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

Phase 2

Completed

Conditions: Clear Cell Renal Cell Carcinoma
Childhood Renal Cell Carcinoma
Clear Cell Sarcoma of the Kidney
Papillary Renal Cell Carcinoma
Stage I Renal Cell Cancer
Stage II Renal Cell Cancer
Rhabdoid Tumor of the Kidney
Stage I Renal Wilms Tumor
Stage IV Renal Wilms Tumor
Stage II Renal Wilms Tumor

Interventions: Drug: Doxorubicin Hydrochloride
Procedure: Conventional Surgery
Drug: Irinotecan Hydrochloride
Biological: Dactinomycin
Drug: Cyclophosphamide
Drug: Etoposide
Drug: Carboplatin
Drug: Vincristine Sulfate
Other: Laboratory Biomarker Analysis
Radiation: Radiation Therapy

Registration Number: NCT00335556

Lead Sponsor: Children's Oncology Group

Brief Summary: This phase II trial is studying how well combination chemotherapy, radiation therapy, and/or surgery work in treating patients with high-risk kidney tumors. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy together with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 291

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment (UH-1)	Vincristine Sulfate	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, and carboplatin. 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 clear cell sarcoma of the kidney (CCSK) receive no further study therapy.
Treatment (window/UH-1)	Vincristine Sulfate	Patients receive vincristine IV on days 1 and 8 and irinotecan hydrochloride IV over 30 minutes on days 1-5 and 8-12 (course 1). 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.
Treatment (UH-1)	Conventional Surgery	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, and carboplatin. 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 clear cell sarcoma of the kidney (CCSK) receive no further study therapy.
Treatment (UH-1)	Laboratory Biomarker Analysis	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, and carboplatin. 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 clear cell sarcoma of the kidney (CCSK) receive no further study therapy.
Treatment (window/UH-1)	Radiation Therapy	Patients receive vincristine IV on days 1 and 8 and irinotecan hydrochloride IV over 30 minutes on days 1-5 and 8-12 (course 1). 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.
Surgery	Conventional Surgery	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.
Treatment (UH-1)	Radiation Therapy	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, and carboplatin. 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 clear cell sarcoma of the kidney (CCSK) receive no further study therapy.
Treatment (window/UH-1)	Conventional Surgery	Patients receive vincristine IV on days 1 and 8 and irinotecan hydrochloride IV over 30 minutes on days 1-5 and 8-12 (course 1). 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.
Treatment (UH-2)	Conventional Surgery	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, carboplatin, and irinotecan hydrochloride. 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.
Treatment (UH-2)	Radiation Therapy	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, carboplatin, and irinotecan hydrochloride. 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.
Treatment (regimen I)	Conventional Surgery	Patients receive vincristine, doxorubicin hydrochloride, cyclophosphamide, and etoposide. 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.
Treatment (regimen I)	Laboratory Biomarker Analysis	Patients receive vincristine, doxorubicin hydrochloride, cyclophosphamide, and etoposide. 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.
Treatment (regimen DD-4A)	Vincristine Sulfate	Patients receive dactinomycin, vincristine, and doxorubicin hydrochloride. 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 (window/UH-1)	Laboratory Biomarker Analysis	Patients receive vincristine IV on days 1 and 8 and irinotecan hydrochloride IV over 30 minutes on days 1-5 and 8-12 (course 1). 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.
Treatment (regimen DD-4A)	Laboratory Biomarker Analysis	Patients receive dactinomycin, vincristine, and doxorubicin hydrochloride. 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 (UH-2)	Laboratory Biomarker Analysis	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, carboplatin, and irinotecan hydrochloride. 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.
Treatment (regimen DD-4A)	Radiation Therapy	Patients receive dactinomycin, vincristine, and doxorubicin hydrochloride. 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 (UH-2)	Vincristine Sulfate	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, carboplatin, and irinotecan hydrochloride. 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.
Treatment (regimen DD-4A)	Dactinomycin	Patients receive dactinomycin, vincristine, and doxorubicin hydrochloride. 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 (regimen I)	Vincristine Sulfate	Patients receive vincristine, doxorubicin hydrochloride, cyclophosphamide, and etoposide. 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.
Treatment (regimen I)	Radiation Therapy	Patients receive vincristine, doxorubicin hydrochloride, cyclophosphamide, and etoposide. 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.
Treatment (regimen DD-4A)	Conventional Surgery	Patients receive dactinomycin, vincristine, and doxorubicin hydrochloride. 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 (window/UH-1)	Cyclophosphamide	Patients receive vincristine IV on days 1 and 8 and irinotecan hydrochloride IV over 30 minutes on days 1-5 and 8-12 (course 1). 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.
Treatment (UH-1)	Cyclophosphamide	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, and carboplatin. 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 clear cell sarcoma of the kidney (CCSK) receive no further study therapy.
Treatment (UH-1)	Doxorubicin Hydrochloride	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, and carboplatin. 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 clear cell sarcoma of the kidney (CCSK) receive no further study therapy.
Treatment (UH-1)	Etoposide	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, and carboplatin. 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 clear cell sarcoma of the kidney (CCSK) receive no further study therapy.
Treatment (UH-1)	Carboplatin	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, and carboplatin. 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 clear cell sarcoma of the kidney (CCSK) receive no further study therapy.
Treatment (window/UH-1)	Doxorubicin Hydrochloride	Patients receive vincristine IV on days 1 and 8 and irinotecan hydrochloride IV over 30 minutes on days 1-5 and 8-12 (course 1). 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.
Treatment (window/UH-1)	Irinotecan Hydrochloride	Patients receive vincristine IV on days 1 and 8 and irinotecan hydrochloride IV over 30 minutes on days 1-5 and 8-12 (course 1). 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.
Treatment (window/UH-1)	Carboplatin	Patients receive vincristine IV on days 1 and 8 and irinotecan hydrochloride IV over 30 minutes on days 1-5 and 8-12 (course 1). 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.
Treatment (window/UH-1)	Etoposide	Patients receive vincristine IV on days 1 and 8 and irinotecan hydrochloride IV over 30 minutes on days 1-5 and 8-12 (course 1). 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.
Treatment (UH-2)	Doxorubicin Hydrochloride	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, carboplatin, and irinotecan hydrochloride. 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.
Treatment (UH-2)	Etoposide	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, carboplatin, and irinotecan hydrochloride. 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.
Treatment (UH-2)	Carboplatin	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, carboplatin, and irinotecan hydrochloride. 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.
Treatment (UH-2)	Irinotecan Hydrochloride	Patients receive combination chemotherapy comprising vincristine, doxorubicin hydrochloride, cyclophosphamide, etoposide, carboplatin, and irinotecan hydrochloride. 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.
Treatment (regimen I)	Doxorubicin Hydrochloride	Patients receive vincristine, doxorubicin hydrochloride, cyclophosphamide, and etoposide. 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.
Treatment (regimen I)	Etoposide	Patients receive vincristine, doxorubicin hydrochloride, cyclophosphamide, and etoposide. 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.
Treatment (regimen I)	Cyclophosphamide	Patients receive vincristine, doxorubicin hydrochloride, cyclophosphamide, and etoposide. 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.
Treatment (regimen DD-4A)	Doxorubicin Hydrochloride	Patients receive dactinomycin, vincristine, and doxorubicin hydrochloride. 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.

Primary Outcome Measures

Name	Time	Method
Response Rate	Up to 2 months	Criteria for response assessed by three-dimensional measurement: Complete Response (CR), Disappearance of all index lesions and non-index lesions. No new lesions; Partial Response (PR), At least a 65% decrease in the sum of the volumes of the index lesions. No new lesions; Response rate (RR) = CR+PR of patients who received window therapy.
Event Free Survival Probability	4 years	Event-free survival will be informally compared to that seem for similar patients treated on NWTS-5 (NCT00002610).
Toxicity Rate	Up to 4 years	Percentage of participants with Grade 4 cardiac toxicities, Grade 4 Sinusoidal Obstruction Syndrome (SOS), and treatment-related deaths determined using CTCAE v4.
Long-term Survival of Patients With Stage I-IV Malignant Rhabdoid Tumors	4 years	The outcome of these patients will be compared with a fixed outcome based on that seen for similar patients treated with NWTS-5 regimen (NCT00002610).
Event-Free Survival of Patients With Diffuse Anaplastic Wilms' Tumor (DAWT)	4 years	Compare the outcome of patients treated with alternating CyCE/VDCy chemotherapy (with or without vincristine/irinotecan cycles) to a fixed outcome based on that seen for similar patients treated with NWTS-5 (NCT00002610).

Secondary Outcome Measures

Name	Time	Method
Number of Patients With INI1 Mutations in Renal and Extrarenal Malignant Rhabdoid Tumor by Fluorescent in Situ Hybridization	At baseline
Frequency of TP53 Mutations	At baseline

Trial Locations

Locations (187): Eastern Maine Medical Center
🇺🇸
Bangor, Maine, United States
University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Advocate Children's Hospital-Oak Lawn
🇺🇸
Oak Lawn, Illinois, United States
Maine Children's Cancer Program
🇺🇸
Scarborough, Maine, United States
Advocate Lutheran General Hospital.
🇺🇸
Park Ridge, Illinois, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Royal Brisbane and Women's Hospital
🇦🇺
Herston, Queensland, Australia
Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
Saint Luke's Mountain States Tumor Institute
🇺🇸
Boise, Idaho, United States
The Toledo Hospital/Toledo Children's Hospital
🇺🇸
Toledo, Ohio, United States
Baylor College of Medicine
🇺🇸
Houston, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸
Miami, Florida, United States
Baptist Hospital of Miami
🇺🇸
Miami, Florida, United States
Miami Children's Hospital
🇺🇸
Miami, Florida, United States
Saint Vincent Hospital and Health Services
🇺🇸
Indianapolis, Indiana, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
University of Texas Health Science Center at San Antonio
🇺🇸
San Antonio, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸
San Antonio, Texas, United States
University of California San Francisco Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Vanderbilt-Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Primary Children's Hospital
🇺🇸
Salt Lake City, Utah, United States
University of Hawaii Cancer Center
🇺🇸
Honolulu, Hawaii, United States
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
Princess Margaret Hospital for Children
🇦🇺
Perth, Western Australia, Australia
University of Rochester
🇺🇸
Rochester, New York, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Newark Beth Israel Medical Center
🇺🇸
Newark, New Jersey, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Saint John Hospital and Medical Center
🇺🇸
Detroit, Michigan, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸
Denver, Colorado, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Saint Joseph Children's Hospital of Tampa
🇺🇸
Tampa, Florida, United States
Walter Reed National Military Medical Center
🇺🇸
Bethesda, Maryland, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Children's Hospital and Medical Center of Omaha
🇺🇸
Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
University of New Mexico
🇺🇸
Albuquerque, New Mexico, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Arizona Health Sciences Center
🇺🇸
Tucson, Arizona, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
Southern California Permanente Medical Group
🇺🇸
Downey, California, United States
Childrens Hospital of Orange County
🇺🇸
Orange, California, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Miller Children's Hospital
🇺🇸
Long Beach, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Children's Hospital Central California
🇺🇸
Madera, California, United States
Children's Hospital and Research Center at Oakland
🇺🇸
Oakland, California, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Children's National Medical Center
🇺🇸
Washington, D.C., District of Columbia, United States
Lombardi Comprehensive Cancer Center at Georgetown University
🇺🇸
Washington, D.C., District of Columbia, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸
Fort Myers, Florida, United States
Broward Health Medical Center
🇺🇸
Fort Lauderdale, Florida, United States
Nemours Children's Clinic-Jacksonville South
🇺🇸
Jacksonville, Florida, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
Tripler Army Medical Center
🇺🇸
Honolulu, Hawaii, United States
Saint Jude Midwest Affiliate
🇺🇸
Peoria, Illinois, United States
Southern Illinois University
🇺🇸
Springfield, Illinois, United States
Loyola University Medical Center
🇺🇸
Maywood, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
University of Iowa Hospitals and Clinics
🇺🇸
Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
🇺🇸
Baltimore, Maryland, United States
University of Massachusetts Medical School
🇺🇸
Worcester, Massachusetts, United States
Michigan State University Clinical Center
🇺🇸
East Lansing, Michigan, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸
Grand Rapids, Michigan, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
Hurley Medical Center
🇺🇸
Flint, Michigan, United States
Kalamazoo Center for Medical Studies
🇺🇸
Kalamazoo, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
Saint John's Mercy Medical Center
🇺🇸
Saint Louis, Missouri, United States
Cardinal Glennon Children's Medical Center
🇺🇸
Saint Louis, Missouri, United States
Nevada Cancer Research Foundation CCOP
🇺🇸
Las Vegas, Nevada, United States
Saint Joseph's Regional Medical Center
🇺🇸
Paterson, New Jersey, United States
Morristown Memorial Hospital
🇺🇸
Morristown, New Jersey, United States
University of New Mexico Cancer Center
🇺🇸
Albuquerque, New Mexico, United States
Overlook Hospital
🇺🇸
Summit, New Jersey, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
New York University Langone Medical Center
🇺🇸
New York, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸
New Hyde Park, New York, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Weill Medical College of Cornell University
🇺🇸
New York, New York, United States
Stony Brook University Medical Center
🇺🇸
Stony Brook, New York, United States
Mission Hospital-Memorial Campus
🇺🇸
Asheville, North Carolina, United States
Carolinas Medical Center
🇺🇸
Charlotte, North Carolina, United States
Novant Health Presbyterian Medical Center
🇺🇸
Charlotte, North Carolina, United States
East Carolina University
🇺🇸
Greenville, North Carolina, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
Mercy Children's Hospital
🇺🇸
Toledo, Ohio, United States
Legacy Emanuel Children's Hospital
🇺🇸
Portland, Oregon, United States
Saint Christopher's Hospital for Children
🇺🇸
Philadelphia, Pennsylvania, United States
Lehigh Valley Hospital - Muhlenberg
🇺🇸
Bethlehem, Pennsylvania, United States
Legacy Emanuel Hospital and Health Center
🇺🇸
Portland, Oregon, United States
Geisinger Medical Center
🇺🇸
Danville, Pennsylvania, United States
Palmetto Health Richland
🇺🇸
Columbia, South Carolina, United States
Penn State Hershey Children's Hospital
🇺🇸
Hershey, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Greenville Cancer Treatment Center
🇺🇸
Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
T C Thompson Children's Hospital
🇺🇸
Chattanooga, Tennessee, United States
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
Texas Tech University Health Science Center-Amarillo
🇺🇸
Amarillo, Texas, United States
St. Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Covenant Children's Hospital
🇺🇸
Lubbock, Texas, United States
Scott and White Memorial Hospital
🇺🇸
Temple, Texas, United States
Inova Fairfax Hospital
🇺🇸
Falls Church, Virginia, United States
Childrens Hospital-King's Daughters
🇺🇸
Norfolk, Virginia, United States
Naval Medical Center - Portsmouth
🇺🇸
Portsmouth, Virginia, United States
Carilion Clinic Children's Hospital
🇺🇸
Roanoke, Virginia, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸
Tacoma, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
Marshfield Clinic
🇺🇸
Marshfield, Wisconsin, United States
Midwest Children's Cancer Center
🇺🇸
Milwaukee, Wisconsin, United States
Madigan Army Medical Center
🇺🇸
Tacoma, Washington, United States
John Hunter Children's Hospital
🇦🇺
Hunter Regional Mail Centre, New South Wales, Australia
Sydney Children's Hospital
🇦🇺
Randwick, New South Wales, Australia
The Children's Hospital at Westmead
🇦🇺
Westmead, New South Wales, Australia
Royal Children's Hospital-Brisbane
🇦🇺
Herston, Queensland, Australia
Royal Children's Hospital
🇦🇺
Parkville, Victoria, Australia
Women's and Children's Hospital-Adelaide
🇦🇺
North Adelaide, South Australia, Australia
Alberta Children's Hospital
🇨🇦
Calgary, Alberta, Canada
University of Alberta Hospital
🇨🇦
Edmonton, Alberta, Canada
British Columbia Children's Hospital
🇨🇦
Vancouver, British Columbia, Canada
Janeway Child Health Centre
🇨🇦
Saint John's, Newfoundland and Labrador, Canada
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦
Hamilton, Ontario, Canada
Chedoke-McMaster Hospitals
🇨🇦
Hamilton, Ontario, Canada
Cancer Centre of Southeastern Ontario at Kingston General Hospital
🇨🇦
Kingston, Ontario, Canada
Children's Hospital of Eastern Ontario
🇨🇦
Ottawa, Ontario, Canada
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Children's Hospital
🇨🇦
London, Ontario, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Centre Hospitalier Universitaire de Quebec
🇨🇦
Ste-Foy, Quebec, Canada
Saskatoon Cancer Centre
🇨🇦
Saskatoon, Saskatchewan, Canada
Starship Children's Hospital
🇳🇿
Grafton, Auckland, New Zealand
San Jorge Children's Hospital
🇵🇷
San Juan, Puerto Rico
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
West Virginia University Charleston
🇺🇸
Charleston, West Virginia, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Dartmouth Hitchcock Medical Center
🇺🇸
Lebanon, New Hampshire, United States
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
Memorial Healthcare System - Joe DiMaggio Children's Hospital
🇺🇸
Hollywood, Florida, United States
Saint Mary's Hospital
🇺🇸
West Palm Beach, Florida, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
UMDNJ - Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Natalie Warren Bryant Cancer Center at Saint Francis
🇺🇸
Tulsa, Oklahoma, United States
University of South Alabama
🇺🇸
Mobile, Alabama, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Memorial University Medical Center
🇺🇸
Savannah, Georgia, United States
University of Vermont College of Medicine
🇺🇸
Burlington, Vermont, United States
Florida Hospital Orlando
🇺🇸
Orlando, Florida, United States
UF Cancer Center at Orlando Health
🇺🇸
Orlando, Florida, United States
Kosair Children's Hospital
🇺🇸
Louisville, Kentucky, United States
The Childrens Mercy Hospital
🇺🇸
Kansas City, Missouri, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
Tulane University Health Sciences Center
🇺🇸
New Orleans, Louisiana, United States
Children's Hospital New Orleans
🇺🇸
New Orleans, Louisiana, United States
Dell Children's Medical Center of Central Texas
🇺🇸
Austin, Texas, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
Rhode Island Hospital
🇺🇸
Providence, Rhode Island, United States