Medpedia

• Sarcoma

DISEASE CHARACTERISTICS:
-  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 surgicopathologic 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
SIRLND
-  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
PATIENT CHARACTERISTICS:
-  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
PRIOR CONCURRENT THERAPY:
-  No prior chemotherapy* (excluding steroids)
-  No prior radiotherapy*
-  No concurrent aprepitant during treatment with cyclophosphamide NOTE: *Patients who
received prior radiotherapy or chemotherapy while enrolled on COG-ARST0331 allowed

OBJECTIVES:

Primary

-  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.

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

Secondary

-  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.

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

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

-  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.

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

-  Correlate CYP2B6, CYP2C9, and GSTA1 genotypes with VAC toxicity.

-  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 37.

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.

PROJECTED ACCRUAL: A total of 486 patients will be accrued for this study.

• Biological: dactinomycin
  Given IV over 1-5 minutes
• Drug: cyclophosphamide
  Given IV over 1 hour
• Drug: irinotecan hydrochloride
  Given IV over 1 hour
• Drug: vincristine sulfate
  Given IV over 1 minute
• Radiation: radiation therapy
  Given 5 days a week for 4-6 weeks beginning in week 4

• Early response rate
  Safety Issue: No
• Failure-free survival
  Safety Issue: No
• Overall survival
  Safety Issue: No
• Acute and late effects of vincristine, dactinomycin, and cyclophosphamide (VAC) vs VAC alternating with vincristine and irinotecan hydrochloride
  Safety Issue: No

• Douglas Hawkins, MD
  Study Chair, Seattle Children's Hospital
• Geoffrey McCowage, MD
  Children's Hospital at Westmead
• Leo Mascarenhas, MD
  Children's Hospital Los Angeles

• Swiss Pediatric Oncology Group Geneva
  Geneva, 1205, Switzerland
  Recruiting
  Ayse H. Ozsahin

  0
• Swiss Pediatric Oncology Group Bern
  Bern, 3010, Switzerland
  Recruiting
  Roland A. Ammann

  0
• San Jorge Children's Hospital
  Santurce, 00912, Puerto Rico
  Recruiting
  Luis A. Clavell

  (787) 728-1575
• Starship Children's Health
  Auckland, 1, New Zealand
  Recruiting
  Lochie R. Teague

  (649) 307-4949
• Centre Hospitalier Universitaire de Quebec
  Quebec, G1V 4G2, Canada
  Recruiting
  Bruno Michon

  (418) 656-4141
• Saskatoon Cancer Centre at the University of Saskatchewan
  Saskatoon, Saskatchewan, S7N 4H4, Canada
  Recruiting
  Christopher Mpofu

  (306) 655-2744
• Allan Blair Cancer Centre at Pasqua Hospital
  Regina, Saskatchewan, S4T 7T1, Canada
  Recruiting
  Mansoor M. Haq

  (306) 766-2498
• Hopital Sainte Justine
  Montreal, Quebec, H3T 1C5, Canada
  Recruiting
  Yvan Samson

  (418) 656-4141
• Hospital for Sick Children
  Toronto, Ontario, M5G 1X8, Canada
  Recruiting
  Sylvain Baruchel

  (416) 813-7795
• Children's Hospital of Eastern Ontario
  Ottawa, Ontario, K1H 8L1, Canada
  Recruiting
  Jacqueline M.L. Halton

  (613) 737-7600
• Children's Hospital of Western Ontario
  London, Ontario, N6A 5W9, Canada
  Recruiting
  Anne E. Cairney

  (519) 685-8494
• Cancer Centre of Southeastern Ontario at Kingston General Hospital
  Kingston, Ontario, K7L 2V7, Canada
  Recruiting
  Mariana P. Silva

  (613) 549-6666

• Children's Oncology Group
  Lead Sponsor
• Unspecified

• Clinical trial summary from the National Cancer Institute's PDQ® database
  http://cancer.gov/clinicaltrials/COG-ARST0531