A Study of Combination Chemotherapy for Patients With Newly Diagnosed DAWT and Relapsed FHWT

Inclusion Criteria:

• Patients with newly diagnosed stages 2 - 4 diffuse anaplastic Wilms tumor must beenrolled on AREN03B2 and have received an initial risk assignment showing DAWT (ifanaplasia first identified at diagnostic, pre-treatment nephrectomy or biopsy) or adelayed nephrectomy classification showing DAWT (if anaplasia first noted at delayednephrectomy) prior to enrollment on AREN1921. Prior enrollment on AREN03B2 is not aneligibility requirement for patients with relapsed favorable histology Wilms tumor.

• Patients must be =< 30 years old at study enrollment

• Patients with the following diagnoses are eligible for this study:

• Newly diagnosed stages 2 - 4 diffuse anaplastic Wilms tumor as confirmed bycentral review

• Favorable histology Wilms tumor at first relapse. Relapsed FHWT patients musthave previously achieved remission for their initial FHWT diagnosis to beeligible for this study. The relapse risk groups are defined as follows,regardless of radiation therapy:

• Standard-Risk relapse: Patients who received two chemotherapy agents forfrontline therapy; primarily actinomycin D and vincristine

• High-Risk relapse: Patients who received three chemotherapy agents forfrontline therapy; primarily vincristine, actinomycin D and doxorubicin orvincristine, actinomycin D and irinotecan

• Very High-Risk relapse: Patients who received four or more chemotherapyagents as part of initial therapy; primarily regimen M or its variations

• Patients with newly diagnosed DAWT must have had histologic verification of themalignancy. For relapsed FHWT patients, biopsy to prove recurrence is encouraged,but not required

• Note: For relapsed FHWT patients, an institutional pathology report confirmingfavorable histology Wilms tumor (from relapse, if available, or from originaldiagnosis) must be available for upload prior to initiation of protocol therapy

• Patients with newly diagnosed Stages 2 - 4 diffuse anaplastic Wilms tumor must beenrolled on AREN1921 within 2 weeks of the tumor-directed surgery or biopsyprocedure that first confirms a diagnosis of DAWT, whether at initial diagnosticprocedure or delayed nephrectomy (such surgery/biopsy is day 0). For patients whoreceived prior therapy for presumed favorable histology Wilms tumor, later confirmedto have diffuse anaplastic Wilms tumor at subsequent review of the initial biopsy

• Patients with newly diagnosed DAWT who undergo upfront nephrectomy must have atleast 1 lymph node sampled prior to study enrollment

• Patients must have a performance status corresponding to Eastern CooperativeOncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years ofage and Lansky for patients =< 16 years of age

• Patients must have a life expectancy of >= 8 weeks

• Diffuse Anaplastic Wilms Tumor: Patients with diffuse anaplastic histology must havehad no prior systemic therapy, except in the following situations:

• Patients with diffuse anaplastic Wilms tumor who received no more than 12 weeksof pre nephrectomy chemotherapy for what was originally presumed to befavorable histology Wilms tumor, subsequently confirmed to be diffuseanaplastic Wilms tumor at delayed nephrectomy

• Patients with diffuse anaplastic Wilms tumor who received no more than 6 weeksof chemotherapy following upfront biopsy, initiated within 14 days of biopsy,for presumed favorable histology Wilms tumor based on institutional review, butsubsequently corrected to diffuse anaplastic Wilms tumor based on the AREN03B2initial risk assignment results (if available per current version of AREN03B2)

• Treatment consisting of vincristine/doxorubicin/cyclophosphamide initiated onan emergent basis and within allowed timing as described

• Note: Patients who received prior therapy for presumed favorable histologyWilms tumor, later identified to have diffuse anaplastic Wilms tumor as perabove, must begin study treatment starting at cycle 3 (week 7) of regimen UH 3.Patients who received emergency radiation to preserve organ function areeligible as noted. Patients who received radiation as part of standard of carefor presumed newly diagnosed favorable histology Wilms tumor, along withchemotherapy as noted above, prior to identification of diffuse anaplasia, arealso eligible

• Relapsed Favorable Histology Wilms Tumor: Patients must not have received priorchemotherapy for their relapsed favorable histology Wilms tumor diagnosis. Inaddition, patients must have fully recovered from the acute toxic effects of allprior chemotherapy, immunotherapy, or radiotherapy prior to entering this study

• Myelosuppressive chemotherapy: Must not have received within 2 weeks of entryonto this study

• Radiation therapy (RT): >= 2 weeks (wks) must have elapsed for local palliativeRT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 wks must have elapsed if other substantialbone marrow (BM) radiation. Patients with relapsed favorable histology Wilmstumor who received emergency radiation to preserve organ function are eligibleand do not need to washout with the above criteria

• Patients may not be receiving any other investigational agents (within 4 weeks priorto study enrollment)

• Peripheral absolute neutrophil count (ANC) >= 750/uL (performed within 7 days priorto enrollment)

• Platelet count >= 75,000/uL (transfusion independent) (performed within 7 days priorto enrollment)

• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (performedwithin 7 days prior to enrollment)

• Patients with high-risk or very high-risk relapsed FHWT who will be treated withregimen ICE/Cyclo/Topo, must have renal function assessed by creatinine clearance orradioisotope glomerular filtration rate (GFR) and meet the following requirement:

• Creatinine clearance or radioisotope GFR >= 60 mL/min/1.73 m^2 (performedwithin 7 days prior to enrollment)

• Patients diagnosed with stage 2-4 DAWT or standard risk relapsed FHWT, who will betreated with regimen UH 3, may either obtain a creatinine clearance, radioisotopeGFR (meeting the above criteria of GFR >= 60 mL/min/1.73 m^2), or an adequate serumcreatinine as per the following table:

• Age: Maximum Serum Creatinine (mg/dL)

• 1 month to < 6 months: 0.4 (male and female)

• 6 months to < 1 year: 0.5 (male and female)

• 1 to < 2 years: 0.6 (male and female)

• 2 to < 6 years: 0.8 (male and female)

• 6 to < 10 years: 1 (male and female)

• 10 to < 13 years: 1.2 (male and female)

• 13 to < 16 years: 1.5 (male), 1.4 (female)

• >= 16 years: 1.7 (male), 1.4 (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age or direct bilirubin =<ULN for patients whose total bilirubin > 1.5 x ULN (performed within 7 days prior toenrollment)

• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) orserum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5x upper limit of normal (ULN) for age or =< 5 x ULN for patients with livermetastases (performed within 7 days prior to enrollment)

• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% byradionuclide angiogram (obtained within 21 days prior to enrollment and start ofprotocol therapy)

Exclusion Criteria:

• Patients with a history of bilateral Wilms tumor (synchronous or metachronous)

• Patients with any uncontrolled, intercurrent illness including, but not limited to,ongoing or active infection, or symptomatic congestive heart failure (defined asgrade 2 or higher heart failure per Common Terminology Criteria for Adverse Events [CTCAE] version 5.0)

• Relapsed FHWT patients who did not receive frontline chemotherapy (e.g., very lowrisk FHWT initially observed without chemotherapy) or received only one chemotherapyagent for frontline therapy

• For patients with high-risk or very high-risk relapsed FHWT:

• Patients with renal tubular acidosis (RTA) as evidenced by serum bicarbonate < 16 mmol/L and serum phosphate =< 2 mg/dL (or < 0.8 mmol/L) withoutsupplementation

• For stages 2-4 DAWT and standard-risk relapsed FHWT patients:

• Chronic inflammatory bowel disease and/or bowel obstruction

• Concomitant use of St. John's wort, which cannot be stopped prior to the startof trial treatment

• Female patients who are pregnant since fetal toxicities and teratogenic effects havebeen noted for several of the study drugs. A pregnancy test is required for femalepatients of childbearing potential

• Lactating females who plan to breastfeed their infants

• Sexually active patients of reproductive potential who have not agreed to use aneffective contraceptive method for the duration of their study participation