Combination Chemotherapy With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed Stage III or Stage IV Wilms' Tumor

Study Overview
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Brief Summary
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This phase III trial is studying how well combination chemotherapy with or without radiation therapy works in treating young patients with newly diagnosed stage III or stage IV Wilms' tumor. 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving more than one drug (combination chemotherapy) with or without radiation therapy may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the 4-year event-free survival (EFS) of patients with stage IV favorable histology (FH) Wilms' tumor with pulmonary metastases only who have complete resolution of pulmonary lesions without whole lung irradiation treated with DD4A chemotherapy comprising vincristine, dactinomycin, and doxorubicin hydrochloride. II. Determine the 4-year EFS of these patients who do not have resolution of pulmonary metastases by week 6 treated with the addition of cyclophosphamide and etoposide to a modified-regimen DD4A (regimen M). III. Determine the 4-year EFS of patients with stage III or IV FH Wilms' tumor with loss of heterozygosity for chromosomes 1p and 16q treated with regimen M. SECONDARY OBJECTIVES: I. Correlate the burden of pulmonary metastatic disease with outcome in patients with stage IV FH Wilms' tumor. OUTLINE: This is a multicenter study. REGIMEN DD4A (weeks 1-6): Patients receive dactinomycin IV over 1-5 minutes once in week 1; vincristine IV once in weeks 1-6; and doxorubicin hydrochloride IV over 15 minutes once in week 4 in the absence of disease progression or unacceptable toxicity. Patients with pulmonary and extra-pulmonary metastases at diagnosis undergo radiotherapy once daily beginning in week 1 and continuing for 5-14 days. After completion of DD4A chemotherapy (week 6), patients undergo evaluation. Patients with stage IV disease and pulmonary metastases only with no loss of heterozygosity (LOH) who are rapid complete responders (RCR) (i.e., pulmonary metastases disappear) proceed to regimen DD4A (weeks 7-25). All other patients (i.e., patients with stage III or IV disease and LOH of both 1p and 16q; stage IV disease with pulmonary metastases only who are slow incomplete responders [SIR] [i.e., pulmonary metastases do not disappear]; or stage IV disease with nonpulmonary metastases or with nonpulmonary metastases in combination with pulmonary metastases) proceed to regimen M (weeks 7-31). Patients with initially unresectable or incompletely resected tumors are reevaluated at week 6, and if resectable, undergo surgery and then proceed to either regimen DD4A or regimen M as described above. REGIMEN DD4A (weeks 7-25): Patients receive dactinomycin IV over 1-5 minutes once in weeks 7, 13, 19, and 25; vincristine IV once in weeks 7-10, 13, 16, 19, 22, and 25; and doxorubicin hydrochloride IV over 15 minutes once in weeks 10, 16, and 22 in the absence of disease progression or unacceptable toxicity. REGIMEN M (weeks 7-31): Patients receive cyclophosphamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 in weeks 7, 10, 19, and 25; vincristine IV once in weeks 8, 9, 11, 12, 13, 16, 22, 28, and 31; and dactinomycin IV and doxorubicin hydrochloride IV over 15 minutes once in weeks 13, 16, 22, 28, and 31 in the absence of disease progression or unacceptable toxicity. Patients with pulmonary metastases only who are SIR also undergo whole lung radiotherapy once daily beginning in week 7 and continuing for 5-14 days. NOTE: Patients who begin study treatment after undergoing resection of pulmonary metastases are treated according to regimen DD4A (weeks 1-25) and undergo whole lung radiotherapy for 5-14 days beginning in week 1. After completion of study treatment, patients are followed periodically for 10 years.

Official Title
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Treatment of Newly Diagnosed Higher Risk Favorable Histology Wilms Tumors

Conditions
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Stage III Kidney Wilms Tumor, Stage IV Kidney Wilms Tumor

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy
* Procedure: Conventional Surgery
* Drug: Cyclophosphamide
* Biological: Dactinomycin
* Drug: Doxorubicin Hydrochloride
* Drug: Etoposide
* Drug: Vincristine Sulfate Liposome


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed Wilms' tumor meeting 1 of the following criteria: Stage IV disease with favorable histology with or without loss of heterozygosity (LOH) for 1p and 16q Stage III disease with favorable histology with LOH for 1p and 16q transferring from clinical trial COG-AREN0532 Patients must begin therapy within 14 days after surgery or biopsy, unless medically contraindicated No bilateral Wilms' tumors (stage IV) Patients should be referred to COG-AREN0534 Previously enrolled in clinical trial COG-AREN03B2 Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) OR Lansky PS 50-100% (for patients ≤ 16 years of age) Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST or ALT < 2.5 times ULN Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior tumor-directed chemotherapy or radiotherapy unless transferring from clinical trial COG-AREN0532 OR treatment for emergent issues, as medically indicated No concurrent aprepitant

Ages Eligible for Study
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Maximum Age: 29 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, surgery, radiotherapy)<br>REGIMEN DD4A (weeks 1-6): Patients receive dactinomycin IV; vincristine IV; and doxorubicin hydrochloride IV. Patients with pulmonary and extra-pulmonary metastases at diagnosis undergo radiotherapy. Patients with initially unresectable or incompletely resected tumors are reevaluated at week 6, and if resectable, undergo surgery and then proceed to either regimen DD4A or regimen M. REGIMEN DD4A (weeks 7-25): Patients receive dactinomycin IV; vincristine IV; and doxorubicin hydrochloride IV. REGIMEN M (weeks 7-31): Patients receive cyclophosphamide IV; vincristine IV; and dactinomycin IV and doxorubicin hydrochloride IV. Patients with pulmonary metastases only who are SIR also undergo whole lung radiotherapy. | Radiation: 3-Dimensional Conformal Radiation Therapy<br> <br> * Other names: Radiation, 3D Conformal;Procedure: Conventional Surgery<br> <br> Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Dactinomycin<br>* Given IV<br>* Other names: Meractinomycin;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Drug: Vincristine Sulfate Liposome<br>* Given IV<br>* Other names: Marqibo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival Probability | Probability of no relapse, secondary malignancy, or death after 4 year in the study. | 4 years | 
| Event Free Survival (EFS) Probability | Probability of no relapse, secondary malignancy, or death after 4 year in the study. | At 4 years | 
| Event Free Survival Probability | Probability of no relapse, secondary malignancy, or death after 4 year in the study | At 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival Associated With the Burden of Pulmonary Metastatic Disease | Probability of no relapse, secondary malignancy, or death after 4 year in the study. | At 4 years |