Inclusion Criteria:

• Subjects must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by the local site investigator. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Subjects who have relapsed and refractory ccRCC with evidence of disease progression on standard-of-care therapies
• ECOG performance status of 0 or 1.
• All subjects must have adequate tumor sample available (slides or archival FFPE blocks)

Exclusion Criteria:

• Prior treatment with an investigational anti-ENPP3/CD203c therapy
• History of serious allergic or anaphylactic/hypersensitivity reaction to monoclonal antibody therapy
• Systemic antineoplastic therapy within 5 half-lives on the first dose of study treatment.
• Failure to recover from any clinically significant toxicity related to previous anticancer treatment
• Have known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable,
• Active known autoimmune disease (except that subjects are permitted to enroll if they have vitiligo; type 1 diabetes mellitus; residual hypothyroidism due to an autoimmune condition that is treatable with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral acetaminophen and nonsteroidal anti-inflammatory drugs)
• Evidence of any serious infection requiring IV anti-infective treatment within 14 days prior to the first dose of study drug
• Have a known additional malignancy that is progressing or has required active treatment within the past 2 years

Inclusion Criteria:

• • Histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features following complete resection of the primary tumor (radical or partial nephrectomy)
• Note: Patients with microscopically positive soft tissue or vascular margins without gross residual disease are permitted
• Intermediate-high risk RCC:
• pT2 grade 4 or sarcomatoid features, N0M0
• pT3 any grade N0, M0
• High-risk RCC
• pT4, any grade, N0, M0
• pT, any stage., any grade, N+, M0
• cM1 no evidence of disease (NED) RCC
• Participants who have had resection of primary tumor (radical or partical nephrectomy) and resection or definitive radiation or ablation of solid, isolated, soft tissue metastases (excluding brain and bone lesions) at the time of primary tumor removal (synchronous) or ≤1 year from primary tumor removal (metachronous)
• Surgery (radical or partial nephrectomy or metastasectomy or ablation) > 4 weeks but =< 16 weeks prior to study registration with no ongoing complications from surgery
• No evidence of disease at time of randomization as assessed by investigator by either CT or MRI scan of the brain and chest, abdomen and pelvis
• No prior systemic treatment for RCC
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%)
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 8 g/dL
• Total bilirubin =< 3 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x upper limit of normal (ULN)
• Calculated (calc.) creatinine clearance >= 30 mL/min (using Cockcroft Gault equation or the estimated glomerular filtration rate from the modification of diet in renal disease trial)
• Urine protein =< 1+ on urine analysis (UA) or urine protein creatinine ration (UPCR) < 2mg/mg
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test is required =< 14 days prior to registration
• HIV status: HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Hepatitis
• Hepatitis B: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with resolved HBV infection, defined as positive hepatitis B core antibody (anti-HBc) and negative hepatitis B surface antigen (HbsAg), are eligible
• Hepatitis C: Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Cardiac Disease: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class IIB or better
• No history of myocarditis
• No history of clinically significant pneumonitis
• No uncontrolled hypertension (systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 90 mm Hg) documented on 2 consecutive measurements taken at least 2 hours apart
• No serious non-healing wound, ulcer or bone fracture within 28 days prior to registration
• No serious/active infection requiring parenteral antibiotics
• No moderate or severe hepatic impairment (child-Pugh B or C)
• No significant bleeding disorders within 1 month prior to registration, for example:
• Hematemesis, hematochezia or other gastrointestinal bleeding grade 3 or higher
• Hemoptysis of pulmonary bleeding grade 3 or higher
• Hematuria or other genitourinary bleeding grade 3 or higher
• No history of allogeneic organ transplantation
• No history of allergy of hypersensitivity to study drugs or components
• No condition requiring systemic treatment with either corticosteroid (> 10 mg daily or prednisone equivalent) within 14 days of treatment initiation or other immunosuppressive medications within 30 days of randomization. Inhaled or topical steroids and adrenal replacement doses ≤10 mg daily prednisone equivalent are permitted in absence of active autoimmune disease
• No active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis or other gastrointestinal condition associated with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 4 weeks prior to registration
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• No patients with a history of autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids > 10 mg/day, or immunosuppressive drugs) with the following exceptions:
• Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
• Brief (<7 days) use of systemic corticosteroids is allowed when use is considered standard of care
• Patients with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy will not be excluded
• Patients requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded
• Patients with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome will not be excluded • Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment

Inclusion Criteria:

• Patients with newly diagnosed stages 2 - 4 diffuse anaplastic Wilms tumor must be enrolled on APEC14B1, consented to Part A - Eligibility Screening, and have received an initial stratum assignment showing DAWT (if anaplasia first identified at diagnostic, pre-treatment nephrectomy or biopsy) or a final stratum assignment showing DAWT (if anaplasia first noted at delayed nephrectomy) prior to enrollment on AREN1921. Prior enrollment on APEC14B1 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 initial stratum assignment on APEC14B1-REN
• 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

Inclusion Criteria:

• Age ≥ 18 years
• Current or prior diagnosis of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, colorectal cancer, renal cancer, melanoma, or sarcoma
• Ability to understand spoken or written English or Spanish in a healthcare context
• Ability to understand and the willingness to sign a written informed consent document
• Black or Latinx (qualitative assessment study only)

Exclusion Criteria:

• Prior cancer genetic testing
• Prior germline genetic testing
• Active hematologic malignancy (e.g. chronic lymphocytic leukemia)
• Currently pregnant
• Currently incarcerated