Clinical trial NCT00379457: Combination Chemotherapy in Treating Young Patients With Nonmetastatic Rhabdomyosarcoma
Official title: A Protocol For Nonmetastatic Rhabdomyosarcoma [RMS-2005]
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Sarcoma
Keywords: alveolar childhood rhabdomyosarcoma
previously untreated childhood rhabdomyosarcoma
childhood malignant mesenchymoma
nonmetastatic childhood soft tissue sarcoma
embryonal childhood rhabdomyosarcoma
embryonal-botryoid childhood rhabdomyosarcoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Italian Association for Pediatric Hematology Oncology
name: Children's Cancer and Leukaemia Group
name: Dutch Childhood Oncology Group
First posted: 2006-09-21
Enrollment: 600
Sex: ALL
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility 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

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

Primary outcomes:
measure: Event-free survival
measure: Disease-free survival (in patients treated with maintenance chemotherapy)
Secondary outcomes:
measure: Overall survival
measure: Progression-free survival
measure: Response rate
measure: Toxicity as measured by NCI-CTC version 3
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: St. Anna Children's Hospital
city: Brussels
country: Belgium
facility: Hopital Universitaire Des Enfants Reine Fabiola
city: Copenhagen
country: Denmark
facility: Rigshospitalet - Copenhagen University Hospital
city: Dublin
country: Ireland
facility: Our Lady's Hospital for Sick Children Crumlin
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Zurich
country: Switzerland
facility: University Children's Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
state: England
city: Bristol
country: United Kingdom
facility: Institute of Child Health at University of Bristol
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Leeds
country: United Kingdom
facility: Leeds Cancer Centre at St. James's University Hospital
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Children's Hospital, Alder Hey
state: England
city: London
country: United Kingdom
facility: Middlesex Hospital
state: England
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
state: England
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Sir James Spence Institute of Child Health at Royal Victoria Infirmary
state: England
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: England
city: Oxford
country: United Kingdom
facility: Oxford Radcliffe Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Children's Hospital - Sheffield
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Belfast
country: United Kingdom
facility: Royal Belfast Hospital for Sick Children
state: Northern Ireland
city: Aberdeen
country: United Kingdom
facility: Royal Aberdeen Children's Hospital
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Cardiff
country: United Kingdom
facility: Childrens Hospital for Wales
state: Wales
Study officials:
affiliation: Azienda Ospedaliera di Padova
name: Gianni Bisogno, MD
role: STUDY_CHAIR
affiliation: Childrens Hospital for Wales
name: Meriel Jenney, MD
role: STUDY_CHAIR
affiliation: Dutch Childhood Oncology Group
name: Hans Merks, MD, PhD
role: STUDY_CHAIR
References:
citation: Orbach D, Van Noesel MM, Brennan B, Corradini N, Alaggio R, Ben Arush M, Schoot RA, Berlanga P, Zanetti I, Hjalgrim LL, Di Corti F, Ramirez G, Casanova M, Ferrari A. Epithelioid hemangioendothelioma in children: The European Pediatric Soft Tissue Sarcoma Study Group experience. Pediatr Blood Cancer. 2022 Oct;69(10):e29882. doi: 10.1002/pbc.29882. Epub 2022 Jul 16.
citation: Schoot RA, Chisholm JC, Casanova M, Minard-Colin V, Geoerger B, Cameron AL, Coppadoro B, Zanetti I, Orbach D, Kelsey A, Rogers T, Guizani C, Elze M, Ben-Arush M, McHugh K, van Rijn RR, Ferman S, Gallego S, Ferrari A, Jenney M, Bisogno G, Merks JHM. Metastatic Rhabdomyosarcoma: Results of the European Paediatric Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study. J Clin Oncol. 2022 Nov 10;40(32):3730-3740. doi: 10.1200/JCO.21.02981. Epub 2022 Jun 16.