week 13 and continuing for 5-6 weeks. Patients with stable or progressive disease in week 9 proceed to second-line therapy and radiotherapy. Patients with residual disease after completion of chemotherapy in week 10 undergo surgical resection followed by ifosfamide, vincristine, and dactinomycin (with or without radiotherapy) as above in weeks 13, 16, 19, 22, and 25. After completion of chemotherapy, patients with a limited quantity of viable tumor proceed to maintenance chemotherapy.

  • Maintenance chemotherapy: Patients receive vinorelbine IV over 5-10 minutes on days 1, 8, and 15 and oral cyclophosphamide once daily on days 1-28. Treatment repeats every 28 days for up to 6 courses.

    • Second-line therapy: Patients in any stratum with stable or progressive disease in week 9 receive 1 of 2 second-line therapy regimens.
  • Regimen 1: Patients receive topotecan IV on days 1-3 and carboplatin IV on days 4 and 5 in weeks 1 and 4. Patients are then evaluated for tumor response. Patients with good response receive topotecan IV on days 1-3 and cyclophosphamide IV on days 1 and 2 in weeks 7 and 13 and etoposide IV on days 1-3 and carboplatin IV on days 4 and 5 in weeks 10 and 16. Patients with no response receive local therapy or a new chemotherapy regimen.
  • Regimen 2: Patients receive doxorubicin IV on day 1 and carboplatin IV on days 1 and 2 in weeks 1 and 4. Patients are then evaluated for tumor response. Patients with good response receive doxorubicin IV on day 1 in weeks 7, 10, 13, and 16; cyclophosphamide IV on days 1 and 2 in weeks 7 and 13; and carboplatin IV on days 1 and 2 of weeks 10 and 16. Patients with no response receive local therapy or a new chemotherapy regimen.

After completion of therapy, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: A total of 600 patients will be accrued for this study.

Study Type

Interventional

Enrollment (Anticipated)

600

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Vienna, Austria, A-1090
        • Recruiting
        • St. Anna Children's Hospital
  • Belgium
      • Brussels, Belgium, 1020
        • Recruiting
        • Hôpital Universitaire des Enfants Reine Fabiola
        • Contact:
          • Christine Devalck, MD
          • Phone Number: 32-2-477-2678
  • Denmark
      • Copenhagen, Denmark, 2100
        • Recruiting
        • Rigshospitalet - Copenhagen University Hospital
        • Contact:
          • Catherine Rechnitzer, MD, PhD
          • Phone Number: 45-3545-1368
          • Email: rechnitzer@rh.dk
  • Ireland
      • Dublin, Ireland, 12
        • Recruiting
        • Our Lady's Hospital for Sick Children Crumlin
  • Spain
      • Barcelona, Spain, 08035
        • Recruiting
        • Vall d'Hebron University Hospital
        • Contact:
  • Sweden
      • Uppsala, Sweden, SE-75185
        • Recruiting
        • Uppsala University Hospital
        • Contact:
          • Gustaf Ljungman, MD
          • Phone Number: 46-18-611-5586
  • Switzerland
      • Zurich, Switzerland, CH-8032
        • Recruiting
        • University Children's Hospital
        • Contact:
          • Felix Niggli, MD
          • Phone Number: 41-44-266-7823
  • United Kingdom
    • England
      • Birmingham, England, United Kingdom, B16 8ET
        • Recruiting
        • Birmingham Children's Hospital
        • Contact:
          • David Hobin, MD
          • Phone Number: 44-121-454-4851
      • Bristol, England, United Kingdom, BS2 8AE
        • Recruiting
        • Institute of Child Health at University of Bristol
        • Contact:
      • Cambridge, England, United Kingdom, CB2 2QQ
        • Recruiting
        • Addenbrooke's Hospital
        • Contact:
          • Denise Williams, MD
          • Phone Number: 44-1223-256-298
      • Leeds, England, United Kingdom, LS9 7TF
        • Recruiting
        • Leeds Cancer Centre at St. James's University Hospital
        • Contact:
          • Martin Elliott, MD
          • Phone Number: 44-113-206-4988
      • Leicester, England, United Kingdom, LE1 5WW
        • Recruiting
        • Leicester Royal Infirmary
      • Liverpool, England, United Kingdom, L12 2AP
        • Recruiting
        • Royal Liverpool Children's Hospital, Alder Hey
      • London, England, United Kingdom, WC1N 3JH
        • Recruiting
        • Great Ormond Street Hospital for Children
        • Contact:
          • Julia Chisholm, MD
          • Phone Number: 44-20-7829-7924
      • London, England, United Kingdom, W1T 3AA
        • Recruiting
        • Middlesex Hospital
      • Manchester, England, United Kingdom, M27 4HA
        • Recruiting
        • Royal Manchester Children's Hospital
      • Newcastle-Upon-Tyne, England, United Kingdom, NE1 4LP
        • Recruiting
        • Sir James Spence Institute of Child Health at Royal Victoria Infirmary
      • Nottingham, England, United Kingdom, NG7 2UH
        • Recruiting
        • Queen's Medical Centre
        • Contact:
      • Oxford, England, United Kingdom, 0X3 9DU
        • Recruiting
        • Oxford Radcliffe Hospital
        • Contact:
          • Sheila Lane, MD
          • Phone Number: 44-1865-234-205
      • Sheffield, England, United Kingdom, S10 2TH
        • Recruiting
        • Children's Hospital - Sheffield
      • Southampton, England, United Kingdom, SO16 6YD
        • Recruiting
        • Southampton General Hospital
      • Sutton, England, United Kingdom, SM2 5PT
        • Recruiting
        • Royal Marsden - Surrey
    • Northern Ireland
      • Belfast, Northern Ireland, United Kingdom, BT12 6BE
        • Recruiting
        • Royal Belfast Hospital for Sick Children
    • Scotland
      • Aberdeen, Scotland, United Kingdom, AB25 2ZG
        • Recruiting
        • Royal Aberdeen Children's Hospital
        • Contact:
          • Derek King, MD
          • Phone Number: 44-1224-681-818
      • Edinburgh, Scotland, United Kingdom, EH9 1LF
        • Recruiting
        • Royal Hospital for Sick Children
      • Glasgow, Scotland, United Kingdom, G3 8SJ
        • Recruiting
        • Royal Hospital for Sick Children
    • Wales
      • Cardiff, Wales, United Kingdom, CF14 4XW
        • Recruiting
        • Childrens Hospital for Wales
        • Contact:
          • Meriel Jenney, MD
          • Phone Number: 44-292-074-2107

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 20 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Histologically confirmed rhabdomyosarcoma (RMS) or other malignant mesenchymal tumor, including undifferentiated soft tissue sarcoma or ectomesenchymoma

    • Has undergone diagnostic surgery within the past 8 weeks

  • Meets criteria for 1 of the following risk groups:

    • Low-risk group

      • Localized nonalveolar RMS at any site
      • Embryonal, spindle cell, or botryoid RMS (favorable pathology)
      • Microscopically completely resected disease (Intergroup Rhabdomyosarcoma Study [IRS] group I)
      • Negative nodes (N0)
      • Tumor size ≤ 5 cm AND age < 10 years (favorable tumor size and age)

    • Standard-risk group, meeting criteria for 1 of the following subgroups:

      • Subgroup B

        • Localized nonalveolar RMS at any site
        • Favorable pathology
        • Microscopically completely resected disease (IRS group I)
        • N0 disease
        • Tumor size > 5 cm OR age ≥ 10 years (unfavorable tumor size or age)

      • Subgroup C

        • Localized nonalveolar RMS in orbit, head and neck nonparameningeal sites, or genitourinary (GU) non bladder prostate (i.e., paratesticular and vagina/uterus) sites (favorable site)
        • Favorable pathology
        • Microscopic residual disease (pT3a) or completely resected disease with nodal involvement (N1) (IRS group II) OR macroscopic residual disease (pT3b) (IRS group III)
        • N0 disease
        • Any tumor size or age

      • Subgroup D

        • Localized nonalveolar RMS in parameningeal sites, extremities, GU bladder prostate sites, or other sites (unfavorable site)
        • Favorable pathology
        • IRS group II or III
        • N0 disease
        • Favorable tumor size and age

    • High-risk group, meeting criteria for 1 of the following subgroups:

      • Subgroup E

        • Localized nonalveolar RMS at unfavorable site
        • Favorable pathology
        • IRS group II or III
        • N0 disease
        • Unfavorable tumor size or age

      • Subgroup F

        • Localized nonalveolar RMS at any site
        • Favorable pathology
        • IRS group I, II, or III
        • Positive nodes (N1)
        • Any tumor size or age

      • Subgroup G

        • Localized alveolar RMS at any site
        • Alveolar RMS, including the solid-alveolar variant (unfavorable pathology)
        • IRS group I, II, or III
        • N0 disease
        • Any tumor size or age

    • Very high-risk group

      • Localized alveolar RMS at any site
      • Unfavorable pathology
      • IRS group I, II, or III
      • N1 disease
      • Any tumor size or age
  • Previously untreated disease (except for primary surgery)
  • No evidence of metastatic disease

PATIENT CHARACTERISTICS:

  • Shortening fraction > 28%
  • Ejection fraction > 47%
  • No prior cardiac disease
  • Renal function must be equivalent to grade 0-1 nephrotoxicity
  • No prior malignant tumors
  • No pre-existing illness preventing treatment

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Event-free survival
Disease-free survival (in patients treated with maintenance chemotherapy)

Secondary Outcome Measures

Outcome Measure
Response rate
Progression-free survival
Overall survival
Toxicity as measured by NCI-CTC version 3

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

European Paediatric Soft Tissue Sarcoma Study Group

Collaborators

Children's Cancer and Leukaemia Group
Dutch Childhood Oncology Group
Italian Association for Pediatric Hematology Oncology

Investigators

  • Study Chair: Gianni Bisogno, MD, Azienda Ospedaliera di Padova
  • Study Chair: Meriel Jenney, MD, Childrens Hospital for Wales
  • Study Chair: Hans Merks, MD, PhD, Dutch Childhood Oncology Group

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2006

Primary Completion (Anticipated)

May 1, 2011

Study Registration Dates

First Submitted

September 19, 2006

First Submitted That Met QC Criteria

September 19, 2006

First Posted (Estimate)

September 21, 2006

Study Record Updates

Last Update Posted (Estimate)

August 12, 2013

Last Update Submitted That Met QC Criteria

August 9, 2013

Last Verified

July 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CCLG-EPSSG-RMS-2005
  • CDR0000508635 (Registry Identifier: PDQ (Physician Data Query))
  • EU-20639
  • EUDRACT-2005-000217-35
  • UKCCSG-RMS-2005

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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