Combination Chemotherapy in Treating Young Patients With Nonmetastatic Rhabdomyosarcoma

Sarcoma Clinical Trial

Official title:

A Protocol For Nonmetastatic Rhabdomyosarcoma [RMS-2005]

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00379457
• Other study ID #: CCLG-EPSSG-RMS-2005
• Secondary ID: CDR0000508635EU-
• Status: Recruiting
• Phase: Phase 3
• First received: September 19, 2006
• Last updated: August 9, 2013
• Start date: June 2006

Study information

• Verified date: July 2009
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unspecified
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 20 Years

Eligibility

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 Design

Allocation: Randomized, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Rhabdomyosarcoma
• Sarcoma

Intervention

Biological:
• dactinomycin

Drug:
• carboplatin

• cyclophosphamide

• doxorubicin hydrochloride

• etoposide

• ifosfamide

• topotecan hydrochloride

• vincristine sulfate

• vinorelbine tartrate

Procedure:
• conventional surgery

Radiation:
• radiation therapy

Locations

Country	Name	City	State
Austria	St. Anna Children's Hospital	Vienna
Belgium	Hopital Universitaire Des Enfants Reine Fabiola	Brussels
Denmark	Rigshospitalet - Copenhagen University Hospital	Copenhagen
Ireland	Our Lady's Hospital for Sick Children Crumlin	Dublin
Spain	Vall d'Hebron University Hospital	Barcelona
Sweden	Uppsala University Hospital	Uppsala
Switzerland	University Children's Hospital	Zurich
United Kingdom	Royal Aberdeen Children's Hospital	Aberdeen	Scotland
United Kingdom	Royal Belfast Hospital for Sick Children	Belfast	Northern Ireland
United Kingdom	Birmingham Children's Hospital	Birmingham	England
United Kingdom	Institute of Child Health at University of Bristol	Bristol	England
United Kingdom	Addenbrooke's Hospital	Cambridge	England
United Kingdom	Childrens Hospital for Wales	Cardiff	Wales
United Kingdom	Royal Hospital for Sick Children	Edinburgh	Scotland
United Kingdom	Royal Hospital for Sick Children	Glasgow	Scotland
United Kingdom	Leeds Cancer Centre at St. James's University Hospital	Leeds	England
United Kingdom	Leicester Royal Infirmary	Leicester	England
United Kingdom	Royal Liverpool Children's Hospital, Alder Hey	Liverpool	England
United Kingdom	Great Ormond Street Hospital for Children	London	England
United Kingdom	Middlesex Hospital	London	England
United Kingdom	Royal Manchester Children's Hospital	Manchester	England
United Kingdom	Sir James Spence Institute of Child Health at Royal Victoria Infirmary	Newcastle-Upon-Tyne	England
United Kingdom	Queen's Medical Centre	Nottingham	England
United Kingdom	Oxford Radcliffe Hospital	Oxford	England
United Kingdom	Children's Hospital - Sheffield	Sheffield	England
United Kingdom	Southampton General Hospital	Southampton	England
United Kingdom	Royal Marsden - Surrey	Sutton	England

Sponsors (4)

Lead Sponsor	Collaborator
European Paediatric Soft Tissue Sarcoma Study Group	Children's Cancer and Leukaemia Group, Dutch Childhood Oncology Group, Italian Association for Pediatric Hematology Oncology

Countries where clinical trial is conducted

Austria,  Belgium,  Denmark,  Ireland,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival			No
Primary	Disease-free survival (in patients treated with maintenance chemotherapy)			No
Secondary	Overall survival			No
Secondary	Progression-free survival			No
Secondary	Response rate			No
Secondary	Toxicity as measured by NCI-CTC version 3			Yes