Combination Chemotherapy, Radiation Therapy, and/or Surgery in Treating Patients With High-Risk Kidney Tumors

PRIMARY OBJECTIVES:

I. Evaluate whether a treatment regimen containing cyclophosphamide, carboplatin, and
etoposide alternating with vincristine, doxorubicin hydrochloride, and cyclophosphamide
(regimen UH-1) improves the event-free and overall survival of patients with diffuse
anaplastic Wilms' tumor (DAWT) as compared to historical controls.

II. Evaluate, in a phase II "window" study, the antitumor activity of a combination of
vincristine and protracted-schedule irinotecan hydrochloride in patients with metastatic
DAWT.

III. Evaluate whether regimen UH-1 improves the event-free and overall survival of patients
with malignant rhabdoid tumor (MRT) as compared to historical controls.

IV. Maintain the excellent event-free survival of patients with stage I clear cell sarcoma
of the kidney (CCSK) without the use of abdominal irradiation.

SECONDARY OBJECTIVES:

I. Describe the outcomes of patients with stage I DAWT or stages I-III focal anaplastic
Wilms' tumor (FAWT) treated with vincristine, dactinomycin, doxorubicin hydrochloride, and
flank radiation.

II. Describe the outcomes of patients with stage IV FAWT or stage IV CCSK treated with
regimen UH-1.

III. Describe event-free and overall survival of children and adolescents with localized
renal cell carcinoma (RCC) (including patients with local lymph node involvement) treated
with surgical resection without adjuvant therapy.

IV. Describe response rate, event-free survival, and overall survival of patients with
unresectable or distantly metastatic RCC treated according to institutional preference.

V. Correlate histologic and molecular cytogenetic findings with outcome in pediatric RCC.

VI. Evaluate the frequency of germline and inherited INI1 mutations in renal and extrarenal
MRT and correlate the presence of detectable INI1 mutation with clinical outcome.

VII. Determine the frequency of TP53 mutations in anaplastic Wilms' tumor and correlate the
presence of detectable TP53 mutation with clinical outcome.

OUTLINE: This is a multicenter study. Patients are assigned to 1 of 6 treatment regimens
according to tumor histology, stage of disease, and response to treatment.

SURGERY (renal cell carcinoma [RCC]): Patients with completely resectable stage I-IV RCC
undergo surgical resection. Patients with incompletely resectable stage III-IV RCC undergo
treatment as per physician's choice.

REGIMEN UH-1 (stage II-III or stage IV [with no measurable disease] diffuse anaplastic
Wilms' tumor [DAWT], stage I-IV malignant rhabdoid tumor [MRT], stage IV focal anaplastic
Wilms' tumor [FAWT], or stage IV clear cell sarcoma of the kidney [CCSK]): Patients receive
vincristine IV on day 1 in weeks 1-3, 10-12, 13-15, 22-24, and 28-30; doxorubicin
hydrochloride IV over 15 minutes on day 1 and cyclophosphamide (CPM2) IV over 15-30 minutes
on day 1 in weeks 1, 10, 13, 22, and 28; and cyclophosphamide (at lower doses [CPM1]) IV
over 1 hour and etoposide IV over 1 hour on days 1-4 and carboplatin IV over 1 hour on day 1
in weeks 4, 7, 16, 19, and 25. Patients whose primary tumors were initially resected undergo
radiotherapy once daily 5 days a week for 4-5½ weeks beginning on day 1 in week 1. Patients
with delayed primary tumor resection undergo radiotherapy beginning on day 1 in week 13. If
the primary tumor was not previously resected, patients undergo resection, if feasible, in
week 13. Patients with unresectable CCSK receive no further study therapy.

IRINOTECAN/VINCRISTINE WINDOW THERAPY* (stage IV DAWT with measurable disease at diagnosis):
Patients receive vincristine IV on day 1 and irinotecan hydrochloride IV over 30 minutes on
days 1-5 in weeks 1 and 2. Patients with progressive disease (PD) are treated with regimen
UH-1. Patients with stable disease (SD), partial response (PR), or complete response (CR)
receive another course of irinotecan hydrochloride/vincristine window therapy beginning on
day 22. After the second course, patients with SD or PD are treated with regimen UH-1 and
patients with PR or CR are treated with regimen UH-2.

NOTE: *Patients who are eligible for but who are unwilling to receive window therapy,
receive therapy on regimen UH-1.

REGIMEN UH-2 (DAWT with CR/PR to irinotecan hydrochloride/vincristine window therapy):
Patients receive vincristine on day 1 in weeks 1-3, 10, 11, 16-21, 25, 26, 28-30, and 34-36
and doxorubicin hydrochloride and CPM2 as in regimen UH-1 in weeks 1, 16, 19, 28, and 34.
Patients also receive CPM1, etoposide, and carboplatin as in regimen UH-1 in weeks 4, 7, 13,
22, and 31 and irinotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 10, 11, 25,
and 26. Patients whose primary tumors were initially resected undergo radiotherapy as in
regimen UH-1 beginning on day 1 in week 1. Patients with delayed primary tumor resection
undergo radiotherapy as in regimen UH-1 beginning on day 1 in week 7. If the primary tumor
was not previously resected, patients undergo resection, if feasible, in week 7.

REGIMEN I (stage I-III CCSK): Patients receive vincristine IV on day 1 in weeks 1-3, 5-9,
8-9, 11-14, 19, and 25; doxorubicin hydrochloride IV over 15 minutes on day 1 and
cyclophosphamide IV over 1 hour on days 1-3 in weeks 1, 7, 13, 19, and 25; and
cyclophosphamide IV and etoposide IV on days 1-5 in weeks 4, 10, 16, and 22. Patients whose
primary tumors were initially resected (except those with stage I CCSK) undergo radiotherapy
as in regimen UH-1 beginning on day 1 in week 1. Patients with delayed primary tumor
resection undergo radiotherapy as in regimen UH-1 beginning on day 1 in week 13. If the
primary tumor was not previously resected, patients undergo resection, if feasible, in week
13.

REGIMEN DD-4A (stage I DAWT or stages I-III FAWT): Patients receive dactinomycin IV over 1-5
minutes on day 1 in weeks 1, 7, 13, 19, and 25; vincristine IV on day 1 in weeks 1-10, 13,
16, 19, 22, and 25; and doxorubicin hydrochloride IV over 15 minutes on day 1 in weeks 4,10,
16, and 22. Patients whose primary tumors were initially resected undergo radiotherapy as in
regimen UH-1 beginning on day 1 in week 1. Patients with delayed primary tumor resection
undergo radiotherapy as in regimen UH-1 beginning on day 1 in week 13. If the primary tumor
was not previously resected, patients undergo resection, if feasible, in week 13. Treatment
continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for at least 3
years.

Inclusion Criteria:

- Newly diagnosed disease of 1 of the following histologic types:

- Focal anaplastic Wilms' tumor

- Diffuse anaplastic Wilms' tumor

- Clear cell sarcoma of the kidney

- Malignant rhabdoid tumor (renal or extrarenal)

- Renal cell carcinoma

- Clear cell

- Papillary

- Renal medullary

- Oncocytoid

- Sarcomatoid

- Chromophobe

- Translocation

- Collecting duct

- Carcinoma associated with neuroblastoma

- Renal cell carcinoma unclassified

- Specimens/materials must be submitted for central review by Day 7

- Patients must begin protocol therapy on AREN0321 by Day 14 after surgery or biopsy
(surgery/biopsy is Day 0), unless medically contraindicated

- Karnofsky performance status (PS) must be >= 50 for patients > 16 years if age and
Lansky PS 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 UNLESS they were enrolled on the AREN0532 or AREN0533 studies
and received prenephrectomy chemotherapy for what was originally presumed to be
favorable histology Wilms tumor; additionally, patients with pediatric RCC who
previously received chemotherapy for another type of malignancy (not the RCC) or
non-malignant condition may enroll on the study

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

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

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

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

- Female patients who are lactating must agree to stop breast-feeding

- 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