Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor

OBJECTIVES:

I. To improve 4-year event-free survival (EFS) to 73% for young patients with bilateral Wilms
tumor (BWT).

II. To prevent complete removal of at least one kidney in 50% of patients with BWT by using
prenephrectomy 3-drug chemotherapy induction with vincristine (vincristine sulfate),
dactinomycin, and doxorubicin (doxorubicin hydrochloride).

III. To evaluate the efficacy of chemotherapy in preserving renal units in children with
diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) and preventing Wilms tumor
development.

IV. To facilitate partial nephrectomy in lieu of nephrectomy in 25% of children with
unilateral tumors and aniridia, Beckwith-Wiedemann syndrome (BWS), hemihypertrophy or other
overgrowth syndromes, by using prenephrectomy 2-drug chemotherapy induction with vincristine
and dactinomycin.

V. To have 75% of patients with BWT undergo definitive surgical treatment by 12 weeks after
initiation of chemotherapy.

OUTLINE: Patients are assigned to 1 of 3 arms.

ARM 1 (Bilateral Wilms Tumors): Patients start with three drug chemotherapy (Regimen VAD;
vincristine, dactinomycin and doxorubicin) and are evaluated and six and 12 weeks for
feasibility of undergoing a partial nephrectomy/renal sparing surgery. At week 12 definitive
surgery takes place followed by chemotherapy and radiation therapy based on histology and
stage. Treatment continues for 25 or 31 weeks depending on histology. Patients are followed
for up to 10 years following end of therapy.

ARM 2 (Unilateral High Risk tumors bilaterally predisposed): Patients start with either 2
drug or three drug chemotherapy (Regimen VA, VAD) and are evaluated a 6 and 12 weeks for
feasibility of undergoing a partial nephrectomy. At week 12 definitive surgery takes place
followed by chemotherapy.

ARM 3 (DHPLN): Patients with this rare disease are diagnosed based on cross-sectional imaging
characteristics and undergo 2 drug chemotherapy (Regimen;VA). Patients are reassessed at 6
weeks and 12 weeks. If disease has responded or stayed stable chemotherapy is completed for
19 weeks (Regimen EE4A). If disease has progress a biopsy is performed to assess histology
and adjust therapy based on the biopsy. This therapy may include, nephrectomy, chemotherapy
or radiation therapy.

VAD REGIMEN: Patients receive vincristine sulfate intravenously (IV) over 1 minute on days 1,
8, 15, 22, 29, and 36 (weeks 1-6) and dactinomycin IV and doxorubicin hydrochloride IV over
15-120 minutes on days 1 and 22 (weeks 1 and 4).

EE4A REGIMEN: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 22, 29,
and 36 (weeks 1-6) and dactinomycin IV over 1-5 minutes on days 1 and 22 (weeks 1 and 4).

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

Inclusion Criteria:

- The patient must have one of the following conditions to be eligible:

- Synchronous bilateral Wilms tumors**; or

- Unilateral Wilms tumor and aniridia, Beckwith-Wiedemann Syndrome, idiopathic
hemihypertrophy, Simpson-Golabi-Behmel-Syndrome, Denys-Drash Syndrome or other
associated genitourinary anomalies associated with bilateral Wilms tumor, such as
hypospadias and undescended testis (to be eligible, these patients must not
undergo any nephrectomy at diagnosis; note-horseshoe kidney is not associated
with bilateral Wilms tumor and these patients should go on the appropriate
unilateral Wilms tumor study); or

- Multicentric Wilms tumor (any age) (to be eligible, these patients must not
undergo any nephrectomy at diagnosis); or

- Unilateral Wilms tumor with contralateral nephrogenic rest(s) (any size) in a
child under one year of age (to be eligible, these patients must not undergo any
nephrectomy at diagnosis); or

- Diffuse hyperplastic perilobar nephroblastomatosis (unilateral or bilateral)
defined by central radiological review; or

- Wilms tumor arising in a solitary kidney (patients with metachronous Wilms tumor
are not eligible)

- The AREN0534 study uses the guideline that Wilms tumor with a single lesion
1 cm or greater in the contralateral kidney or multiple lesions (of any
size) in the contralateral kidney should be treated on the synchronous
bilateral Wilms tumor stratum; patients with an isolated lesion less than 1
cm in the contralateral kidney should be treated on the appropriate study
for unilateral Wilms tumor OR on the unilateral Wilms tumor/contralateral
nephrogenic rest stratum of this study if they have not undergone
nephrectomy and are under one year of age

- Loss of heterozygosity (LOH) results?which are used in the unilateral Wilms tumor
studies?are not a requirement for enrollment on AREN0534; blood samples can be
submitted but will not be used to direct AREN0534 therapy

- Specimens/materials must be submitted for central review by day 7; for enrollment on
AREN0534, unless a biopsy was done, the submission requirements at enrollment on
AREN03B2 refer to imaging studies; tissue samples are only required if a surgical
procedure (biopsy or nephrectomy) was performed at the time of enrollment on AREN03B2

- Patients must begin protocol therapy on AREN0534 by day 14 following surgery or
diagnosis by initial computed tomography (CT)/magnetic resonance imaging (MRI), unless
medically contraindicated

- Karnofsky performance status must be >= 50% for patients > 16 years of age and Lansky
performance status must be >= 50% (for patients =< 16 years of age

- Patients must not have received systemic chemotherapy or radiation therapy prior to
treatment on this study

- Patients with unilateral Wilms tumor and aniridia, Beckwith-Wiedemann Syndrome,
idiopathic hemihypertrophy, Simpson-Golabi-Behmel-Syndrome, Denys-Drash Syndrome or
other associated genitourinary anomalies; or multicentric or unilateral Wilms tumor
with contralateral nephrogenic rest(s) (any size) in a child under 1 year of age who
undergo a nephrectomy at diagnosis are not eligible for this study and should be
directed to a unilateral Wilms tumor study

- Total bilirubin =< 1.5 times upper limit of normal (ULN) for age

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5
times upper limit of normal (ULN) for age

- Shortening fraction >= 27% by echocardiogram, OR ejection fraction >= 50% by
radionuclide angiogram

- (Cardiac function does not need to be assessed in patients who will not receive
doxorubicin as part of their initial therapy on this study [i.e., patients who
start on regimen EE-4A])

- Female patients of childbearing age must have a negative pregnancy test

- Female patients who are lactating must agree to stop breastfeeding

- Sexually active patients of childbearing potential must agree to use effective
contraception

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met

- No concurrent aprepitant