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


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Trial ID: NCT04322318


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).

Official Title

Treatment of Newly Diagnosed Diffuse Anaplastic Wilms Tumors (DAWT) and Relapsed Favorable Histology Wilms Tumors (FHWT)

Stanford Investigator(s)


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

   - 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

   - 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


drug: Carboplatin

drug: Cyclophosphamide

drug: Doxorubicin

drug: Etoposide

drug: Ifosfamide

drug: Irinotecan

drug: Topotecan

drug: Vincristine

procedure: Biopsy

procedure: Biospecimen Collection

procedure: Bone Scan

procedure: Computed Tomography

procedure: Magnetic Resonance Imaging

procedure: Positron Emission Tomography

radiation: Radiation Therapy

procedure: Surgical Procedure

procedure: Transabdominal Ultrasound

procedure: X-Ray Imaging


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Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Richard Fu

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