A Study of Combination Chemotherapy for Patients With Newly Diagnosed DAWT and Relapsed FHWT
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| ClinicalTrials.gov Identifier: NCT04322318 |
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Recruitment Status :
Recruiting
First Posted : March 26, 2020
Last Update Posted : November 21, 2023
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Sponsor:
Children's Oncology Group
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Anaplastic Kidney Wilms Tumor Recurrent Kidney Wilms Tumor Stage II Kidney Wilms Tumor Stage III Kidney Wilms Tumor Stage IV Kidney Wilms Tumor | Procedure: Biopsy Procedure: Biospecimen Collection Procedure: Bone Scan Drug: Carboplatin Procedure: Computed Tomography Drug: Cyclophosphamide Drug: Doxorubicin Drug: Etoposide Drug: Ifosfamide Drug: Irinotecan Procedure: Magnetic Resonance Imaging Procedure: Positron Emission Tomography Radiation: Radiation Therapy Procedure: Surgical Procedure Drug: Topotecan Procedure: Transabdominal Ultrasound Drug: Vincristine Procedure: X-Ray Imaging | Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 221 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Treatment of Newly Diagnosed Diffuse Anaplastic Wilms Tumors (DAWT) and Relapsed Favorable Histology Wilms Tumors (FHWT) |
| Actual Study Start Date : | October 19, 2020 |
| Estimated Primary Completion Date : | July 1, 2027 |
| Estimated Study Completion Date : | July 1, 2027 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Wilms tumor
MedlinePlus related topics:
Wilms Tumor
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I (Regimen UH-3)
See outline in detailed description section.
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Procedure: Biopsy
Undergo a biopsy
Other Names:
Procedure: Biospecimen Collection Undergo blood sample collection
Other Names:
Procedure: Bone Scan Undergo a bone scan
Other Name: Bone Scintigraphy Drug: Carboplatin Given IV
Other Names:
Procedure: Computed Tomography Undergo a CT scan
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Drug: Cyclophosphamide Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Etoposide Given IV
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Drug: Irinotecan Given IV Procedure: Magnetic Resonance Imaging Undergo MRI
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Procedure: Positron Emission Tomography Undergo a PET scan
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Radiation: Radiation Therapy Undergo RT
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Procedure: Transabdominal Ultrasound Undergo abdominal ultrasound
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Drug: Vincristine Given IV
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Procedure: X-Ray Imaging Undergo a chest x-ray
Other Names:
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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. |
Procedure: Biopsy
Undergo a biopsy
Other Names:
Procedure: Biospecimen Collection Undergo blood sample collection
Other Names:
Procedure: Bone Scan Undergo a bone scan
Other Name: Bone Scintigraphy Drug: Carboplatin Given IV
Other Names:
Procedure: Computed Tomography Undergo a CT scan
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Ifosfamide Given IV
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Procedure: Positron Emission Tomography Undergo a PET scan
Other Names:
Radiation: Radiation Therapy Undergo RT
Other Names:
Procedure: Surgical Procedure Undergo surgery
Other Names:
Drug: Topotecan Given IV
Other Names:
Procedure: Transabdominal Ultrasound Undergo abdominal ultrasound
Other Names:
Procedure: X-Ray Imaging Undergo a chest x-ray
Other Names:
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Primary Outcome Measures :
- 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).
Secondary Outcome Measures :
- 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.
Other Outcome Measures:
- 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.
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| Ages Eligible for Study: | up to 30 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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
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Patients with the following diagnoses are eligible for this study:
- Newly diagnosed stages 2 - 4 diffuse anaplastic Wilms tumor as confirmed by central review
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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
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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
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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
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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)
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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)
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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
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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
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04322318
Locations
Show 191 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | James I Geller | Children's Oncology Group |
| Responsible Party: | Children's Oncology Group |
| ClinicalTrials.gov Identifier: | NCT04322318 |
| Other Study ID Numbers: |
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 ) |
| First Posted: | March 26, 2020 Key Record Dates |
| Last Update Posted: | November 21, 2023 |
| Last Verified: | November 2023 |
| 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 |
Additional relevant MeSH terms:
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Neoplasms Wilms Tumor Neoplasms, Complex and Mixed Neoplasms by Histologic Type Kidney Neoplasms Urologic Neoplasms Urogenital Neoplasms Neoplasms by Site Neoplastic Syndromes, Hereditary Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Urogenital Diseases Kidney Diseases Urologic Diseases Male Urogenital Diseases |
Genetic Diseases, Inborn Cyclophosphamide Ifosfamide Isophosphamide mustard Carboplatin Doxorubicin Liposomal doxorubicin Irinotecan Etoposide Vincristine Etoposide phosphate Daunorubicin Topotecan Podophyllotoxin Immunosuppressive Agents |