IRB Study Number 22-494
Status Recruiting
Institute Taussig Cancer Institute
Description
1.1 Primary Objectives
1.1.1 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.
1.1.2 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.
1.2 Secondary Objectives
1.2.1 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.
1.2.2 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.
1.2.3 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.
1.2.4 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.
Inclusion Criteria
3.2.1 Enrollment on AREN03B2
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.
3.2.2 Age
Patients must be ≤ 30 years old at study enrollment.
3.2.3 Diagnosis
Patients with the following diagnoses are eligible for this study:
Newly diagnosed Stages 2 - 4 diffuse anaplastic Wilms tumor as confirmed by central review. Wilms tumor staging criteria can be found in Appendix III.
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:
a. Standard-Risk relapse: Patients who received two chemotherapy agents for frontline therapy; primarily actinomycin D and vincristine.
b. High-Risk relapse: Patients who received three chemotherapy agents for frontline therapy; primarily vincristine, actinomycin D and doxorubicin or vincristine, actinomycin D and irinotecan.
c. Very High-Risk relapse: Patients who received four or more chemotherapy agents as part of initial therapy; primarily Regimen M or its variations.
3.2.3.1 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. Please refer to Section 14.2.1 for further details.
3.2.4 Timing
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, please see Section 3.2.8.1.
3.2.5 Lymph Node Sampling
Patients with newly diagnosed DAWT who undergo upfront nephrectomy must have at least 1 lymph node sampled prior to study enrollment per Section 13.2.4.
3.2.6 Performance Level
Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. Refer to Performance Status Scales Scoring on the COG members website (Protocol Reference Material) and use appropriate score for study population.
3.2.7 Life Expectancy
Patients must have a life expectancy of ≥ 8 weeks.
3.2.8 Prior Therapy
3.2.8.1 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 in Section 3.1.5.1. 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. For treatment details specific to this group of patients, refer to Sections 4.1 and 4.3.1 for further details. Patients who received emergency radiation to preserve organ function are eligible as noted in Section 3.1.5.1. 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.
3.2.8.2 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.
a. Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study.
b. Radiation therapy (RT): 2 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 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.
3.2.9 Concomitant Medications Restrictions
a. Patients may not be receiving any other investigational agents (within 4 weeks prior to study enrollment). Please see Section 4.1.2 for the concomitant therapy restrictions for patients during treatment.
3.2.10 Organ Function Requirements
3.2.10.1 Adequate Bone Marrow Function Defined As:
Peripheral absolute neutrophil count (ANC) 750/L
Platelet count 75,000/L (transfusion independent)
Hemoglobin 8.0 g/dL (may receive RBC transfusions)
3.2.10.2 Adequate Renal Function:
Patients with high-risk or very high-risk relapsed FHWT (Section 3.2.3), who will be treated with Regimen ICE/Cyclo/Topo, must have renal function assessed by creatinine clearance or radioisotope GFR and meet the following requirement:
- Creatinine clearance or radioisotope GFR 60 mL/min/1.73 m2 Patients diagnosed with Stage 2-4 DAWT or standard-risk relapsed FHWT (Section 3.2.3), 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 m2), or an adequate serum creatinine as per the following table: (See protocol)
3.2.10.3 Adequate Liver Function Defined As:
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, and
SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age or ≤ 5x ULN for patients with liver metastases.
3.2.10.4 Adequate Cardiac Function Defined As:
Shortening fraction of 27% by echocardiogram, or
Ejection fraction of ≥ 50% by radionuclide angiogram
Exclusion Criteria
3.2.11 Patients with a history of bilateral Wilms tumor (synchronous or metachronous)
3.2.12 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 CTCAE version 5.0)
3.2.13 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
3.2.14 For patients with high-risk or very high-risk relapsed FHWT:
3.2.14.1 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
3.2.15 For Stages 2-4 DAWT and standard-risk relapsed FHWT patients:
3.2.15.1 Chronic inflammatory bowel disease and/or bowel obstruction
3.2.15.2 Concomitant use of St. John’s wort, which cannot be stopped prior to the start of trial treatment
3.2.16 Pregnancy and Breastfeeding
3.2.16.1 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.
3.2.16.2 Lactating females who plan to breastfeed their infants.
3.2.16.3 Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.
