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Randomized Study of Vincristine, Dactinomycin and Cyclophosphamide (VAC) Versus VAC Alternating With Vincristine and Irinotecan (VI) for Patients With Intermediate-Risk Rhabdomyosarcoma (RMS)

Phase 3
50 Years
Open (Enrolling)
Adult Malignant Mesenchymoma, Adult Rhabdomyosarcoma, Alveolar Childhood Rhabdomyosarcoma, Childhood Malignant Mesenchymoma, Embryonal Childhood Rhabdomyosarcoma, Embryonal-botryoid Childhood Rhabdomyosarcoma, Nonmetastatic Childhood Soft Tissue Sarcoma, Previously Untreated Childhood Rhabdomyosarcoma, Stage I Adult Soft Tissue Sarcoma, Stage II Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma

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Trial Information

Randomized Study of Vincristine, Dactinomycin and Cyclophosphamide (VAC) Versus VAC Alternating With Vincristine and Irinotecan (VI) for Patients With Intermediate-Risk Rhabdomyosarcoma (RMS)


I. Compare the early response rates in patients with intermediate-risk rhabdomyosarcoma
(RMS) treated with vincristine, dactinomycin, and cyclophosphamide (VAC) vs VAC alternating
with vincristine and irinotecan hydrochloride (VI) in combination with radiotherapy.

II. Compare failure-free survival (FFS) and overall survival of patients treated with these


I. Compare FFS, local control, and survival of patients with intermediate-risk RMS treated
with VAC and early (week 4) radiotherapy vs delayed (week 10) radiotherapy, using data from
IRS-IV for historic comparison.

II. Compare the acute and late effects of VAC vs VAC alternating with VI, including the
toxicity associated with concurrent VI and radiotherapy.

III. Compare the acute and late effects of VAC as delivered on this study to that
administered on COG-D9803.

IV. Correlate change in fludeoxyglucose F^18 positron emission tomography (FDG-PET) maximum
standard uptake value from week 1 to week 4 and 15 with FFS.

V. Correlate UGT1A1 genotype with VI toxicity in patients receiving VAC alternating with VI.

VI. Correlate CYP2B6, CYP2C9, and GSTA1 genotypes with VAC toxicity. VII. Prospectively
evaluate and validate gene expression values with the intent to define the best diagnostic
predictors and more powerful prognostic classifiers.

OUTLINE: This is a prospective, historic control, randomized, multicenter study. Patients
are stratified according to histology, disease stage, and clinical group (group III, stage 2
or 3 embryonal rhabdomyosarcoma [RMS] vs group I, stage 1 alveolar RMS vs group II or III,
stage 2 or 3 alveolar RMS). Patients are randomized to 1 of 2 treatment arms within 42 days
of initial surgery or biopsy.

ARM I (VAC): Patients receive VAC chemotherapy comprising vincristine IV over 1 minute on
day 1 of weeks 1-13, 16, 19-25, 28, 31-37, and 40; dactinomycin IV over 1-5 minutes on day 1
of weeks 1, 4, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40; and cyclophosphamide IV over 1
hour on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40.

ARM II (VAC/VI): Patients receive VAC chemotherapy alternating with VI chemotherapy
comprising vincristine IV over 1 minute on day 1 of weeks 1-13,16, 17, 19, 20, 22-26, 28,
31-34, 37, 38, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1,13, 22, 28, 34,
and 40; cyclophosphamide IV over 1 hour on day 1 of weeks 1,10, 13, 22, 28, 34, and 40; and
irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 4, 7, 16, 19, 25, 31, and

In both arms, treatment continues in the absence of disease progression or unacceptable
toxicity. Patients* in both arms also undergo radiotherapy 5 days a week for 4-6 weeks
beginning in week 4 (except patients with alveolar RMS rendered group I by amputation OR
patients needing week 1 emergency radiotherapy for symptomatic spinal cord compression).

NOTE: *Individualized local control plan that deviates from protocol-mandated radiotherapy
allowed for patients ≤ 24 months of age.

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

Inclusion Criteria:

- Histologically or cytologically confirmed rhabdomyosarcoma (RMS)

- Must be concurrently enrolled on COG-D9902 to confirm local histologic diagnosis

- Intermediate-risk disease, defined by 1 of the following surgicopathological and
staging criteria:

- Group III, stage 2 or 3 embryonal, botryoid, or spindle cell RMS

- Group III, stage 2 or 3 ectomesenchymoma

- Group I-III, stage 1-3 alveolar RMS

- Newly diagnosed disease

- Staging ipsilateral retroperitoneal lymph node dissection (SIRLND) required for
patients ≥ 10 years of age with paratesticular tumors and for patients < 10 years
with clinically or radiographically involved lymph nodes

- Patients with extensive lymph node involvement, defined as ≥ 2 lymph nodes > 2
cm in dimension, identified by imaging studies, are not required to undergo

- Regional lymph node sampling or sentinel lymph node procedure is required for
histologic evaluation in patients with extremity tumors

- Has undergone initial surgery or biopsy within the past 42 days

- Must be able to undergo radiotherapy

- ECOG performance status (PS) 0-2 (Karnofsky PS 50-100% [≥ 16 years of age] or Lansky
PS 50-100% [< 16 years of age])

- Absolute neutrophil count ≥ 750/mm^3

- Platelet count ≥ 75,000/mm^3 (transfusion independent)

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- 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 have unimpeded urinary flow
established via decompression of the obstructed portion of the urinary tract

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 1 month after
completion of study treatment

- No evidence of uncontrolled infection

- No prior chemotherapy* (excluding steroids)

- No prior radiotherapy*

- No concurrent aprepitant during treatment with cyclophosphamide

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Comparison of failure-free survival (FFS) between the two treatment groups

Outcome Description:

A 1-sided alpha level was chosen as primary interest is in detecting an improvement in FFS under the more intensive therapy. The FFS distributions will be estimated using the Kaplan-Meier method and will be compared between the therapy groups using a log-rank test.

Outcome Time Frame:

Up to 7 years

Safety Issue:


Principal Investigator

Douglas Hawkins

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Institutional Review Board

Study ID:




Start Date:

December 2006

Completion Date:

Related Keywords:

  • Adult Malignant Mesenchymoma
  • Adult Rhabdomyosarcoma
  • Alveolar Childhood Rhabdomyosarcoma
  • Childhood Malignant Mesenchymoma
  • Embryonal Childhood Rhabdomyosarcoma
  • Embryonal-botryoid Childhood Rhabdomyosarcoma
  • Nonmetastatic Childhood Soft Tissue Sarcoma
  • Previously Untreated Childhood Rhabdomyosarcoma
  • Stage I Adult Soft Tissue Sarcoma
  • Stage II Adult Soft Tissue Sarcoma
  • Stage III Adult Soft Tissue Sarcoma
  • Mesenchymoma
  • Rhabdomyosarcoma
  • Rhabdomyosarcoma, Embryonal
  • Sarcoma
  • Liver Neoplasms



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