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

Alternate Title

High-Dose Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Metastatic Rhabdomyosarcoma or Ectomesenchymoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	Under 50	NCI	COG-ARST0431 ARST0431, NCT00354744

Objectives

Primary

1. Improve the early disease control interval for patients with newly diagnosed, high-risk, metastatic rhabdomyosarcoma or ectomesenchymoma using intensive, interval-compression therapy (comprising vincristine, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, and dactinomycin) that permits maximal early exposure to known effective agents.
2. Determine the feasibility of concurrent irinotecan hydrochloride and radiotherapy in these patients.
3. Assess immediate- and short-term side effects of concurrent irinotecan hydrochloride and radiotherapy in these patients.

Secondary

1. Expand the available data for response to irinotecan hydrochloride and vincristine in previously untreated patients with high-risk rhabdomyosarcoma.
2. Evaluate, prospectively, and validate gene expression values with the intent to define the best diagnostic predictors and more powerful prognostic classifiers.

Entry Criteria

Disease Characteristics:

• Histologically confirmed high-risk rhabdomyosarcoma or ectomesenchymoma
  • Prior enrollment on COG-D9902 to confirm local histological diagnosis required
    • Tissue must be submitted for pathologic review within 2 days of patient registration on COG-D9902
  • Newly diagnosed disease
  • Metastatic disease (stage IV, clinical group IV)



• Has undergone initial surgical procedure (including biopsy) that provided the definitive diagnosis within the past 42 days



• Parameningeal and paraspinal tumors allowed
  • Patients with parameningeal (without intracranial extension [ICE]) and paraspinal tumors should begin study chemotherapy at week 1 and radiotherapy at week 20



• Patients with evidence of ICE, as defined by contrast MRI showing that primary tumor touches, displaces, invades, distorts, or otherwise causes a signal abnormality of the dura in contiguity to the primary site in brain or spinal cord, are eligible
  • ICE is presumed to exist if the cerebrospinal fluid cytopathology is positive for tumor at diagnosis



• Patients requiring emergency radiotherapy are eligible
  • Patients requiring emergency radiotherapy (for intracranial extension or spinal cord impingement) should begin study chemotherapy at week 1 (irinotecan hydrochloride and vincristine) concurrently with radiation therapy

Prior/Concurrent Therapy:

• No prior chemotherapy except steroids
• No prior radiotherapy
• No concurrent aprepitant during ifosfamide or doxorubicin hydrochloride chemotherapy
• No concurrent dexrazoxane
• No concurrent sargramostim (GM-CSF) or pegfilgrastim

Patient Characteristics:

• ECOG or Zubrod performance status (PS) 0-2 (Lansky PS 50-100% for patients < 10 years of age and Karnofsky PS 50-100% for patients ≥ 10 years of age)
• Absolute neutrophil count ≥ 750/mm³*
• Platelet count ≥ 75,000/mm³*
• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (≥ 40 mL/min for infants < 1 year of age)
• Patients 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
• SGPT < 2.5 times normal
• Bilirubin < 1.5 mg/dL
• Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by MUGA
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during study and for ≥ 1 month after study completion
• No evidence of uncontrolled infection
• Able to undergo radiotherapy

 [Note: *Abnormal blood counts allowed if there is bone marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma]

Expected Enrollment

A total of 75 patients will be accrued for this study.

Outcomes

Early disease control
Feasibility
Toxicity

Outline

This is a prospective, nonrandomized, multicenter study. Patients are stratified according to prognostic factors predictive of outcome (e.g. histology, bone/bone marrow involvement, and number of metastatic sites).

Patients receive high-dose chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-5, 7, 8, 11, 12, 15, 16, 20-24, 28, 29, 32, 33, 35, 38, 41-44, 47, 48, 50, and 51; irinotecan hydrochloride IV over 1 hour on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; and ifosfamide IV over 1 hour and etoposide IV over 30-60 minutes on days 1-5 of weeks 9, 13, 17, 26, and 30. Patients also receive doxorubicin hydrochloride IV continuously over 24 hours on days 1 and 2 of weeks 7*, 11, 15, 28, and 32; cyclophosphamide IV over 30-60 minutes on day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41, and 44; and dactinomycin IV over 1-5 minutes on day 1 of weeks 35, 38, 41, and 44 in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim (G-CSF) subcutaneously in weeks 7-9, 11-13, 15-17, 22, 26, 28-30, 32, 33, 35, 38, and 41-44 beginning 24-36 hours after the last chemotherapy dose and continuing until blood counts recover.

 [Note: *Patients undergoing early radiotherapy for intracranial extension do not receive doxorubicin in week 7.]

Beginning at week 20 (or week 1 for patients with parameningeal tumors with intracranial extension [or spinal cord compression] requiring emergency radiotherapy), patients also undergo radiotherapy once a day, 5 days a week, for approximately 5½ weeks. Some patients may also undergo second-look surgery.

After completion of study treatment, patients are followed periodically for ≥ 10 years.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Brenda Weigel, MD, Protocol chair		Ph: 612-626-5501; 888-226-2376
Carola Arndt, MD, Protocol co-chair		Ph: 507-284-2511 Email: carndt@mayo.edu

Related Information

PDQ® clinical trial COG-D9902

Registry Information
Official Title		Intensive Multi-Agent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide (IE) and Vincristine/Doxorubicin/Cyclophosphamide (VDC) for Patients with High-Risk Rhabdomyosarcoma
Trial Start Date		2006-07-17
Trial Completion Date		2008-08-05 (estimated)
Registered in ClinicalTrials.gov		NCT00354744
Date Submitted to PDQ		2006-06-01
Information Last Verified		2008-10-20
NCI Grant/Contract Number		CA98543