Metastatic Renal Cell Carcinoma - Refractory

Key Eligibilty Criteria:
Inclusion:
1. Metastatic disease defined as new or progressive lesions on cross-sectional imaging or bone scan. Patients must have at least:
a. One bone lesion on bone scan (tec99 or sodium fluoride [NaF] PET/CT, CT or MRI) for the bone-only cohort.
b. Histologically confirmed diagnosis of one of the following metastatic cohorts:
- Small cell/ neuroendocrine carcinoma of the bladder (Cohort A)- All urothelial carcinomas with any amount of neuroendocrine differentiation (including small cell differentiation) will be included. If the tumor is purely neuroendocrine, metastasis from another site of origin should be clinically excluded
- Squamous cell carcinoma of the bladder (Cohort C) - must be pure (i.e. urothelial carcinoma with squamous differentiation is not considered a pure squamous cell carcinoma)
- Plasmacytoid urothelial carcinoma (Cohort D) - Tumor should show predominantly > or equal ~ 50% plasmacytoid histology (including all types of discohesive growth, such as tumors with signet-ring and/or rhabdoid features as well)
- Sarcomatoid urothelial carcinoma (Cohort H) - Tumor should show predominantly ~ 50% sarcomatoid differentiation
- Bone-only metastatic GU tumors (non-prostate) (Cohort J) - All genitourinary histologies, except prostate are eligible
- Urethra carcinoma (Cohort L) - May be of any histology but if urothelial carcinoma then must be isolated to the urethra and not have metachronous or synchronous urothelial carcinoma of the bladder
c. H&E slides from diagnostic tumor tissue for retrospective central pathology review
2. Patients may have received up to 2 systemic anti-cancer treatments or be treatment naive. Patients with small cell carcinoma should have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients in the bone-only cohort may be urothelial carcinoma histology but must receive standard cisplatin-based chemotherapy (if cisplatin-eligible)
3. Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib will not be allowed. Also, patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed.
4. No prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4/CTLA-4 inhibitors with the exception of patients with "urothelial carcinoma" histology (cohorts D, H, J, L)
5. The patient has received no radionuclide treatment within 6 weeks of the first dose of study treatment

Key Eligibility Criteria:

Inclusion Criteria:

1. Unresectable locally advanced or metastatic renal cell carcinoma with a primary clear cell component.
2. Must have received anti-PD-1 or anti-PD-L1 therapy as part of the most recent regimen (either adjuvant monotherapy or first-line in combination with anti-CTLA-4 or VEGFR-TKI), with no more than 1 prior regimen in the metastatic setting.
a) Patients must have received at least 2 doses of anti-PD-1 or anti-PD-L1 therapy.
b) For patients who received anti-PD-1 in adjuvant setting, radiographic progression must have occurred on or within 12 months of last dose.

Exclusion Criteria:
1. Received prior treatment with a HIF-2α inhibitor.
2. Received prior treatment with cabozantinib.
3. Concomitant treatment with therapeutic doses of anticoagulants such as heparin, warfarin, thrombin, or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel).
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and prophylactic low molecular weight heparin (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in patients who are on a stable dose of LMWH for at least 1 week before administration of the first dose of study treatment, and who have had no complications from a thromboembolic event or the anticoagulation regimen.
4. Uncontrolled or poorly controlled hypertension, as defined by a sustained blood pressure > 140/90 mm Hg on more than three antihypertensives.
Note: Blood pressure medication may not be started nor changed within the 14 days prior to randomization.

For pre-screening, please contact: Message Basket: VICC RESEARCH UROTHELIAL

Key Eligibility Criteria:

Inclusion Criteria:
1. Histologically confirmed metastatic clear cell renal cell carcinoma (ccRCC).
2. Patients must have received at least one immune-oncology (IO) agent and at least one VEGF-targeted therapy (alone or in combination).
3. No exercise-induced desaturation on a 6-minute walk test, defined as a blood oxygen saturation by pulse oximetry </= 88%.
4. No active pneumonitis at screening as assessed by CT scan.
5. No medical history of severe chronic obstructive pulmonary disease (COPD).

Exclusion Criteria:
1. Prior treatment with HIF-2α inhibitors (e.g. belzutifan or related agents).
2. Contraindications to biopsy (e.g. bleeding diathesis, uncorrectable coagulopathy).

For internal pre-screening, please contact: Epic message basket- VICC RESEARCH UROTHELIAL

Key Eligibility Criteria:

Inclusion Criteria:
1. Histologically confirmed metastatic clear cell renal cell carcinoma (ccRCC).
2. Patients must have received at least one immune-oncology (IO) agent and at least one VEGF-targeted therapy (alone or in combination).
3. No exercise-induced desaturation on a 6-minute walk test, defined as a blood oxygen saturation by pulse oximetry </= 88%.
4. No active pneumonitis at screening as assessed by CT scan.
5. No medical history of severe chronic obstructive pulmonary disease (COPD).

Exclusion Criteria:
1. Prior treatment with HIF-2α inhibitors (e.g. belzutifan or related agents).
2. Contraindications to biopsy (e.g. bleeding diathesis, uncorrectable coagulopathy).

For internal pre-screening, please contact: Epic message basket- VICC RESEARCH UROTHELIAL

Key Eligibility Criteria:
Inclusion Criteria:
1. Must have one of the following diagnoses under study:
a. RCC: Have histologically or cytologically confirmed advanced or metastatic RCC and have progressed on, are intolerant to, or have a contraindication to treatment with a VEGFR-TKI and an anti-PD-(L)1 antibody.
b. Urothelial carcinoma: Have histologically or cytologically confirmed advanced or metastatic urothelial carcinoma and have progressed on, are intolerant to, or have a contraindication to treatment with an anti-PD-(L)1 antibody and enfortumab vedotin-ejfv. Participants with susceptible FGFR3 or FGFR2 tumor genetic alterations must have progressed on, be intolerant to, or have a contraindication to treatment with an FGFR inhibitor, if approved and available in the study site's region.
c. Castration-resistant prostate cancer: Have a histologically or cytologically confirmed advanced or metastatic prostate cancer after treatment with at least 1 androgen receptor signaling inhibitor (such as abiraterone, enzalutamide, apalutamide, and darolutamide). Participants with prostate cancer must also fulfill both of the following:
i. Ongoing androgen deprivation from prior orchiectomy or continued luteinizing hormone-releasing hormone agonist or antagonist therapy with leuprolide, goserelin, buserelin, triptorelin, or degarelix and a Screening testosterone level of 50 ng/dL or less.
ii. At least 1 metastatic lesion outside the prostate and at least one of the following: any soft tissue lesion that is measurable according to RECIST v1.1 and/or a PSA level of at least 1 ng/mL.

Exclusion Criteria:
1. Has history of systemic arterial thrombotic or embolic events, such as cerebrovascular accident (including ischemic attacks) or moderate hemoptysis within 6 months prior to the first dose of study drug.
2. Has history of systemic venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (eg, pulmonary embolism) unless they have been on stable anticoagulation for at least 30 days or the event has completely resolved and there is no need for ongoing treatment.


For pre-screening, please contact: VICC RESEARCH PHASE 1