Combination Chemotherapy With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed Stage III or Stage IV Wilms' Tumor

PRIMARY OBJECTIVES:

I. Determine the 4-year event-free survival (EFS) of patients with stage IV favorable
histology (FH) Wilms' tumor with pulmonary metastases only who have complete resolution of
pulmonary lesions without whole lung irradiation treated with DD4A chemotherapy comprising
vincristine, dactinomycin, and doxorubicin hydrochloride.

II. Determine the 4-year EFS of these patients who do not have resolution of pulmonary
metastases by week 6 treated with the addition of cyclophosphamide and etoposide to a
modified-regimen DD4A (regimen M).

III. Determine the 4-year EFS of patients with stage III or IV FH Wilms' tumor with loss of
heterozygosity for chromosomes 1p and 16q treated with regimen M.

SECONDARY OBJECTIVES:

I. Correlate the burden of pulmonary metastatic disease with outcome in patients with stage
IV FH Wilms' tumor.

OUTLINE: This is a multicenter study.

REGIMEN DD4A (weeks 1-6): Patients receive dactinomycin IV over 1-5 minutes once in week 1;
vincristine IV once in weeks 1-6; and doxorubicin hydrochloride IV over 15 minutes once in
week 4 in the absence of disease progression or unacceptable toxicity. Patients with both
pulmonary and extra-pulmonary metastases at diagnosis undergo radiotherapy once daily
beginning in week 1 and continuing for 5-14 days. After completion of DD4A chemotherapy
(week 6), patients undergo evaluation. Patients with stage IV disease and pulmonary
metastases only with no loss of heterozygosity (LOH) who are rapid complete responders (RCR)
(i.e., all pulmonary metastases disappear) proceed to regimen DD4A (weeks 7-25).

All other patients (i.e., patients with stage III or IV disease and LOH of both 1p and 16q;
stage IV disease with pulmonary metastases only who are slow incomplete responders [SIR]
[i.e., pulmonary metastases do not disappear]; or stage IV disease with nonpulmonary
metastases or with nonpulmonary metastases in combination with pulmonary metastases proceed
to regimen M (weeks 7-31).

Patients with initially unresectable or incompletely resected tumors are reevaluated at week
6, and if resectable, undergo surgery and then proceed to either regimen DD4A or regimen M
as described above.

REGIMEN DD4A (weeks 7-25): Patients receive dactinomycin IV over 1-5 minutes once in weeks
7, 13, 19, and 25; vincristine IV once in weeks 7-10, 13, 16, 19, 22, and 25; and
doxorubicin hydrochloride IV over 15 minutes once in weeks 10, 16, and 22 in the absence of
disease progression or unacceptable toxicity.

REGIMEN M (weeks 7-31): Patients receive cyclophosphamide IV over 1 hour and etoposide IV
over 1 hour on days 1-5 in weeks 7, 10, 19, and 25; vincristine IV once in weeks 8, 9, 11,
12, 13, 16, 22, 28, and 31; and dactinomycin IV or doxorubicin hydrochloride IV over 15
minutes once in weeks 13, 16, 22, 28, and 31 in the absence of disease progression or
unacceptable toxicity. Patients with pulmonary metastases only who are SIR also undergo
whole lung radiotherapy once daily beginning in week 7 and continuing for 5-14 days.

NOTE: Patients who begin study treatment after undergoing resection of all pulmonary
metastases are not eligible for this study. It is recommended that these patients be treated
as per the current gold standard of therapy which is chemotherapy according to regimen DD4A
(weeks 1-25) and whole lung radiotherapy for 5-14 days beginning in week 1.

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

Inclusion Criteria:

- Newly diagnosed Wilms' tumor meeting 1 of the following criteria:

- Stage IV disease with favorable histology with or without loss of heterozygosity
(LOH) for 1p and 16q

- Stage III disease with favorable histology with LOH for 1p and 16q transferring
from clinical trial COG-AREN0532

- Patients must begin therapy within 14 days after surgery or biopsy, unless medically
contraindicated

- No bilateral Wilms' tumors (stage IV)

- Patients should be referred to COG-AREN0534

- Previously enrolled in clinical trial COG-AREN03B2

- Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) OR Lansky
PS 50-100% (for patients ≤ 16 years of age)

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

- AST or ALT < 2.5 times ULN

- Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by
radionuclide angiogram

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No prior tumor-directed chemotherapy or radiotherapy unless transferring from
clinical trial COG-AREN0532 OR treatment for emergent issues, as medically indicated

- No concurrent aprepitant