A Study of Combination Chemotherapy for Patients With Newly Diagnosed DAWT and Relapsed FHWT
M
Melissa Bear, MD
Primary Investigator
Overview
This phase II trial studies how well combination chemotherapy works in treating patients withwly 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 suchH-3 (vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide, and irinotecan)d ICE/Cyclo/Topo (ifosfamide, carboplatin, etoposide, cyclophosphamide, and topotecan) workdifferent ways to stop the growth of tumor cells, either by killing the cells, by stoppinghem 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 anddard risk relapsed FHWT (those treated with only 2 drugs for the initial WT) and regimenCE/Cyclo/Topo has on patients with high and very high risk relapsed FHWT (those treated with
3 or more drugs for the initial WT).
Description
PRIMARY OBJECTIVES:
I. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/boplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves thevent-free survival (EFS) of patients with newly diagnosed stage 4 diffuse anaplastic Wilmsumor (DAWT) as compared to historical controls.
II. To evaluate whether the addition of vincristine/irinotecan toyclophosphamide/carboplatin/etoposide alternating with
vincristine/doxorubicin/cyclophosphamide improves the EFS of patients with standard-riskd favorable histology Wilms tumor (SRrFHWT) as compared to historical controls.
SECONDARY OBJECTIVES:
I. To evaluate whether the addition of vincristine/irinotecan toyclophosphamide/carboplatin/etoposide alternating with
vincristine/doxorubicin/cyclophosphamide improves the overall survival (OS) of patients withwly diagnosed stage 4 DAWT as compared to historical controls.
II. To evaluate whether the addition of vincristine/irinotecan toyclophosphamide/carboplatin/etoposide alternating with
vincristine/doxorubicin/cyclophosphamide improves the OS of patients with SRrFHWT as comparedhistorical controls.
III. To evaluate whether the addition of vincristine/irinotecan toyclophosphamide/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) relapsedvorable 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 VHRrFHWTusing conventional and novel biomarkers of renal toxicity (urine NGAL, cystatin Cd 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 DAWTd 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 withwly 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 neoadjuvanthemotherapy.
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 anverarching 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 perutional policy on days 1, 8, and 15. Patients also receive doxorubicin IV over 1-15utes 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 unacceptabley.
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 hoursdays 1-4. Treatment repeats every 21 days during cycles 2, 6, 9, 12, and 14 in the absencedisease progression or unacceptable toxicity.
CYCLES 3, 4, 8, AND 11: Patients receive vincristine IV via minibag per institutional policydays 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 unacceptabley.
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,hest x-ray, magnetic resonance imaging (MRI), an abdominal ultrasound, and/or a bone scanhroughout the trial. Patients may also undergo blood specimen collection and biopsyhroughout 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 topotecanV over 30 minutes on days 1-5. Treatment repeats every 21 days during cycles 3, 6, 8, and 10he 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,very 6 months for years 3-4, and once at year 5.
Eligibility
You may be eligible for this study if you meet the following criteria:
-
Conditions:
Anaplastic Kidney Wilms Tumor, Recurrent Kidney Wilms Tumor, Stage II Kidney Wilms Tumor, Stage III Kidney Wilms Tumor, Stage IV Kidney Wilms Tumor
-
Age: - 30 Years
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Gender: All
Inclusion Criteria:
- Patients with newly diagnosed stages 2 - 4 diffuse anaplastic Wilms tumor must bed on AREN03B2 and have received an initial risk assignment showing DAWT (ifdentified at diagnostic, pre-treatment nephrectomy or biopsy) or adelayed nephrectomy classification showing DAWT (if anaplasia first noted at delayedhrectomy) prior to enrollment on AREN1921. Prior enrollment on AREN03B2 is not angibility 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 byview
- Favorable histology Wilms tumor at first relapse. Relapsed FHWT patients musthave previously achieved remission for their initial FHWT diagnosis to begible for this study. The relapse risk groups are defined as follows,gardless of radiation therapy:
- Standard-Risk relapse: Patients who received two chemotherapy agents forherapy; primarily actinomycin D and vincristine
- High-Risk relapse: Patients who received three chemotherapy agents forherapy; primarily vincristine, actinomycin D and doxorubicin orvincristine, actinomycin D and irinotecan
- Very High-Risk relapse: Patients who received four or more chemotherapygents 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, butquired
- Note: For relapsed FHWT patients, an institutional pathology report confirmingvorable histology Wilms tumor (from relapse, if available, or from originaldiagnosis) 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 procedurehat first confirms a diagnosis of DAWT, whether at initial diagnostic procedure ordelayed nephrectomy (such surgery/biopsy is day 0). For patients who received priorherapy for presumed favorable histology Wilms tumor, later confirmed to have diffuseWilms tumor at subsequent review of the initial biopsy
- Patients with newly diagnosed DAWT who undergo upfront nephrectomy must have at least1 lymph node sampled prior to study enrollment
- Patients must have a performance status corresponding to Eastern Cooperative OncologyGroup (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age andLansky 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 havehad no prior systemic therapy, except in the following situations:
- Patients with diffuse anaplastic Wilms tumor who received no more than 12 weekshrectomy chemotherapy for what was originally presumed to be favorablehistology Wilms tumor, subsequently confirmed to be diffuse anaplastic Wilmsumor at delayed nephrectomy
- Patients with diffuse anaplastic Wilms tumor who received no more than 6 weeks ofhemotherapy following upfront biopsy, initiated within 14 days of biopsy, forumed favorable histology Wilms tumor based on institutional review, butubsequently corrected to diffuse anaplastic Wilms tumor based on the AREN03B2k assignment results (if available per current version of AREN03B2)
- Treatment consisting of vincristine/doxorubicin/cyclophosphamide initiated on angent basis and within allowed timing as described
- Note: Patients who received prior therapy for presumed favorable histology Wilmsumor, later identified to have diffuse anaplastic Wilms tumor as per above, mustbegin study treatment starting at cycle 3 (week 7) of regimen UH 3. Patients whoved emergency radiation to preserve organ function are eligible as noted.Patients who received radiation as part of standard of care for presumed newlydiagnosed favorable histology Wilms tumor, along with chemotherapy as notedbove, 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. Inddition, patients must have fully recovered from the acute toxic effects of all priorhemotherapy, immunotherapy, or radiotherapy prior to entering this study
- Myelosuppressive chemotherapy: Must not have received within 2 weeks of entryhis study
- Radiation therapy (RT): >= 2 weeks (wks) must have elapsed for local palliativeRT (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 bonew (BM) radiation. Patients with relapsed favorable histology Wilms tumor whoved emergency radiation to preserve organ function are eligible and do notd 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)
- Platelet count >= 75,000/uL (transfusion independent) (performed within 7 days prior)
- Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (performedwithin 7 days prior to enrollment)
- Patients with high-risk or very high-risk relapsed FHWT who will be treated withgimen ICE/Cyclo/Topo, must have renal function assessed by creatinine clearance ordioisotope glomerular filtration rate (GFR) and meet the following requirement:
- Creatinine clearance or radioisotope GFR >= 60 mL/min/1.73 m^2 (performed within7 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 serumhe 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)
- Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) orum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 xupper 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% bydionuclide angiogram (obtained within 21 days prior to enrollment and start ofherapy)
Exclusion Criteria:
- Patients with a history of bilateral Wilms tumor (synchronous or metachronous)
- Patients with any uncontrolled, intercurrent illness including, but not limited to,going or active infection, or symptomatic congestive heart failure (defined as grade2 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 riskFHWT initially observed without chemotherapy) or received only one chemotherapy agentherapy
- For patients with high-risk or very high-risk relapsed FHWT:
- Patients with renal tubular acidosis (RTA) as evidenced by serum bicarbonate < 16/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
- 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 femalehildbearing potential
- Lactating females who plan to breastfeed their infants
- Sexually active patients of reproductive potential who have not agreed to use anve contraceptive method for the duration of their study participation
Updated on
28 Apr 2024.
Study ID: AREN1921
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