NCT06401330 | NOT YET RECRUITING | Stage I Kidney Wilms Tumor

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 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) 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) 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 \< 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.