Risk Adapted Treatment of Unilateral Favorable Histology Wilms Tumors (FHWT)

Investigating Treatment for Children with Favorable Histology Wilms Tumors

M
Marissa Just

Primary Investigator

Enrolling By Invitation
30 years or below
All
Phase 3
1 participants needed
1 Location

Brief description of study

This phase III trial studies using risk factors in determining treatment for children with favorable tissue (histology) Wilms tumors (FHWT). Wilms Tumor is the most common type of kidney cancer in children, and FHWT is the most common subtype. Previous large clinical trials have established treatment plans that are likely to cure most children with FHWT, however some children still have their cancer come back (called relapse) and not all survive. Previous research has identified features of FHWT that are associated with higher or lower risks of relapse. The term "risk" refers to the chance of the cancer coming back after treatment. Using results of tumor histology tests, biology tests, and response to therapy may be able to improve treatment for children with FHWT.

THIS STUDY IS ENROLLING BY INVITATION ONLY - Consistent with most oncology trials, patients are not actively “recruited,” but are screened by their physician for appropriate clinical trial(s) at the time of their routine clinic visit. Occasionally, a patient may be a self-referral or physician referral, but are still screened for appropriate clinical trials at the time of their routine clinic visit. PI and staff may send copies of relevant consent forms to these patients to look over prior to actually consenting or enrolling them. This may take place at the patient's visit at which the consent is presented or the patient's next visit to the outpatient hematology/oncology clinic. 
 
Interested in participating? For more information about this research study or other cancer-related clinical trials at IU Simon Comprehensive Cancer Center, please contact:
IU Clinical Trials Office 
Phone: (317) 278-5632

Detailed description of study

STAGE I FHWT: Patients < 4 years old at diagnosis or with epithelial FHWT, regardless of age, undergo observation until disease relapse. At the time of disease relapse, patients with adverse biology are assigned to Arm I, and patients with standard biology are assigned to Arm II. Patients ≥ 4 years of age at diagnosis without epithelial FHWT are assigned to Arm I without

  • ARM I: Patients receive the EE-4A regimen: Dactinomycin intravenously (IV) over 1-5 or 10-15 minutes on day 1 and vincristine IV on days 1, 8, & 15 of each cycle. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive dactinomycin IV over 1-5 or 10-15 minutes on day 1 and vincristine IV on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
  • ARM II: Patients undergo nephrectomy on study.

STAGE II FHWT: Patients receive one cycle of the EE-4A regimen as in STAGE I FHWT Arm I. Patients with standard biology are assigned to Arm I below. Patients with adverse biology are randomized to Arm II or Arm III below.

  • ARM I: Patients receive six cycles of the EE-4A regimen as in STAGE I FHWT Arm I.
  • ARM II: Patients receive cycles 2-9 of the DD-4A regimen: Dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycles 3, 5, 7, & 9, vincristine IV on days 1, 8, & 15 of cycles 2-3 and day 1 of cycles 4-8, irinotecan IV over 90 minutes daily on days 1-5 of cycles 2, 4, 6, & 8. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity.
  • ARM III: Patients receive cycles 2-9 of the VIVA regimen: Dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycles 3, 5, 7, and 9, vincristine IV on days 1, 8, and 15 of cycles 2-3 and day 1 of cycles 4-8, and doxorubicin IV over 3-15 minutes on day 1 of cycles 2, 4, 6, & 8. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

STAGE III FHWT: Patients able to undergo an upfront nephrectomy receive cycle 1 treatment of the DD-4A regimen: Dactinomycin IV over 1-5 or 10-15 minutes on day 1 and vincristine IV on days 1, 8, and 15. Patients with standard biology are assigned to Arm I below. Patients with adverse biology are assigned to Arm II below.

  • ARM I: Patients receive cycles 2-7 of the EE-4A regimen as in STAGE I FHWT Arm I.
  • ARM II: Patients receive cycle 2 treatment of the DD-4A regimen as in STAGE II FHWT Arm II above.
    • ARM IIA: Patients receive the MVI regimen: Vincristine IV on days 1, 8, & 15 of cycle 3, days 8 & 15 of cycle 4, and day 1 of cycles 5 & 7-13, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycles 3, 7, 9, 11, & 13, doxorubicin IV over 3-15 minutes on day 1 of cycles 3, 7, 9, 11, & 13, cyclophosphamide IV over 15-30 minutes daily on days 1-5 of cycles 4 and 6, irinotecan IV over 90 minutes daily on days 1-5 of cycles 5, 8, 10 & 12, and etoposide IV over 60-120 minutes daily on days 1-5 of cycle 6. Treatment repeats every 21 days for 11 cycles in the absence of disease progression or unacceptable toxicity.
    • ARM IIB: Patients receive the M regimen: Cyclophosphamide IV over 15-30 minutes daily on days 1-5 of cycles 3, 4, 7, & 9, etoposide IV over 60-120 minutes daily on days 1-5 of cycles 3, 4, 7, & 9, vincristine IV on days 8 & 15 of cycles 3 & 4 and day 1 of cycles 5, 6, 8, 10, & 11, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of cycles 5, 6, 8, 10, & 11, and doxorubicin IV over 3-15 minutes of cycles 5, 6, 8, 10, & 11. Treatment repeats every 21 days for 9 cycles in the absence of disease progression or unacceptable toxicity.

STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY): Patients receive cycles 1-2 of the DD-4A regimen as in STAGE II FHWT and STAGE III FHWT Arm II above.

  • PATIENTS ABLE TO UNDERGO A DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with standard biology and low or intermediate risk histology are assigned to Arm I below. Patients with high risk histology are assigned to Arm II below. Patients with adverse biology are randomized to Arm III or Arm IV below.
  • PATIENTS UNABLE TO UNDERGO A DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with standard biology are assigned to Arm V below. Patients with adverse biology are randomized to Arm VI or Arm VII below.
  • ARM I: Patients receive cycles 3-7 of the EE-4A regimen as in STAGE I FHWT Arm I above.
  • ARM II: Patients receive the UH-3 regimen: Vincristine IV on days 1, 8, & 15 of cycles 1, 5, 7, 10, & 13, and days 1 & 8 of cycles 3, 4, 8, & 11, doxorubicin IV 3-15 minutes on day 1 of cycles 1, 5, 7, 10, & 13, cyclophosphamide IV over 30-60 minutes on day 1 of cycles 1, 5, 7, 10, & 13, and days 1-4 of cycles 2, 6, 9, 12, & 14, carboplatin IV over 15-60 minutes on day 1 of cycles 2, 6, 9, 12, and 14, etoposide IV over 60-120 minutes on days 1-4 of cycles 2, 6, 9, 12, & 14, and irinotecan IV over 90 minutes on days 1-5 of cycles 3, 4, 8, & 11. Treatment repeats every 21 days for 14 cycles in the absence of disease progression or unacceptable toxicity.
  • ARM III: Patients receive the MVI regimen as in STAGE III FHWT Arm IIA above.
  • ARM IV: Patients receive the M regimen as in STAGE III FHWT Arm IIB above.
  • ARM V: Patients receive cycles 3-4 of the DD-4A regimen as in STAGE II FHWT Arm II above. Patients with low or intermediate risk histology without LOH 1p or 16q genetic results are then assigned to Arm VA. Patients with low or intermediate risk histology, positive lymph nodes, and 1p or 16q genetic results are then assigned to Arm VB. Patients with high risk histology are assigned to Arm VIII below.
    • ARM VA: Patients receive cycles 5-9 of the DD-4A regimen as in STAGE II FHWT Arm II above.
    • ARM VB: Patients receive the M regimen as in STAGE III FHWT Arm IIB above.
  • ARM VI: Patients receive cycles 3-4 of the MVI regimen as in STAGE III FHWT Arm IIA above. Patients with high risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm VIII. Patients with low or intermediate risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm IX.
  • ARM VII: Patients receive cycles 3-4 of the M regimen as in STAGE III FHWT Arm IIB above. Patients with high risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm VIII. Patients with low or intermediate risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm X.
  • ARM VIII: Patients receive the UH-3 regimen as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) Arm II above.
  • ARM IX: Patients receive cycles 5-13 of the MVI regimen as in STAGE III FHWT Arm IIA above.
  • ARM X: Patients receive cycles 5-11 of the M regimen as in STAGE III FHWT Arm IIB above.

STAGE IV FHWT LUNG METASTASES (UPFRONT NEPHRECTOMY): Patients receive cycles 1-2 of the DD-4A regimen as in STAGE II FHWT and STAGE III FHWT Arm II above. Patients with standard biology and rapid complete lung response (RCR) are assigned to Arm I below. Patients with standard biology and slow incomplete lung response (SIR), or adverse biology are randomized to Arm II or Arm III below.

  • ARM I: Patients receive cycles 3-9 of the DD-4A regimen as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) Arms V and VA above.
  • ARM II: Patients receive the M regimen as in STAGE III FHWT Arm IIB above.
  • ARM III: Patients receive the MVI regimen as in STAGE III FHWT Arm IIA above.

STAGE IV FHWT LUNG METASTASES (UPFRONT BIOPSY/DELAYED NEPHRECTOMY): Patients receive cycles 1-2 of the DD-4A regimen as in STAGE II FHWT and STAGE III FHWT Arm II above.

  • PATIENTS ABLE TO UNDERGO A DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with standard biology, low or intermediate risk histology, and RCR are assigned to Arm I below. Patients with high risk histology are assigned to Arm II below. Patients with adverse biology and low or intermediate risk histology are randomized to Arm III or Arm IV below.
  • PATIENTS UNABLE TO UNDERGO A DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with standard biology and RCR are assigned to Arm V below. Patients with standard biology and SIR OR adverse biology and either SIR or RCR are randomized to Arm VI or Arm VI below.
  • ARM I: Patients receive cycles 3-7 of the EE-4A regimen as in STAGE I FHWT Arm I above.
  • ARM II: Patients receive the UH-3 regimen as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) Arm II.
  • ARM III: Patients receive the MVI regimen as in STAGE III FHWT Arm IIA above.
  • ARM IV: Patients receive the M regimen as in STAGE III FHWT Arm IIB above.
  • ARM V: Patients receive cycles 3-4 of the DD-4A regimen as in STAGE II FHWT Arm II above. Patients with low or intermediate risk histology without LOH 1p or 16q genetic results are then assigned to Arm VA. Patients with low or intermediate risk histology, positive lymph nodes, and 1p or 16q genetic results are then assigned to Arm VB. Patients with high risk histology are assigned to Arm VIII below.
    • ARM VA: Patients receive cycles 5-9 of the DD-4A regimen as in STAGE II FHWT Arm II above.
    • ARM VB: Patients receive the M regimen as in STAGE III FHWT Arm IIB above.
  • ARM VI: Patients receive cycles 3-4 of the MVI regimen as in STAGE III FHWT Arm IIA above. Patients with high risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm VIII. Patients with low or intermediate risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm IX.
  • ARM VII: Patients receive cycles 3-4 of the M regimen as in STAGE III FHWT Arm IIB above. Patients with high risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm VIII. Patients with low or intermediate risk histology after delayed nephrectomy in cycle 3 or 4 are assigned to Arm X.
  • ARM VIII: Patients receive the UH-3 regimen as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) Arm II above.
  • ARM IX: Patients receive cycles 5-13 of the MVI regimen as in STAGE III FHWT Arm IIA above.
  • ARM X: Patients receive cycles 5-11 of the M regimen as in STAGE III FHWT Arm IIB above.

STAGE IV FHWT EXTRAPULMONARY METASTASES: Patients receive cycles 1-2 of the DD-4A regimen as in STAGE II FHWT and STAGE III FHWT Arm II above.

PATIENTS ABLE TO UNDERGO UPFRONT NEPHRECTOMY: Patients are randomized to Arm I or II below.

PATIENTS ABLE TO UNDERGO DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with low or intermediate risk histology are randomized to Arm III or IV.

PATIENTS ABLE TO UNDERGO DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients with high risk histology are assigned to Arm V.

PATIENTS UNABLE TO UNDERGO DELAYED NEPHRECTOMY AFTER CYCLE 2: Patients are randomized to Arm VI or VII.

  • ARM I: Patients receive the MVI regimen as in STAGE III FHWT Arm IIA above.
  • ARM II: Patients receive the M regimen as in STAGE III FHWT Arm IIB above.
  • ARM III: Patients receive the MVI regimen as in STAGE III FHWT Arm IIA above.
  • ARM IV: Patients receive the M regimen as in STAGE III FHWT Arm IIB above.
  • ARM V: Patients receive the UH-3 regimen as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) Arm II above.
  • ARM VI: Patients receive cycles 3-4 of the MVI regimen as in STAGE III FHWT Arm IIA above. Patients undergoing nephrectomy after cycles 3 or 4 and with low or intermediate risk histology are assigned to Arm IX below. Patients undergoing nephrectomy after cycles 3 or 4 and with high risk histology are assigned to Arm VIII below
  • ARM VII: Patients receive cycles 3-4 of the M regimen as in STAGE III FHWT Arm IIB above. Patients undergoing nephrectomy after cycles 3 or 4 and with low or intermediate risk histology are assigned to Arm X below. Patients undergoing nephrectomy after cycles 3 or 4 and with high risk histology are assigned to Arm VIII below.
  • ARM VIII: Patients receive the UH-3 regimen as in STAGE III FHWT (UPFRONT BIOPSY/DELAYED NEPHRECTOMY) Arm II above.
  • ARM IX: Patients receive cycles 5-13 of the MVI regimen as in STAGE III FHWT Arm IIA above.
  • ARM X: Patients receive cycles 5-11 of the M regimen as in STAGE III FHWT Arm IIB above.
    • NOTE: Patients receiving EE-4A, DD-4A & VIVA regimens also undergo CT, CT/MRI, ultrasound, and X-ray imaging throughout the trial. Patients receiving M, MVI & UH3 regimens also undergo CT, CT/MRI, ultrasound, X-ray, and bone scan/positron emission tomography (PET) scans throughout the trial.

After completion of study treatment, patients are followed for 10 years.

Eligibility of study

You may be eligible for this study if you meet the following criteria:

  • Conditions: Favorable Tissue Histology Kidney Wilms Tumor, Cancer, FHWT, Riley
  • Age: 30 years or below
  • Gender: All

Inclusion Criteria:

  • Patients must be enrolled on APEC14B1 and consent to Part A - Eligibility Screening prior to enrollment on AREN2231.
  • Patients must be < 30 years old at enrollment.
  • Patients with newly diagnosed Stage I-IV Favorable Histology Wilms Tumor confirmed by central review and with a qualifying Initial Stratum Assignment on APEC14B1.
  • Patients must receive a qualifying Initial Stratum Assignment on APEC14B1 by Day 14 post-diagnostic procedure (nephrectomy or biopsy), where that procedure is Day 0.
    • Patients must enroll on AREN2231 by Day 14.
    • Exceptions: If patient reaches Day 14 (post initial diagnostic nephrectomy or biopsy) without receiving an Initial Stratum Assignment on APEC14B1, patient will not be eligible for enrollment on AREN2231 unless all required materials (reports and Case Report Forms and specimens) for an Initial Stratum Assignment arrived by Day 7, but an Initial Stratum Assignment was not completed by Day 14. In these circumstances, after obtaining appropriate protocol consent, the patient may proceed with treatment according to local institutional staging and enroll within 5 calendar days of notification of the central Initial Stratum Assignment being issued, only if the AREN2231 Initial Stratum Assignment is in agreement with any treatment already initiated. If the Initial Stratum Assignment is not in agreement with the local institution's assessment then the patient will be ineligible for AREN2231.
  • All sites must have sent or plan to send diagnostic tumor sample for molecular testing through a Clinical Laboratory Improvement Act (CLIA)-certified (or equivalent if outside of the United States [US]) laboratory that can detect Loss of Heterozygosity (LOH) of chromosome 1p AND 16q, and gain of chromosome 1q. Patients potentially eligible for mVLR must also have LOH of chromosome 11p15 included.
    • Note: Patients are eligible for enrollment before these results are available; however, molecular results must be returned and uploaded to APEC14B1 for integration into risk stratification by the required timepoints (specific timelines vary by treatment arm). Patients who do not have molecular results available by the arm-specific timepoints may be taken off protocol therapy.
  • Patients who have an upfront nephrectomy must have at least one lymph node sampled and confirmed as a lymph node by central pathology review to be eligible.
    • Note: Lymph node sampling will also be required at delayed nephrectomy. Patients who do not have a lymph node sampled and confirmed as a lymph node by central pathology review at delayed nephrectomy will be taken off protocol therapy.
  • Karnofsky performance status must be 50 for patients > 16 years of age and the Lansky performance status must be 50 for patients ≤ 16 years of age.
  • Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) OR direct bilirubin ≤ 3X ULN for subjects with total bilirubin levels > 1.5 ULN (within 7 days prior to enrollment).
  • Aspartate aminotransferase (AST/serum glutamate oxaloacetic transaminase [SGOT]) OR alanine transaminase (ALT/serum glutamic pyruvate transaminase [SGPT]) ≤ 3X ULN OR ≤ 5 X ULN for patients with liver metastases (within 7 days prior to enrollment).
  • Shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% (within 7 days prior to enrollment)
    • Note: This criteria only applies to patients centrally classified as Stage IV. Stage II and III patients subsequently assigned to a doxorubicin arm will be off protocol therapy if they do not meet this criteria at time of cardiac function assessment.
  • Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
  • 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:

  • Patient with a diagnosis of Stage V Bilateral Wilms Tumor.
  • Patients who in the opinion of the investigator are not able to comply with the study procedures are not eligible.
  • Patients with any uncontrolled, intercurrent illness including but not limited to symptomatic congestive heart failure.
  • Patients with Stage I FHWT with a known or suspected Wilms Tumor predisposition syndrome or condition (contralateral nephrogenic rests and/or unilateral multicentric tumors) are excluded from treatment on the mVLR (Nephrectomy Only) arm.
    • Notes:
      • In the context of the renal tumor protocols, multicentric tumors and multifocal tumors are equivalent terms, and refer to the occurrence of two or more tumors arising within one kidney.
      • Exclusion from the Nephrectomy Only arm applies to two groups of patients:
        • Patients < 4 years with Stage I FHWT other than epithelial subtype AND
        • Stage I patients of any age with Epithelial WT
      • For the purpose of exclusion from the Nephrectomy Only Arm, known or suspected WT predisposition syndromes or conditions are defined as follows:
        • WT Predisposition Syndromes: Beckwith Wiedemann Spectrum, Denys Drash, Trisomy 18, Idiopathic Hemihypertrophy/Isolated Lateralized Overgrowth, WAGR, Simpson-Golabi-Behmel, Bohring-Opitz, or other conditions considered by treating physician to predispose to WT.
        • WT Predisposing Conditions:
          • A unilateral WT and (radiologic or pathologic) determination of contralateral nephrogenic rest(s) AND/OR
          • Unilateral multicentric WT
  • Patients treated with partial nephrectomy at initial diagnosis are excluded from mVLR (Nephrectomy Only) arm.
  • Patients with lung metastases as the only metastatic site who already had complete resection of all radiologically evident lung nodules, and have at least one nodule confirmed pathologically as tumor.
    • Please note: Those with lung metastases as the only metastatic site who have complete resection of all radiologically evident lung nodules after enrollment but prior to the lung imaging following Cycle 2 of DD-4A will be inevaluable for lung assessment and subsequent stratum assignment and will, therefore, come Off Protocol Therapy.
  • Patients who have had prior tumor-directed chemotherapy or radiotherapy for the current diagnosis except for therapy delivered for an emergent issue, as medically indicated.
  • Patients who will potentially require doxorubicin on this study and have previously received doxorubicin for another diagnosis.
  • Patients receiving concurrent chemotherapy for a different diagnosis.
  • Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
  • Lactating females who plan to breastfeed their infants.
  • Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.

Updated on 22 Jul 2025. Study ID: PHO-COG-AREN2231, 27515

This study investigates treatment strategies for children with favorable histology Wilms tumors (FHWT), which is a common type of kidney cancer in children. The study aims to use risk factors, such as tumor histology, biology, and response to therapy, to determine the most effective treatment plan. Wilms Tumor is a kidney cancer where favorable histology refers to a subtype that generally has a good prognosis. By understanding these risk factors, the study seeks to improve outcomes and reduce the chance of cancer relapse.

Participants in this study will be assigned to different study arms based on their risk factors and tumor characteristics. For instance, some children may undergo observation, while others receive specific chemotherapy regimens. Treatments include various cycles of chemotherapy drugs administered intravenously, such as dactinomycin, vincristine, and doxorubicin. The study involves regular imaging tests, including CT scans and MRIs, to monitor the tumor's response to treatment.

  • Who can participate: Children under 30 years old with newly diagnosed Stage I-IV Favorable Histology Wilms Tumor are eligible. Participants must meet specific clinical criteria, including molecular testing and performance status.
  • Study details: Participants will undergo different chemotherapy regimens based on their risk assessment.
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Interested in the study?

This study is accepting only persons who receive care at a certain clinic or doctor or who are part of an invited group. Questions about this study can be directed to the study team listed in the description or contact your doctor to see if you are eligible.

Accepting Referrals by Invitation Only