Trial Information

Treatment of High Risk Renal Tumors

OBJECTIVES:

Primary

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

- 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.

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

- 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

- 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.

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

- 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.

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

- Correlate histologic and molecular cytogenetic findings with outcome in pediatric RCC.
(exploratory)

- 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.
(exploratory)

- Determine the frequency of TP53 mutations in anaplastic Wilms tumor and correlate the
presence of detectable TP53 mutation with clinical outcome. (exploratory)

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.

- Patients with initially unresectable or incompletely resected tumors receive
chemotherapy and undergo imaging reevaluation after 4 cycles (approximately 12
weeks). If the tumor is deemed resectable at week 13, surgery is performed.

- Revised 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 60-90 minutes on days 1-5 in weeks 1 and 2. Patients with progressive disease (PD)
are treated with revised 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 revised regimen UH-1 and patients with PR or CR
are treated with revised regimen UH-2.

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

- Some patients will have received pre-operative chemotherapy on AREN0532 or AREN0533 for
what was presumed to be favorable histology Wilms tumor. Patients designated to receive
revised regimen UH-1 receive this regimen in its entirety starting from week 1, except
that the week-28 doxorubicin dose is withheld to maintain a cumulative doxorubicin dose
≤ 225 mg/m^2.

- Revised 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
revised regimen UH-1 in weeks 1, 16, 19, 28, and 34. Patients also receive CPM1,
etoposide, and carboplatin as in revised regimen UH-1 in weeks 4, 7, 13, 22, and
31 and irinotecan hydrochloride IV over 60-90 minutes on days 1-5 in weeks 10, 11,
25, and 26. Patients whose primary tumors were initially resected undergo
radiotherapy** as in revised regimen UH-1 beginning on day 1 in week 1. Patients
with delayed primary tumor resection undergo radiotherapy** as in revised 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 revised regimen UH-1 beginning on day 1 in
week 1. Patients with delayed primary tumor resection undergo radiotherapy** as in
revised 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 revised regimen UH-1 beginning on
day 1 in week 1. Patients with delayed primary tumor resection undergo
radiotherapy** as in revised 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.

- Patients designated to receive Regimen DD-4A may resume this regimen where they left
off on the AREN0532 or AREN0533 studies. For example, if a patient received 6 weeks of
DD-4A therapy on AREN0532 and then had a nephrectomy showing FAWT, they may transfer to
AREN0321 and resume therapy at week 7.

NOTE: **Radiation therapy should be delayed for patients less than 6 months of age.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up until the fifth anniversary of
the date the patient was enrolled on this study.

PROJECTED ACCRUAL: A total of 295 patients will be accrued for this study.