Ignite Creation Date:
2024-05-11 @ 8:31 AM
Last Modification Date:
2024-10-26 @ 3:28 PM
Study NCT ID:
NCT06401330
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-07-08
First Post:
2024-05-02
Brief Title:
A Study Using Risk Factors to Determine Treatment for Children With Favorable Histology Wilms Tumors FHWT
Sponsor:
Childrens Oncology Group
Organization:
Childrens Oncology Group
Study Overview
Official Title:
Risk Adapted Treatment of Unilateral Favorable Histology Wilms Tumors FHWT
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
Detailed Description:
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 with standard 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 Childrens 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 tomographymagnetic resonance imaging CTMRI 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 andor 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 andor 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 andor 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 with central quality assurance QA monitoring within the prescribed time frame
XIII To determine the lung tumor and liver tumor control rate using intensity modulated radiation therapy IMRT andor 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 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 CTMRI ultrasound and X-ray imaging throughout the trial Patients receiving M MVI UH3 regimens also undergo CT CTMRI ultrasound X-ray and bone scanpositron emission tomography PET scans throughout the trial
After completion of study treatment patients are followed for 10 years
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 with standard 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 Childrens 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 tomographymagnetic resonance imaging CTMRI 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 andor 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 andor 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 andor 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 with central quality assurance QA monitoring within the prescribed time frame
XIII To determine the lung tumor and liver tumor control rate using intensity modulated radiation therapy IMRT andor 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 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 BIOPSYDELAYED 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 CTMRI ultrasound and X-ray imaging throughout the trial Patients receiving M MVI UH3 regimens also undergo CT CTMRI ultrasound X-ray and bone scanpositron emission tomography PET scans throughout the trial
After completion of study treatment patients are followed for 10 years
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| NCI-2024-03424 | REGISTRY | None | None |
| AREN2231 | OTHER | None | None |
| AREN2231 | OTHER | None | None |
| U10CA180886 | NIH | CTEP | httpsreporternihgovquickSearchU10CA180886 |