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

Alternate Title

Comparison of Chemotherapy Regimens in Treating Children With Relapsed or Progressive Rhabdomyosarcoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Closed	Under 21 at time of initial diagnosis	NCI	COG-ARST0121 NCT00025363, ARST0121

Objectives

1. Compare response rate in children with relapsed or progressive rhabdomyosarcoma, undifferentiated sarcoma, or ectomesenchymoma treated with 2 different schedules of irinotecan and vincristine in an upfront phase II window.
2. Determine the progression-free and overall survival of patients treated with multiagent chemotherapy.
3. Determine the toxic effects of tirapazamine, doxorubicin, and cyclophosphamide in these patients.
4. Determine the toxic effects of irinotecan and vincristine in these patients.
5. Determine whether conversion of irinotecan to its active metabolite SN-38 predicts tumor response in these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed rhabdomyosarcoma, undifferentiated sarcoma, or ectomesenchymoma
  • First relapse or first occurrence of disease progression



• Unfavorable-risk patients eligible for study window therapy with irinotecan and vincristine meeting the following criteria:
  • Unfavorable risk defined by any of the following:
    • Embryonal histology with stage I or group I at initial diagnosis with distant recurrence or with local or regional recurrence after prior cyclophosphamide
    • Embryonal histology with initial stage II, III, or IV or group II, III, or IV with any relapse pattern
    • Alveolar histology with any stage or group at initial diagnosis
  • At least unidimensionally measurable disease
  • No prior irinotecan
  • Bone marrow must not be only site of relapse

  OR




• Unfavorable-risk patients ineligible for study window therapy with irinotecan meeting the following criteria:
  • Either no measurable disease OR patient received prior irinotecan
  • Bone marrow as only site of relapse allowed

  OR




• Favorable-risk patients meeting the following criteria:
  • Initial botryoid histology (any stage, any group, or any pattern of relapse)
  • Embryonal histology if either stage I or group I (with either local or regional recurrence)
  • No prior cyclophosphamide



• No CNS metastases

Prior/Concurrent Therapy:

Biologic therapy:

• No prior myeloablative therapy with stem cell transplantation
• At least 1 week since prior antineoplastic biologic agent
• At least 1 week since prior growth factor(s)
• Recovered from prior immunotherapy
• No concurrent immunomodulating agents

Chemotherapy:

• See Disease Characteristics
• See Biologic therapy
• No more than 1 prior chemotherapy regimen
• No prior doxorubicin or daunorubicin
• At least 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered
• No other concurrent anticancer chemotherapy

Endocrine therapy:

• Concurrent corticosteroid therapy allowed

Radiotherapy:

• At least 2 weeks since prior small-port radiotherapy.
• At least 6 months since prior radiotherapy to 50% or more of pelvis
• At least 6 weeks since other prior substantial radiotherapy to bone marrow
• Recovered from prior radiotherapy
• Concurrent radiotherapy to localized painful lesions allowed provided at least 1 measurable lesion is not irradiated
• No concurrent intensity-modulated radiotherapy

Surgery:

• Not specified

Patient Characteristics:

Age:

• Under 21 at time of initial diagnosis

Performance status:

• ECOG 0-2
• Zubrod 0-2

Life expectancy:

• At least 2 months

Hematopoietic:

• Absolute neutrophil count at least 750/mm³
• Platelet count at least 75,000/mm³ (transfusion independent)
• Hemoglobin at least 10.0 g/dL (red blood cell transfusion allowed)

Hepatic:

• Bilirubin no greater than 1.5 times normal
• SGPT less than 2.5 times normal

Renal:

• Creatinine no greater than 1.5 times normal

  OR

• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

Cardiovascular:

• Shortening fraction at least 27% by echocardiogram

  OR

• Ejection fraction at least 50% by MUGA
• No prior ischemic heart disease

Other:

• Seizure disorder allowed if well controlled by anticonvulsants
• No CNS toxicity greater than grade 2
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Expected Enrollment

A total of 102-120 patients with unfavorable-risk disease (51 per treatment arm) will be accrued for this study within 2.5-3 years. A total of 20-30 patients with favorable-risk disease will be accrued for this study.

Outcomes

Safety
Response at week 6 of investigational window therapy

Toxicity
Blood metabolite SN-38 levels
Progression-free survival
Survival

Outline

This is a randomized, multicenter study. Patients are stratified according to risk status and window therapy eligibility (unfavorable risk and eligible vs unfavorable risk and ineligible vs favorable risk).

• Unfavorable-risk patients eligible for window therapy: Patients are stratified according to prior topotecan (yes vs no). These patients are randomized to 1 of 2 treatment arms.
  • Arm I: Patients receive vincristine IV on days 1 and 8 and irinotecan IV over 1 hour on days 1-5 and 8-12. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.
  
  
  
  • Arm II: Patients receive vincristine IV on days 1 and 8 and irinotecan IV over 1 hour on days 1-5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.
  
  
  
  • Patients in both arms with partial response (PR) or complete response (CR) receive 5 additional courses of irinotecan and vincristine on the previous schedule. In addition, patients with PR or CR also receive cyclophosphamide/doxorubicin (CD) and ifosfamide/etoposide (IE) chemotherapy.
    • CD/IE Chemotherapy: Patients receive cyclophosphamide IV over 1 hour and doxorubicin IV over 15-30 minutes on day 1 of weeks 7, 16, 28, 37, and 40. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of weeks 10, 19, 22, 31, and 43. Treatment continues in the absence of disease progression or unacceptable toxicity.
  
  
  
  • Patients with no response or progressive disease on arm I or II proceed to tirapazamine/cyclophosphamide/doxorubicin (TCD) and ifosfamide/etoposide (IE) chemotherapy.
    • TCD/IE Chemotherapy: Patients receive tirapazamine IV over 2 hours, cyclophosphamide IV over 1 hour, and doxorubicin IV over 15-30 minutes on day 1 of weeks 7, 10, 16, 25, and 34. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of weeks 13, 19, 22, 28, 31, and 37.
  
  
  



• Patients with unfavorable risk and ineligible for window therapy: Patients receive tirapazamine IV over 2 hours, cyclophosphamide IV over 1 hour, and doxorubicin IV over 15-30 minutes on day 1 of weeks 1, 4, 10, 19, and 28. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of weeks 7, 13, 16, 22, 25, and 31. Patients also receive filgrastim (G-CSF) or sargramostim (GM-CSF) subcutaneously (SC) beginning 1 day after each course of chemotherapy and continuing until blood counts recover. Treatment continues in the absence of disease progression or unacceptable toxicity.



• Patients with favorable risk: Patients receive cyclophosphamide IV over 1 hour and doxorubicin IV over 15-30 minutes on day 1 of weeks 1, 4, 10, 19, and 28. Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of weeks 7, 13, 16, 22, 25, and 31. Patients also receive G-CSF or GM-CSF SC beginning 1 day after each course of chemotherapy and continuing until blood counts recover. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 2 months for 1 year, every 4 months for 2 years, and then annually thereafter.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Philip Breitfeld, MD, Protocol chair		Ph: 919-668-1728

Registry Information
Official Title		A Groupwide Randomized Phase II Window Study of Two Different Schedules of Irinotecan in Combination with Vincristine And Pilot Assessment of Safety and Efficacy of Tirapazamine Combined with Multiagent Chemotherapy for First Relapse or Progressive Disease in Rhabdomyosarcoma and Related Tumors
Trial Start Date		2001-11-02
Registered in ClinicalTrials.gov		NCT00025363
Date Submitted to PDQ		2001-08-02
Information Last Verified		2006-10-27
NCI Grant/Contract Number		CA13539

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