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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04322318
Recruitment Status : Recruiting
First Posted : March 26, 2020
Last Update Posted : April 22, 2024
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE March 17, 2020
First Posted Date  ICMJE March 26, 2020
Last Update Posted Date April 22, 2024
Actual Study Start Date  ICMJE October 19, 2020
Estimated Primary Completion Date July 1, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 24, 2020)		 Event-free survival (EFS) [ Time Frame: From study entry to the earliest of relapse or disease progression, second malignant neoplasm, or death from any cause, assessed up to 5 years after study enrollment ]
For Strata 1-3, the primary analysis of EFS will consist of a one-sample, one-sided log rank test versus a historical control cohort (or representative distribution) with stratum-specific type I error levels. For Stratum 4, the primary analysis of EFS is descriptive, but with a desired level of precision to estimate 4-year EFS at the time of the final analysis (2 years after the last patient enrolls).
Original Primary Outcome Measures  ICMJE
 (submitted: March 24, 2020)		 Event-free survival (EFS) [ Time Frame: From study entry to the earliest of relapse or disease progression, second malignant neoplasm, or death from any cause, assessed up to 2 years after last patient enrollment ]
For Strata 1-3, the primary analysis of EFS will consist of a one-sample, one-sided log rank test versus a historical control cohort (or representative distribution) with stratum-specific type I error levels. For Stratum 4, the primary analysis of EFS is descriptive, but with a desired level of precision to estimate 4-year EFS at the time of the final analysis (2 years after the last patient enrolls).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 24, 2020)		 Overall survival (OS) [ Time Frame: From study entry to death due to any cause, assessed up to 5 years after study enrollment ]
For each stratum, OS will be estimated at the same time as the conclusive (interim or final) analysis and reported descriptively with 95% pointwise confidence bands.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2020)		 Overall survival (OS) [ Time Frame: From study entry to death due to any cause, assessed up to 5 years post-treatment ]
For each stratum, OS will be estimated at the same time as the conclusive (interim or final) analysis and reported descriptively with 95% pointwise confidence bands.
Current Other Pre-specified Outcome Measures
 (submitted: August 24, 2020)
  • Incidence of grade 3-5 renal toxicity [ Time Frame: Up to 30 weeks on average for Stratum 4 only ]
    Incidence of grade 3-5 renal toxicity during protocol therapy will be monitored for Stratum 4 as part of a prospective safety monitoring plan. At the time of final study analysis, renal toxicity will be described by factors including age, relapse risk group, and timing and association (descriptive) with the exploratory renal toxicity biomarkers.
  • Collection of blood and urine samples [ Time Frame: Up to 42 weeks on average for Strata 1-3 and up to 30 weeks on average for Stratum 4 ]
    For all Strata 1-4, serial blood and urine samples will be collected (during protocol therapy, at the end of protocol therapy, and at first relapse) and banked for future analysis such as evaluation of minimal residual disease by assessing levels of circulating tumor-derived deoxyribonucleic acid.
  • p53 biomarker analysis [ Time Frame: Based on tissue collected at diagnosis (Strata 1 and 2 only), with outcomes collected up to 5 years after study entry ]
    For patients with diffuse anaplastic Wilms tumors (DAWT) (Strata 1 and 2), p53 from diagnostic tissue will be assessed, and rates of p53 mutations described overall and within each stratum. Degree of anaplasia as a predictor of p53 mutation status will be analyzed in logistic regression models, and association of p53 status with EFS and OS will be analyzed in Cox regression models, stratified by disease stage. Possible interactions between p53 mutation status and degree of anaplasia in outcome models will be explored.
  • EFS for patients with gross total disease resection [ Time Frame: From study entry to the earliest of relapse or disease progression, second malignant neoplasm, or death from any cause, assessed up to 5 years after study enrollment ]
    EFS will be described for newly diagnosed disease stage 2-4 DAWT patients (Strata 1 and 2) and relapsed favorable histology Wilms tumors (FHWT) patients (Strata 3 and 4) who have gross total disease resection prior to enrollment or at the time of delayed nephrectomy following adjuvant chemotherapy. Kaplan-Meier curves will be reported by strata with 95% confidence bands. Potential prognostic factors for these patients will be explored in Cox regression models.
  • OS for patients with gross total disease resection [ Time Frame: From study entry to death due to any cause, assessed up to 5 years after study entry ]
    OS will be described for newly diagnosed disease stage 2-4 DAWT patients (Strata 1 and 2) and relapsed FHWT patients (Strata 3 and 4) who have gross total disease resection prior to enrollment or at the time of delayed nephrectomy following adjuvant chemotherapy. Kaplan-Meier curves will be reported by strata with 95% confidence bands. Potential prognostic factors for these patients will be explored in Cox regression models.
  • Association of the number of nodes examined with EFS and OS [ Time Frame: Nodal information from upfront or delayed nephrectomy, with outcomes collected for up to 5 years after study entry ]
    The number of lymph nodes examined at the time of primary nephrectomy and number of positive nodes will be collected for all DAWT patients who enroll to Strata 1 or 2. The association of the number of nodes examined with EFS and OS will be explored in Cox regression models stratified by disease stage. For each of these analyses, association will be expressed either as a single hazard ratio if the effect is found to be linear, or as continuous functions on the hazard ratio scale if the effect is found to be non-linear. Similar models will be fit to examine the association between ratio of positive nodes to nodes examined and outcomes. Confidence intervals or bands will be reported for all quantities.
Original Other Pre-specified Outcome Measures
 (submitted: March 24, 2020)
  • Incidence of grade 3-5 renal toxicity [ Time Frame: Up to 5 years post-treatment ]
    Incidence of grade 3-5 renal toxicity will be monitored for Stratum 4 as part of a prospective safety monitoring plan. At the time of final study analysis, renal toxicity will be described by factors including age, relapse risk group, and timing and association (descriptive) with the exploratory renal toxicity biomarkers.
  • Collection of blood and urine samples [ Time Frame: Up to 5 years post-treatment ]
    For all Strata 1-4, serial blood and urine samples will be collected and banked for future analysis such as evaluation of minimal residual disease by assessing levels of circulating tumor-derived deoxyribonucleic acid.
  • p53 biomarker analysis [ Time Frame: Up to 5 years post-treatment ]
    For patients with diffuse anaplastic Wilms tumors (DAWT) (Strata 1 and 2), p53 will be assessed, and rates of p53 mutations described overall and within each stratum. Degree of anaplasia as a predictor of p53 mutation status will be analyzed in logistic regression models, and association of p53 status with EFS and OS will be analyzed in Cox regression models, stratified by disease stage. Possible interactions between p53 mutation status and degree of anaplasia in outcome models will be explored.
  • EFS for patients with gross total disease resection [ Time Frame: From study entry to the earliest of relapse or disease progression, second malignant neoplasm, or death from any cause, assessed up to 2 years after last patient enrollment ]
    EFS will be described for newly diagnosed disease stage 2-3 DAWT patients (Stratum 1) and relapsed favorable histology Wilms tumors (FHWT) patients (Strata 2-3) who have gross total disease resection prior to enrollment or at the time of delayed nephrectomy following adjuvant chemotherapy. Kaplan-Meier curves will be reported by strata with 95% confidence bands. Potential prognostic factors for these patients will be explored in Cox regression models.
  • OS for patients with gross total disease resection [ Time Frame: From study entry to death due to any cause, assessed up to 5 years post-treatment ]
    OS will be described for newly diagnosed disease stage 2-3 DAWT patients (Stratum 1) and relapsed FHWT patients (Strata 2-3) who have gross total disease resection prior to enrollment or at the time of delayed nephrectomy following adjuvant chemotherapy. Kaplan-Meier curves will be reported by strata with 95% confidence bands. Potential prognostic factors for these patients will be explored in Cox regression models.
  • Association of the number of nodes examined with EFS and OS [ Time Frame: Up to 5 years post-treatment ]
    The number of lymph nodes examined at the time of primary nephrectomy and number of positive nodes will be collected for all DAWT patients who enroll to Strata 1 or 2. The association of the number of nodes examined with EFS and OS will be explored in Cox regression models stratified by disease stage. For each of these analyses, association will be expressed either as a single hazard ratio if the effect is found to be linear, or as continuous functions on the hazard ratio scale if the effect is found to be non-linear. Similar models will be fit to examine the association between ratio of positive nodes to nodes examined and outcomes. Confidence intervals or bands will be reported for all quantities.
 
Descriptive Information
Brief Title  ICMJE A Study of Combination Chemotherapy for Patients With Newly Diagnosed DAWT and Relapsed FHWT
Official Title  ICMJE Treatment of Newly Diagnosed Diffuse Anaplastic Wilms Tumors (DAWT) and Relapsed Favorable Histology Wilms Tumors (FHWT)
Brief Summary This phase II trial studies how well combination chemotherapy works in treating patients with newly diagnosed stage II-IV diffuse anaplastic Wilms tumors (DAWT) or favorable histology Wilms tumors (FHWT) that have come back (relapsed). Drugs used in chemotherapy regimens such as UH-3 (vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide, and irinotecan) and ICE/Cyclo/Topo (ifosfamide, carboplatin, etoposide, cyclophosphamide, and topotecan) work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial may help doctors find out what effects, good and/or bad, regimen UH-3 has on patients with newly diagnosed DAWT and standard risk relapsed FHWT (those treated with only 2 drugs for the initial WT) and regimen ICE/Cyclo/Topo has on patients with high and very high risk relapsed FHWT (those treated with 3 or more drugs for the initial WT).
Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/ carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the event-free survival (EFS) of patients with newly diagnosed stage 4 diffuse anaplastic Wilms tumor (DAWT) as compared to historical controls.

II. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the EFS of patients with standard-risk relapsed favorable histology Wilms tumor (SRrFHWT) as compared to historical controls.

SECONDARY OBJECTIVES:

I. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the overall survival (OS) of patients with newly diagnosed stage 4 DAWT as compared to historical controls.

II. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the OS of patients with SRrFHWT as compared to historical controls.

III. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the EFS and OS of patients with newly diagnosed stage 2 and 3 DAWT as compared to historical controls.

IV. To establish EFS and OS for high-risk (HRrFHWT) and very high risk (VHRrFHWT) relapsed favorable histology Wilms tumor treated with ifosfamide/carboplatin/etoposide alternating with cyclophosphamide/ topotecan.

EXPLORATORY OBJECTIVES:

I. To describe renal toxicity of ifosfamide/carboplatin/etoposide in HRrFHWT and VHRrFHWT patients using conventional and novel biomarkers of renal toxicity (urine NGAL, cystatin C and Kim1) in the context of the chemotherapy regimens used on this study.

II. To collect and bank serial blood and urine samples in patients with newly diagnosed DAWT or relapsed FHWT and tumor tissue in patients with relapsed FHWT, for future analysis.

III. To assess the impact of p53 gene and protein expression on outcome for patients with newly diagnosed DAWT.

IV. To determine EFS/OS in the subsets of patients with newly diagnosed DAWT or relapsed FWHT who undergo gross total resection at all disease sites at diagnosis or after neoadjuvant chemotherapy.

V. To describe the rate of regional lymph node sampling at the time of nephrectomy with the use of a pre-operative surgical checklist for patients with newly diagnosed DAWT.

VI. To determine the feasibility of intensity modulated radiation therapy (IMRT) with central quality assurance (QA) monitoring to reduce radiation induced toxicity to the heart, thyroid, breast and solitary kidney for children with lung and liver metastases (part of an overarching aim in this study and across frontline favorable histology Wilms tumor studies).

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I (REGIMEN UH-3):

CYCLES 1, 5, 7, 10, AND 13: Patients receive vincristine intravenously (IV) via minibag per institutional policy on days 1, 8, and 15. Patients also receive doxorubicin IV over 1-15 minutes and cyclophosphamide IV over 30-60 minutes on day 1. Treatment repeats every 21 days during cycles 1, 5, 7, 10, and 13 in the absence of disease progression or unacceptable toxicity.

CYCLES 2, 6, 9, 12, AND 14: Patients receive carboplatin IV over 15-60 minutes on day 1. Patients also receive cyclophosphamide IV over 15-30 minutes and etoposide IV over 1-2 hours on days 1-4. Treatment repeats every 21 days during cycles 2, 6, 9, 12, and 14 in the absence of disease progression or unacceptable toxicity.

CYCLES 3, 4, 8, AND 11: Patients receive vincristine IV via minibag per institutional policy on days 1 and 8 and irinotecan IV over 90 minutes on days 1-5. Treatment repeats every 21 days during cycles 3, 4, 8, and 11 in the absence of disease progression or unacceptable toxicity.

Patients undergo radiation therapy (RT) at week 7 of cycle 3 as clinically indicated. Patients undergo a computed tomography (CT) scan, a positron emission tomography (PET) scan, a chest x-ray, magnetic resonance imaging (MRI), an abdominal ultrasound, and/or a bone scan throughout the trial. Patients may also undergo blood specimen collection and biopsy throughout the trial.

ARM II (REGIMEN IFOSFAMIDE, CARBOPLATIN, ETOPOSIDE [ICE]/CYCLOPHOSPHAMIDE [CYCLO]/TOPOTECAN [TOPO]):

CYCLES 1, 2, 4, 5, 7, AND 9: Patients receive carboplatin IV over 15-60 minutes on day 1. Patients also receive etoposide IV over 1-2 hours and ifosfamide IV over 2-4 hours on days 1-3. Treatment repeats every 21 days during cycles 1, 2, 4, 5, 7, and 9 in the absence of disease progression or unacceptable toxicity.

CYCLES 3, 6, 8, AND 10: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days during cycles 3, 6, 8, and 10 in the absence of disease progression or unacceptable toxicity.

Patients undergo surgery and/or RT during cycles 4, 7, and 10 as clinically indicated. Patients undergo a CT scan, a PET scan, a chest x-ray, MRI, an abdominal ultrasound, and/or a bone scan throughout the trial. Patients may also undergo blood specimen collection and biopsy throughout the trial.

After completion of study treatment, patients are followed up every 3 months for years 1-2, every 6 months for years 3-4, and once at year 5.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Anaplastic Kidney Wilms Tumor
  • Recurrent Kidney Wilms Tumor
  • Stage II Kidney Wilms Tumor
  • Stage III Kidney Wilms Tumor
  • Stage IV Kidney Wilms Tumor
Intervention  ICMJE
  • Procedure: Biopsy
    Undergo a biopsy
    Other Names:
    • BIOPSY_TYPE
    • Bx
  • Procedure: Biospecimen Collection
    Undergo blood sample collection
    Other Names:
    • Biological Sample Collection
    • Biospecimen Collected
    • Specimen Collection
  • Procedure: Bone Scan
    Undergo a bone scan
    Other Name: Bone Scintigraphy
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • JM8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Procedure: Computed Tomography
    Undergo a CT scan
    Other Names:
    • CAT
    • CAT Scan
    • Computed Axial Tomography
    • Computerized Axial Tomography
    • Computerized axial tomography (procedure)
    • Computerized Tomography
    • CT
    • CT Scan
    • tomography
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Asta B 518
    • B-518
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamide Monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
    • WR-138719
  • Drug: Doxorubicin
    Given IV
    Other Names:
    • Adriablastin
    • Hydroxydaunomycin
    • Hydroxyl Daunorubicin
    • Hydroxyldaunorubicin
  • Drug: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16
    • VP 16-213
    • VP 16213
    • VP-16
    • VP-16-213
    • VP16
  • Drug: Ifosfamide
    Given IV
    Other Names:
    • Asta Z 4942
    • Asta Z-4942
    • Cyfos
    • Holoxan
    • Holoxane
    • Ifex
    • IFO
    • IFO-Cell
    • Ifolem
    • Ifomida
    • Ifomide
    • Ifosfamidum
    • Ifoxan
    • IFX
    • Iphosphamid
    • Iphosphamide
    • Iso-Endoxan
    • Isoendoxan
    • Isophosphamide
    • Mitoxana
    • MJF 9325
    • MJF-9325
    • Naxamide
    • Seromida
    • Tronoxal
    • Z 4942
    • Z-4942
  • Drug: Irinotecan
    Given IV
  • Procedure: Magnetic Resonance Imaging
    Undergo MRI
    Other Names:
    • Magnetic Resonance
    • Magnetic resonance imaging (procedure)
    • Magnetic Resonance Imaging Scan
    • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    • MR
    • MR Imaging
    • MRI
    • MRI Scan
    • NMR Imaging
    • NMRI
    • Nuclear Magnetic Resonance Imaging
  • Procedure: Positron Emission Tomography
    Undergo a PET scan
    Other Names:
    • Medical Imaging, Positron Emission Tomography
    • PET
    • PET Scan
    • Positron emission tomography (procedure)
    • Positron Emission Tomography Scan
    • Positron-Emission Tomography
    • proton magnetic resonance spectroscopic imaging
    • PT
  • Radiation: Radiation Therapy
    Undergo RT
    Other Names:
    • Cancer Radiotherapy
    • Energy Type
    • ENERGY_TYPE
    • Irradiate
    • Irradiated
    • Irradiation
    • Radiation
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
  • Procedure: Surgical Procedure
    Undergo surgery
    Other Names:
    • Operation
    • Surgery
    • Surgery Type
    • Surgery, NOS
    • Surgical
    • Surgical Intervention
    • Surgical Interventions
    • Surgical Procedures
    • Type of Surgery
  • Drug: Topotecan
    Given IV
    Other Names:
    • Hycamptamine
    • Topotecan Lactone
  • Procedure: Transabdominal Ultrasound
    Undergo abdominal ultrasound
    Other Names:
    • abdominal ultrasound
    • TUS
  • Drug: Vincristine
    Given IV
    Other Names:
    • LCR
    • Leurocristine
    • VCR
    • Vincrystine
  • Procedure: X-Ray Imaging
    Undergo a chest x-ray
    Other Names:
    • Conventional X-Ray
    • Diagnostic Radiology
    • Medical Imaging, X-Ray
    • Plain film radiographs
    • Radiographic Imaging
    • Radiographic imaging procedure (procedure)
    • Radiography
    • RG
    • Static X-Ray
    • X-Ray
Study Arms  ICMJE
  • Experimental: Arm I (Regimen UH-3)
    See outline in detailed description section.
    Interventions:
    • Procedure: Biopsy
    • Procedure: Biospecimen Collection
    • Procedure: Bone Scan
    • Drug: Carboplatin
    • Procedure: Computed Tomography
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin
    • Drug: Etoposide
    • Drug: Irinotecan
    • Procedure: Magnetic Resonance Imaging
    • Procedure: Positron Emission Tomography
    • Radiation: Radiation Therapy
    • Procedure: Transabdominal Ultrasound
    • Drug: Vincristine
    • Procedure: X-Ray Imaging
  • Experimental: Arm II (Regimen ICE/Cyclo/Topo)

    CYCLES 1, 2, 4, 5, 7, AND 9: Patients receive carboplatin IV over 15-60 minutes on day 1. Patients also receive etoposide IV over 1-2 hours and ifosfamide IV over 2-4 hours on days 1-3. Treatment repeats every 21 days during cycles 1, 2, 4, 5, 7, and 9 in the absence of disease progression or unacceptable toxicity.

    CYCLES 3, 6, 8, AND 10: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days during cycles 3, 6, 8, and 10 in the absence of disease progression or unacceptable toxicity.

    Patients undergo surgery and/or RT during cycles 4, 7, and 10 as clinically indicated. Patients undergo a CT scan, a PET scan, a chest x-ray, MRI, an abdominal ultrasound, and/or a bone scan throughout the trial. Patients may also undergo blood specimen collection and biopsy throughout the trial.

    Interventions:
    • Procedure: Biopsy
    • Procedure: Biospecimen Collection
    • Procedure: Bone Scan
    • Drug: Carboplatin
    • Procedure: Computed Tomography
    • Drug: Cyclophosphamide
    • Drug: Etoposide
    • Drug: Ifosfamide
    • Procedure: Magnetic Resonance Imaging
    • Procedure: Positron Emission Tomography
    • Radiation: Radiation Therapy
    • Procedure: Surgical Procedure
    • Drug: Topotecan
    • Procedure: Transabdominal Ultrasound
    • Procedure: X-Ray Imaging
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 24, 2020)		 221
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 1, 2027
Estimated Primary Completion Date July 1, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with newly diagnosed stages 2 - 4 diffuse anaplastic Wilms tumor must be enrolled on AREN03B2 and have received an initial risk assignment showing DAWT (if anaplasia first identified at diagnostic, pre-treatment nephrectomy or biopsy) or a delayed nephrectomy classification showing DAWT (if anaplasia first noted at delayed nephrectomy) prior to enrollment on AREN1921. Prior enrollment on AREN03B2 is not an eligibility requirement for patients with relapsed favorable histology Wilms tumor.
  • Patients must be =< 30 years old at study enrollment

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

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

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

      • Standard-Risk relapse: Patients who received two chemotherapy agents for frontline therapy; primarily actinomycin D and vincristine
      • High-Risk relapse: Patients who received three chemotherapy agents for frontline therapy; primarily vincristine, actinomycin D and doxorubicin or vincristine, actinomycin D and irinotecan
      • Very High-Risk relapse: Patients who received four or more chemotherapy agents as part of initial therapy; primarily regimen M or its variations

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

    • Note: For relapsed FHWT patients, an institutional pathology report confirming favorable histology Wilms tumor (from relapse, if available, or from original diagnosis) must be available for upload prior to initiation of protocol therapy
  • Patients with newly diagnosed Stages 2 - 4 diffuse anaplastic Wilms tumor must be enrolled on AREN1921 within 2 weeks of the tumor-directed surgery or biopsy procedure that first confirms a diagnosis of DAWT, whether at initial diagnostic procedure or delayed nephrectomy (such surgery/biopsy is day 0). For patients who received prior therapy for presumed favorable histology Wilms tumor, later confirmed to have diffuse anaplastic Wilms tumor at subsequent review of the initial biopsy
  • Patients with newly diagnosed DAWT who undergo upfront nephrectomy must have at least 1 lymph node sampled prior to study enrollment
  • Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
  • Patients must have a life expectancy of >= 8 weeks

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

    • Patients with diffuse anaplastic Wilms tumor who received no more than 12 weeks of pre nephrectomy chemotherapy for what was originally presumed to be favorable histology Wilms tumor, subsequently confirmed to be diffuse anaplastic Wilms tumor at delayed nephrectomy
    • Patients with diffuse anaplastic Wilms tumor who received no more than 6 weeks of chemotherapy following upfront biopsy, initiated within 14 days of biopsy, for presumed favorable histology Wilms tumor based on institutional review, but subsequently corrected to diffuse anaplastic Wilms tumor based on the AREN03B2 initial risk assignment results (if available per current version of AREN03B2)
    • Treatment consisting of vincristine/doxorubicin/cyclophosphamide initiated on an emergent basis and within allowed timing as described
    • Note: Patients who received prior therapy for presumed favorable histology Wilms tumor, later identified to have diffuse anaplastic Wilms tumor as per above, must begin study treatment starting at cycle 3 (week 7) of regimen UH 3. Patients who received emergency radiation to preserve organ function are eligible as noted. Patients who received radiation as part of standard of care for presumed newly diagnosed favorable histology Wilms tumor, along with chemotherapy as noted above, prior to identification of diffuse anaplasia, are also eligible

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

    • Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study
    • Radiation therapy (RT): >= 2 weeks (wks) must have elapsed for local palliative RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 wks must have elapsed if other substantial bone marrow (BM) radiation. Patients with relapsed favorable histology Wilms tumor who received emergency radiation to preserve organ function are eligible and do not need to washout with the above criteria
  • Patients may not be receiving any other investigational agents (within 4 weeks prior to study enrollment)
  • Peripheral absolute neutrophil count (ANC) >= 750/uL (performed within 7 days prior to enrollment)
  • Platelet count >= 75,000/uL (transfusion independent) (performed within 7 days prior to enrollment)
  • Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (performed within 7 days prior to enrollment)

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

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

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

    • Age: Maximum Serum Creatinine (mg/dL)
    • 1 month to < 6 months: 0.4 (male and female)
    • 6 months to < 1 year: 0.5 (male and female)
    • 1 to < 2 years: 0.6 (male and female)
    • 2 to < 6 years: 0.8 (male and female)
    • 6 to < 10 years: 1 (male and female)
    • 10 to < 13 years: 1.2 (male and female)
    • 13 to < 16 years: 1.5 (male), 1.4 (female)
    • >= 16 years: 1.7 (male), 1.4 (female)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age or direct bilirubin =< ULN for patients whose total bilirubin > 1.5 x ULN (performed within 7 days prior to enrollment)
  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age or =< 5 x ULN for patients with liver metastases (performed within 7 days prior to enrollment)
  • Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram (obtained within 21 days prior to enrollment and start of protocol therapy)

Exclusion Criteria:

  • Patients with a history of bilateral Wilms tumor (synchronous or metachronous)
  • Patients with any uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection, or symptomatic congestive heart failure (defined as grade 2 or higher heart failure per Common Terminology Criteria for Adverse Events [CTCAE] version 5.0)
  • Relapsed FHWT patients who did not receive frontline chemotherapy (e.g., very low risk FHWT initially observed without chemotherapy) or received only one chemotherapy agent for frontline therapy

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

    • Patients with renal tubular acidosis (RTA) as evidenced by serum bicarbonate < 16 mmol/L and serum phosphate =< 2 mg/dL (or < 0.8 mmol/L) without supplementation

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

    • Chronic inflammatory bowel disease and/or bowel obstruction
    • Concomitant use of St. John's wort, which cannot be stopped prior to the start of trial treatment
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 30 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   Saudi Arabia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04322318
Other Study ID Numbers  ICMJE AREN1921
NCI-2020-01561 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AREN1921 ( Other Identifier: Children's Oncology Group )
AREN1921 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Children's Oncology Group
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Children's Oncology Group
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: James I Geller Children's Oncology Group
PRS Account Children's Oncology Group
Verification Date April 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP