Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy in Treating Young Patients With Nonmetastatic Rhabdomyosarcoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	Under 21	Other	CCLG-EPSSG-RMS-2005 EU-20639, EUDRACT-2005-000217-35, UKCCSG-RMS-2005, NCT00379457

Objectives

1. Improve the outcome in pediatric patients with low-risk rhabdomyosarcoma (RMS) treated with vincristine and dactinomycin alone.
2. 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.
3. Evaluate whether chemotherapy intensity for patients with standard-risk RMS can be reduced, by lowering the cumulative dose of ifosfamide.
4. 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.
5. 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.
6. Determine the role of low-dose maintenance chemotherapy comprising 6 months of cyclophosphamide and vinorelbine in patients with high-risk RMS.
7. 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.

Entry Criteria

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

Prior/Concurrent Therapy:

• See Disease Characteristics

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

Expected Enrollment

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

Outcomes

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

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

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.

Trial Contact Information

Trial Lead Organizations

European Paediatric Soft Tissue Sarcoma Study Group

Gianni Bisogno, MD, Protocol chair		Ph: 39-049-821-1481

Italian Association for Pediatric Hematology Oncology

Gianni Bisogno, MD, Protocol chair		Ph: 39-049-821-1481

Children's Cancer and Leukaemia Group

Meriel Jenney, MD, Protocol chair		Ph: 44-292-074-2107

Dutch Childhood Oncology Group

Hans Merks, MD, PhD, Protocol chair		Ph: 31-70-367-4545

Austria
	Vienna
	St. Anna Children's Hospital
		Ruth Ladenstein, MD	Ph:  43-1-404-700
Belgium
	Brussels
	Hopital Universitaire Des Enfants Reine Fabiola
		Christine Devalck, MD	Ph:  32-2-477-2678
Denmark
	Copenhagen
	Rigshospitalet - Copenhagen University Hospital
		Catherine Rechnitzer, MD, PhD	Ph:  45-3545-1368
			Email: rechnitzer@rh.dk
Ireland
	Dublin
	Our Lady's Hospital for Sick Children Crumlin
		Fin Breatnach, MD, FRCPE	Ph:  353-1-409-6659
			Email: fin.breatnach@olhsc.ie
Spain
	Barcelona
	Vall d'Hebron University Hospital
		Soledad Gallego, MD, PhD	Ph:  34-93-489-3090
			Email: sgallego@vhebron.net
Sweden
	Uppsala
	Uppsala University Hospital
		Gustaf Ljungman, MD	Ph:  46-18-611-5586
Switzerland
	Zurich
	University Children's Hospital
		Felix Niggli, MD	Ph:  41-44-266-7823
United Kingdom
England
	Birmingham
	Birmingham Children's Hospital
		David Hobin, MD	Ph:  44-121-454-4851
	Bristol
	Institute of Child Health at University of Bristol
		M. C. G. Stevens, MD	Ph:  44-117-342-0205
			Email: m.stevens@bristol.ac.uk
	Cambridge
	Addenbrooke's Hospital
		Denise Williams, MD	Ph:  44-1223-256-298
	Leeds
	Leeds Cancer Centre at St. James's University Hospital
		Martin Elliott, MD	Ph:  44-113-206-4988
	Leicester
	Leicester Royal Infirmary
		Johann Visser, MD	Ph:  44-116-258-5309
			Email: johannes.visser@uhl-tr.nhs.uk
	Liverpool
	Royal Liverpool Children's Hospital, Alder Hey
		Heather McDowell, MD	Ph:  44-151-293-3679
	London
	Great Ormond Street Hospital for Children
		Julia Chisholm, MD	Ph:  44-20-7829-7924
	Middlesex Hospital
		Ananth Shankar, MD	Ph:  44-20-7380-9300 ext. 9950
	Manchester
	Royal Manchester Children's Hospital
		Bernadette Brennan, MD	Ph:  44-161-922-2227
			Email: bernadette.brennan@cmmc.nhs.uk
	Newcastle-Upon-Tyne
	Sir James Spence Institute of Child Health at Royal Victoria Infirmary
		Juliet Hale, MD	Ph:  44-191-282-4101
			Email: j.p.hale@ncl.ac.uk
	Nottingham
	Queen's Medical Centre
		Martin Hewitt, MD, BSc, FRCP, FRCPCH	Ph:  44-115-924-9924 ext. 63394
			Email: martin.hewitt@nuh.nhs.uk
	Oxford
	Oxford Radcliffe Hospital
		Sheila Lane, MD	Ph:  44-1865-234-205
	Sheffield
	Children's Hospital - Sheffield
		Mary Gerrard, MBChB, FRCP, FRCPCH	Ph:  44-114-271-7366
			Email: mary.gerrard@sch.nhs.uk
	Southampton
	Southampton General Hospital
		Janice Kohler, MD, FRCP	Ph:  44-23-8079-6942
	Sutton
	Royal Marsden - Surrey
		Kathy Pritchard-Jones, MD	Ph:  44-20-8661-3452 ext 3498
Northern Ireland
	Belfast
	Royal Belfast Hospital for Sick Children
		Anthony McCarthy, MD	Ph:  44-289-063-3631
			Email: anthonymcarthy@royalhospital.n.i.nhs.uk
Scotland
	Aberdeen
	Royal Aberdeen Children's Hospital
		Derek King, MD	Ph:  44-1224-681-818
	Edinburgh
	Royal Hospital for Sick Children
		W. Hamish Wallace, MD	Ph:  44-131-536-0426
	Glasgow
	Royal Hospital for Sick Children
		Milind Ronghe, MD	Ph:  44-141-201-9309
Wales
	Cardiff
	Childrens Hospital for Wales
		Meriel Jenney, MD	Ph:  44-292-074-2107

Registry Information
Official Title		A Protocol For Nonmetastatic Rhabdomyosarcoma [RMS-2005]
Trial Start Date		2006-06-01
Trial Completion Date		2011-05-01 (estimated)
Registered in ClinicalTrials.gov		NCT00379457
Date Submitted to PDQ		2006-09-01
Information Last Verified		2009-07-06

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