A Study Using Risk Factors to Determine Treatment for Children With Favorable Histology Wilms Tumors (FHWT)

PRIMARY OBJECTIVES:

I. To maintain event-free survival (EFS) for Stage I favorable histology Wilms tumor (FHWT) patients without adverse biology who are also (1) 2 to \< 4 years of age, OR (2) age \< 2 years with tumor weight of 550 grams or more, OR (3) age 4+ years with epithelial histology subtype while reducing post-nephrectomy therapy from vincristine, actinomycin (EE-4A) to Nephrectomy Only. (Stage I Nephrectomy Only Stratum 2) II. To improve EFS for Stage I FHWT patients with age \< 2 years AND nephrectomy weight \< 550g AND whose tumors have adverse biology by treating with EE-4A instead of Nephrectomy Only. (Stage I EE-4A Stratum 3) III. To evaluate whether addition of vincristine and irinotecan to standard EE-4A (novel vincristine, actinomycin, irinotecan \[Regimen VIVA\]) is non-inferior to vincristine, actinomycin, doxorubicin (DD-4A) in terms of EFS among Stage II FHWT patients whose tumors demonstrate adverse biology. (Stage II: VIVA versus \[vs\] DD-4A Randomization) IV. To evaluate whether omission of doxorubicin (EE-4A) is non-inferior to historical DD-4A in Stage III FHWT patients without adverse biology or post-therapy blastemal predominance. (Stage III: EE-4A) V. To demonstrate the non-inferiority of vincristine, actinomycin, doxorubicin, cyclophosphamide, etoposide and irinotecan (Regimen MVI) to vincristine, dactinomycin, doxorubicin, cyclophosphamide and etoposide (Regimen M) in the treatment of Stage III FHWT patients whose tumors exhibit adverse biology (post-chemotherapy blastemal predominance excluded). (Stage III: Regimen MVI vs Regimen M Randomization) VI. To demonstrate the non-inferiority of Regimen MVI to Regimen M in the treatment of Stage IV FHWT patients with adverse biology, slow incomplete lung response (SIR), or extrapulmonary metastases (EPM) (post-therapy blastemal predominance excluded). (Stage IV: Regimen MVI vs Regimen M Randomization) VII. To demonstrate the superiority of vincristine, doxorubicin, cyclophosphamide, etoposide, carboplatin and irinotecan (Regimen UH-3) vs historical DD-4A or Regimen M in treatment of Stage III or IV FHWT patients with blastemal predominance at delayed nephrectomy. (Stage III-IV: UH-3 \[Blastemal Predominance\])

SECONDARY OBJECTIVES:

I. To describe outcomes for Stage I FHWT patients without adverse biology who are either less than 4 years of age OR 4+ years of age with epithelial subtype who are treated with Nephrectomy Only and assess consistency with a matched historical control from the prior Children's Oncology Group (COG) therapeutic era. (Stage I: Nephrectomy Only) II. To describe outcomes for Stage I FHWT patients with adverse biology OR age \> 4 and not epithelial subtype who are treated with post-nephrectomy EE-4A and assess consistency with a matched historical control from the prior COG therapeutic era. (Stage I: EE-4A) III. To describe overall survival in the cohort of modified very low risk (mVLR) patients who relapse following treatment with nephrectomy only and are assigned at relapse to DD-4A (if presumed or confirmed favorable histology Wilms tumor at relapse) or UH-3 (if evidence of anaplasia at relapse). (Stage I: Nephrectomy Only Relapse) IV. To describe outcomes for Stage II FHWT patients without adverse biology who are treated with post-nephrectomy EE-4A and assess consistency with a matched historical control from the prior COG therapeutic era. (Stage II: EE-4A) V. To compare outcomes of Stage II FHWT patients whose tumors are negative for combined loss of heterozygosity (LOH) but positive for 1q gain who are randomized to VIVA vs DD-4A on AREN2231 against historically matched patients treated with EE-4A during the prior COG therapeutic era. (Stage II VIVA vs DD-4A Stratum 1) VI. To compare outcomes of Stage II FHWT patients whose tumors are positive for combined LOH 1p AND 16q and who are randomized to VIVA vs DD-4A on AREN2231 against historically matched patients treated with DD-4A during the prior COG therapeutic era. (Stage II VIVA vs DD-4A Stratum 2) VII. To compare outcomes of Stage III FHWT patients whose tumors have adverse biology other than combined LOH and who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with DD-4A during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage III Regimen MVI vs Regimen M Stratum 1) VIII. To compare outcomes of Stage III FHWT patients whose tumors have combined LOH and who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with Regimen M during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage III Regimen MVI vs Regimen M Stratum 2) IX. To describe outcomes for Stage IV FHWT patients with rapid complete response of lung only metastases and no adverse biology who are treated with DD-4A on AREN2231 and assess consistency with a matched historical control from the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage IV: DD-4A) X. To compare outcomes of Stage IV lung only patients with either combined LOH 1p AND 16q or SIR who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with Regimen M during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage IV Regimen MVI vs Regimen M Stratum 1) XI. To compare outcomes of Stage IV lung only rapid complete response (RCR) patients without combined LOH 1p AND 16q who are positive for other adverse biological factors and who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with DD-4A during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage IV Regimen MVI vs Regimen M Stratum 2) XII. To compare outcomes of Stage IV patients with extrapulmonary metastases (EPM) who are randomized to Regimen MVI vs Regimen M on AREN2231 against historically matched patients treated with Regimen M during the prior COG therapeutic era (post-chemotherapy blastemal predominance excluded). (Stage IV Regimen MVI vs Regimen M Stratum 3) XIII. To report a pooled comparison of Regimen MVI vs Regimen M in Stage III or Stage IV randomized patients. (Stage III-IV Regimen MVI vs Regimen M) XIV. To compare outcomes of Stage III or IV FHWT patients with blastemal predominance at delayed nephrectomy who are treated with Regimen UH-3 on AREN2231 vs a historically matched cohort that received DD-4A in the prior COG therapeutic era. (Stage III-IV UH-3 Stratum 1) XV. To compare outcomes of Stage III or IV FHWT patients with blastemal predominance at delayed nephrectomy who are treated with Regimen UH-3 on AREN2231 vs a historically matched cohort that received Regimen M in the prior COG therapeutic era. (Stage III-IV UH-3 Stratum 2) XVI. To describe outcomes of Stage III or IV FHWT patients with delayed nephrectomy occurring after the start of Cycles 3 or 4 (super delayed) who are assigned to Regimen M or continued DD4A. (Stage III-IV Super Delayed Nephrectomy)

EXPLORATORY OBJECTIVES:

I. To determine the impact of imaging schedule and modality (chest x-ray \[CXR\], ultrasound \[US\], versus computed tomography/magnetic resonance imaging \[CT/MRI\], versus clinical symptoms) on relapse, timing of detection of relapse, burden of disease at relapse (as assessed by retrospective central imaging review), as well as impact on survival.

II. To analyze the impact of radiologically determined pulmonary tumor burden on outcomes.

III. To assess whether imaging modality (ultrasound, CT, MRI with or without hepatocyte specific contrast agent) at diagnosis is associated with detection of increased number of liver metastases, and whether modality choice impacts surgery and/or radiation planning for liver metastases.

IV. To accurately describe the responses of extrapulmonary metastases to the various therapeutic modalities (chemotherapy, radiation therapy, and surgery) through central review of institutional imaging at various stages of treatment, and to correlate institutionally interpreted radiologic response interpretations with central review.

V. To describe the association of the number of anatomically relevant and pathologically confirmed lymph nodes sampled and percent of positive lymph nodes (LNs) on EFS and overall survival (OS).

VI. To document the surgical and/or medical rationale and approach for biopsy (including type of biopsy, number of biopsies, and site of biopsy) for all patients who are treated with the approach of initial biopsy and delayed nephrectomy.

VII. To describe sites of recurrence for patients with liver metastases according to the surgery and/or radiation therapy administered for residual liver lesions at Week 6 and 12.

VIII. To increase the number of patients eligible to avoid lung radiation therapy (RT) by encouraging resection of residual pulmonary nodules for patients defined as Stage IV FHWT with standard biology and who have 1-3 residual pulmonary nodules on imaging after Cycle 2, by omitting lung RT for those who are found to have no viable tumor in resected nodules.

IX. To describe whether residual lung lesions at end of therapy are associated with relapse.

X. To improve the reliability of data derived from central surgical review through the implementation of a standardized operative note.

XI. To describe the treatment, perioperative morbidity and outcome of patients noted to have inferior vena cava (IVC) tumor thrombus at time of diagnosis, including surgical approach, pathology findings and specific radiation therapy received.

XII. To determine the feasibility of employing intensity modulated radiation therapy (IMRT) and proton therapy with central quality assurance (QA) monitoring within the prescribed time frame.

XIII. To determine the lung tumor and liver tumor control rate using IMRT and/or proton therapy and compare it to standard 3-dimensional radiotherapy in the current study and the AREN0533 study.

XIV. To determine the flank and abdominal tumor control rates in children with Stage IV FHWT who received abdominal radiotherapy after 2 cycles of chemotherapy in this study (delayed abdominal radiation) and compare it to AREN0533 study where abdominal radiotherapy was performed within 2 weeks of nephrectomy (upfront abdominal radiation).

XV. To compare abdominal relapse according to protocol-recommended radiotherapy fields (flank vs. whole abdominal) in the current study and compare it to the abdominal relapse according to radiotherapy fields (flank vs. whole abdominal) in the AREN0532 and AREN0533 studies.

XVI. To determine the impact of radiotherapy on local and distant control rates for EPM sites and compare them to EPM sites not receiving radiation.

XVII. To describe the rate and severity of recurrent hepatotoxicity in patients who undergo re-introduction of chemotherapy after experiencing hepatopathy.

XVIII. To collect serial blood and urine samples to bank for future research studies.

OUTLINE:

STAGE I FHWT: Patients will have already undergone nephrectomy and lymph node sampling prior to trial enrollment. Patients \< 4 years old at diagnosis or with epithelial subtype FHWT of any age, undergo observation until tumor biomarker testing returns. Patients with adverse biology are assigned to Arm I. Patients with standard biology are assigned to Arm II and undergo observation post-nephrectomy until disease relapse. At the time of disease relapse, patients with favorable histology are assigned to Arm III, and patients with unfavorable (anaplastic) histology are assigned to Arm IV. Patients ≥ 4 years of age at diagnosis without epithelial FHWT are assigned to Arm I regardless of biology results.

* ARM I: Patients receive regimen EE-4A: Dactinomycin intravenously (IV) over 1-5 or 10-15 minutes on day 1 of cycles 1-7 and vincristine IV on days 1, 8, \& 15 of cycles 1-3 and day 1 of cycles 4-7. Trea

• Overall survival (OS) [Срок оценки: Up to 4 years from study entry]