| Study Summary: |
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OBJECTIVES:
Primary
- 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.
- 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 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
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.
- 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.
- 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.
PROJECTED ACCRUAL: A total of 295 patients will be accrued for this study.
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