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

Phase 2

Completed

• Conditions: Alveolar Childhood Rhabdomyosarcoma; Embryonal Childhood Rhabdomyosarcoma; Embryonal-botryoid Childhood Rhabdomyosarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Rhabdomyosarcoma
• Interventions: Drug: vincristine sulfate; Drug: irinotecan hydrochloride; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: ifosfamide; Drug: etoposide; Drug: tirapazamine; Biological: filgrastim; Biological: sargramostim; Other: pharmacological study; Other: pharmacogenomic studies; Other: laboratory biomarker analysis

• Registration Number: NCT00025363
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

Randomized phase II trial to compare the effectiveness of different combination chemotherapy regimens in treating children who have rhabdomyosarcoma. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells

Detailed Description

OBJECTIVES:

I. 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.

II. Determine the progression-free and overall survival of patients treated with multiagent chemotherapy.

III. Determine the toxic effects of tirapazamine, doxorubicin, and cyclophosphamide in these patients.

IV. Determine the toxic effects of irinotecan and vincristine in these patients.

V. Determine whether conversion of irinotecan to its active metabolite SN-38 predicts tumor response in these patients.

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.

Study Timeline

• Study First Submitted: 2001-10-11
• Study Start: 2001-11
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2007-10
• Status Verified: 2013-01
• Last Update Submitted: 2013-01-16
• Last Update Posted: 2013-01-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

• 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

• 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

• 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

• Performance status - ECOG 0-2

• Performance status - Zubrod 0-2

• At least 2 months

• Absolute neutrophil count at least 750/mm^3

• Platelet count at least 75,000/mm^3 (transfusion independent)

• Hemoglobin at least 10.0 g/dL (red blood cell transfusion allowed)

• Bilirubin no greater than 1.5 times normal

• SGPT less than 2.5 times normal

• Creatinine no greater than 1.5 times normal

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

• Shortening fraction at least 27% by echocardiogram

• Ejection fraction at least 50% by MUGA

• No prior ischemic heart disease

• 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

• 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

• 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

• Concurrent corticosteroid therapy allowed

• 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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I	vincristine sulfate	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 I	tirapazamine	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 I	filgrastim	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 I	sargramostim	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 I	pharmacological study	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 I	pharmacogenomic studies	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 I	etoposide	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 I	laboratory biomarker analysis	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	vincristine sulfate	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.
Arm II	cyclophosphamide	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.
Arm II	ifosfamide	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.
Arm II	etoposide	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.
Arm II	filgrastim	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.
Arm II	sargramostim	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.
Arm II	pharmacological study	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.
Arm II	pharmacogenomic studies	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.
Arm II	laboratory biomarker analysis	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.
Arm I	irinotecan hydrochloride	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 I	cyclophosphamide	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 I	doxorubicin hydrochloride	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 I	ifosfamide	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	irinotecan hydrochloride	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.
Arm II	doxorubicin hydrochloride	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.
Arm II	tirapazamine	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.

Primary Outcome Measures

Name	Time	Method
Response at week 6 of investigational window therapy (unfavorable risk patients)	At week 6
Incidence of DLT when tirapazamine is given in combination with cyclophosphamide and doxorubicin, graded according to the NCI CTC v 2.0	Up to 6 years

Secondary Outcome Measures

Name	Time	Method
Incidence of toxicities associated with the two administration schedules of irinotecan in combination with vincristine, graded according to the NCI CTC v 2.0 (unfavorable risk patients)	Up to 6 years
Blood metabolite SN-38 levels (unfavorable risk patients)	Up to 6 years
Progression-free survival	Up to 6 years
Survival	Up to 6 years

Trial Locations

Locations (1)

Children's Oncology Group; 🇺🇸 Arcadia, California, United States