Inclusion Criteria:

• Cytologically or histologically and radiologically confirmed solid tumor that is inoperable locally advanced, metastatic, or recurrent:

Dose-Escalation Stage:

• Subjects with UC (including renal pelvis, ureter, urinary bladder, urethra) after prior platinum-based therapy, or
• Subjects with RCC (clear cell, non-clear cell histology) with or without prior systemic anticancer therapy.

Expansion Stage:

• Expansion Cohort 1: Subjects with RCC with clear cell histology (including those with mixed sarcomatoid component) and without prior systemic anticancer therapy.
• Expansion Cohort 2: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after platinum-containing chemotherapy including subjects who received prior neoadjuvant or adjuvant platinum-containing therapy with disease recurrence < 12 months from the end of last therapy.
• Expansion Cohort 3: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who are ineligible for cisplatin-based chemotherapy and have not received prior systemic anticancer therapy for inoperable locally advanced or metastatic disease.
  • Ineligible for cisplatin-based chemotherapy is defined by meeting one of the following criteria:
  • Impaired renal function (glomerular filtration rate [GFR] < 60 mL/min/1.73 m2), hearing loss of ≥ 25 dB at two contiguous frequencies, or ≥ Grade 2 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE) v4.
  • Prior neoadjuvant or adjuvant platinum-based chemotherapy is allowed if disease recurrence took place > 12 months from end of last therapy.
• Expansion Cohort 4: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic anticancer therapy for inoperable locally advanced or metastatic disease.
  • Prior neoadjuvant or adjuvant platinum-based chemotherapy is allowed if disease recurrence took place > 12 months from end of last therapy.
• Expansion Cohort 5: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) for the treatment of inoperable locally advanced or metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy to treat inoperable locally advanced or metastatic UC including prior treatment with an anti-CTLA-4 agent.
  • Excluded are subjects who had a prior combination therapy of an immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) with a VEGFR-targeting TKI.
• Expansion Cohort 6: Subjects with metastatic CRPC (adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features) who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.
  • Note: prostate-specific antigen [PSA] progression or bone progression alone are not allowed to determine eligibility.
  • Prior chemotherapy is not allowed with the exception of docetaxel given in combination with androgen deprivation therapy (ADT) for progressive castration-sensitive disease prior to treatment with enzalutamide and/or abiraterone acetate.
  • Subject must have castrate-level testosterone (< 50 ng/dL [< 2 nM]) following bilateral orchiectomy or by ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) analog that was initiated ≥ 4 weeks prior to first dose of study treatment and must be continued throughout the study.
• Expansion Cohort 7: Subjects with Stage IV non-squamous NSCLC who have radiographically progressed on or after treatment with one prior immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) for metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy to treat metastatic NSCLC including prior treatment with an anti-CTLA-4 agent.
  • Excluded are subjects who had a prior VEGFR-targeting TKI.
  • Excluded are subjects who have been diagnosed with an EGFR sensitizing mutation, ALK rearrangement, ROS1 rearrangement, or BRAF V600E mutation.
• Expansion Cohort 8: Subjects with Stage IV non-squamous NSCLC with positive PD-L1 expression (TC ≥ 1% [TC = tumor cell]) and without prior systemic anticancer therapy for metastatic disease.
  • Acceptable reports for prior PD-L1 expression testing by immunohistochemical (IHC) assessment include the following:
    • US sites: FDA-approved Dako PD-L1 IHC 22C3 pharmDx assay;
    • Ex-US sites: health authority-approved or CE-marked Dako PD-L1 IHC 22C3 pharmDx assay.
  • A prior local laboratory PD-L1 report using a validated assay may be accepted if slides can be provided to the central laboratory to assess PD-L1 expression using the FDA-approved Dako PD-L1 IHC 22C3 pharmDx assay.
  • Excluded are subjects who have been diagnosed with an EGFR sensitizing mutation, ALK translocation, ROS1 rearrangement, or BRAF V600E mutation.
• Expansion Cohort 9: Subjects with Stage IV nonsquamous NSCLC with documentation of a sensitizing EGFR mutation who have radiographically progressed during or following prior treatment with an EGFR targeting TKI (e.g., osimertinib, gefitinib, erlotinib, afatinib) for metastatic disease.
  • There is no limit on the number of prior lines of systemic anticancer therapy including chemotherapy for inoperable locally advanced, recurrent, or metastatic disease.
  • Prior treatment with ICIs (anti-PD-1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
• Expansion Cohort 10: Subjects with RCC with non-clear cell histology (including those with sarcomatoid component)
  • Allowed is prior therapy with up to one VEGFR-targeting TKI (eg, sunitinib, pazopanib) for inoperable locally advanced, recurrent, or metastatic disease.
  • TKIs targeting MET or prior therapy with immune checkpoint inhibitors is not allowed.
• Expansion Cohort 15: Subjects with gastric or gastroesophageal junction adenocarcinoma who have radiographically progressed during or following platinum-containing or fluoropyrimidine-containing chemotherapy for inoperable locally advanced, recurrent, or metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy for inoperable locally advanced, recurrent, or metastatic disease.
  • Prior HER-2/neu directed therapy is allowed if given combined with systemic chemotherapy.
• Expansion Cohort 16: Subjects with colorectal adenocarcinoma who have radiographically progressed during or following systemic chemotherapy that contained fluoropyrimidine in combination with oxaliplatin or irinotecan for metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy for inoperable locally advanced, recurrent, or metastatic disease.
  • Prior EGFR-targeted therapy given with concurrent chemotherapy is allowed.
  • Subjects with known microsatellite instability-high (MSI-H) and/or mismatch repair (MMR) deficient disease are excluded.

Exploratory Single-Agent Cabozantinib (SAC) Cohorts:

• Single-Agent Cohort 19: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior ICI (anti-PD-1 or anti-PD-L1) for the treatment of inoperable locally advanced or metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy to treat inoperable locally advanced or metastatic UC including prior treatment with an anti-CTLA-4 agent.
  • Excluded are subjects who had a prior combination therapy of an immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) with a VEGFR-targeting TKI.
• Single-Agent Cohort 20: Subjects with Stage IV non-squamous NSCLC who have radiographically progressed on or after treatment with one prior ICI (anti-PD-1 or anti-PD-L1) for metastatic disease.
  • Allowed are up to 2 lines of prior systemic anticancer therapy to treat metastatic NSCLC including prior treatment with an anti-CTLA-4 agent.
  • Excluded are subjects who had a prior combination therapy of an immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) with a VEGFR-targeting TKI and subjects who have been diagnosed with an EGFR sensitizing mutation, ALK translocation, ROS1 rearrangement, or BRAF V600E mutation.
• Exploratory Single-Agent Cabozantinib (SAC) Cohort 21, Exploratory Single-AgentAtezolizumab (SAA) Cohort 22, and Combination-Therapy Expansion Cohort 23:Subjects with metastatic CRPC who have histologically or cytologically confirmedadenocarcinoma of the prostate without small cell component (Note: Neuroendocrinedifferentiation and other histologic components are permitted if adenocarcinoma is theprimary histology) with the following requirements:
  • Prior treatment with one, and only one, NHT (eg, abiraterone, apalutamide,darolutamide, or enzalutamide) for castration-sensitive locally advanced (T3 or T4) ormetastatic castration-sensitive prostate cancer (mCSPC), M0 CRPC, or mCRPC. Note: Subjects may have previously received taxane-based chemotherapy for mCSPCbut no other approved or experimental nonhormonal systemic therapies formetastatic prostate cancer.
  • Bilateral orchiectomy or ongoing androgen deprivation therapy with a GnRHagonist/antagonist (surgical or medical castration), with serum testosterone≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.
  • Progressive disease at study entry as defined by at least one of the following two criteria:
    • a. PSA progression defined by a minimum of 2 rising PSA values from 3 or 4 consecutive assessments with an interval of at least 7 days between assessments.The most recent qualifying PSA value must be drawn within 28 days of plannedenrollment. (Note: If qualifying solely by PSA progression, the screening central lab PSA value must be at least 2 ng/mL [2 μg/L] but need not serve as last PSA value for determination of PSA progression; up to one PSA decrease is permitted as long as it is not the most recent value), OR
    • Soft tissue disease progression in the opinion of the Investigator. Note: Bone disease progression alone does not qualify.

• High risk metastatic disease per Investigator read as defined by at least one of the
following:

• Measurable visceral disease (eg, adrenal, kidney, liver, lung, pancreas, spleen), OR
• Measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation)
• Combination-Therapy Expansion Cohort 24: Subjects with metastatic CRPC who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell component (Note: Neuroendocrine differentiation and other histologic componentsare permitted if adenocarcinoma is the primary histology) with the following requirements:
  • Prior taxane-based chemotherapy initiated for mCRPC (Note: Subjects may have previously received taxane-based chemotherapy for CSPC but no other approved or experimental nonhormonal systemic therapies for metastatic prostate cancer.)
  • Prior treatment with at least one NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (mCSPC), M0 CRPC, or mCRPC.
  • Bilateral orchiectomy or ongoing androgen deprivation therapy with a GnRH agonist/antagonist (surgical or medical castration), with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.
  •  Progressive disease at study entry as defined by at least one of the following two criteria:
    •  Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA values from 3 or 4 consecutive assessments with an interval of at least 7 days between assessments. The most recent qualifying PSA value must be drawn within 28 days of planned enrollment. (Note: If qualifying solely by PSA progression, the screening central lab PSA value must be at least 2 ng/mL [2 μg/L] but need not serve as last PSA value for determination of PSA progression; up to one PSA decrease is permitted as long as it is not the mostrecent value), OR
    • Soft tissue disease progression in the opinion of the Investigator. Note: Bone disease progression alone does not qualify.
  • High risk metastatic disease per Investigator read as defined by at least one of the following:
    • Measurable visceral disease (eg, adrenal, kidney, liver, lung, pancreas, spleen, but not bladder or other pelvic structure) OR
    • Measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation)
• Measurable disease per RECIST 1.1 as determined by the investigator. Measurable disease must be outside the radiation field if prior radiation therapy was administered.
• Tumor tissue material available (archival or recent tumor biopsy).
• Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
• Age eighteen years or older on the day of consent.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment:
  • Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocyte colony-stimulating factor support within 2 weeks before screening laboratory sample collection.
  • White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L).
  • Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without transfusion within 2 weeks before screening laboratory sample collection. For subjects with HCC ≥ 75,000/mm3 (≥ 75 GI/L).
  • Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 2 weeks before screening laboratory sample collection.
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 × upper limit of normal (ULN). ALP ≤ 5 × ULN with documented bone metastases. For subjects with HCC: ALT, AST, and ALP ≤ 5 × ULN.  For subjects with mCRPC with documented bone metastases: ALT ≤ 3 × ULN, AST ≤ 3 × ULN, and ALP ≤ 10 × ULN. If ALP > 5 × ULN in mCRPC subjects, then it must be demonstrated that it is predominantly bone-specific ALP.
  • Total bilirubin ≤ 1.5 × ULN (for subjects with Gilbert’s disease ≤3 × ULN). For subjects with HCC ≤ 2 mg/dL (≤ 34.2 μmol/L).
  • Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min (≥ 0.67 mL/sec) using the Cockcroft-Gault equation (see Table 5-2 for Cockcroft-Gault formula).
  • Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol). For subjects with UC: ≤ 2 mg/mg (≤ 226.4 mg/mmol) creatinine.
• Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
• Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception that alone or in combination result in a failure rate of less than 1% per year when used consistently and correctly during the course of the study and for 5 months after the last dose of study treatment.  An additional contraceptive method, such as a barrier method (eg, condom), is recommended.
• Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria are met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman over 45 years-of-age in the absence of other biological or physiological causes. In addition, females under 55 years-of-age must have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.

Exclusion Criteria:

• Prior treatment with cabozantinib or ICIs including anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-OX-40, anti-CD137 therapy except for Expansion Cohorts 5 and 7 and SAC Cohorts 19 and 20 in which prior anti-PD-1 or anti-PD-L1 therapy is required for eligibility (see Inclusion Criteria 1g, 1i, 1u, and 1v, respectively, for details).
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
• For CRPC subjects: receipt of abiraterone within 1 week before first dose of study treatment or receipt of any other androgen-receptor inhibitors within 2 weeks before first dose of study treatment.
• HCC subjects who meet any of the following criteria are ineligible:
  • a. Received prior local anticancer therapy (including embolization and ablation) within 4 weeks before first dose of study treatment. For prior radiation for bone metastases, refer to Exclusion Criteria 6.
  • b. Subjects with fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma.
• Receipt of any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before first dose of study treatment, except in Expansion Cohorts 5 and 7 and SAC Cohorts 19 and 20 for which receipt of a PD-1, PD-L1, or CTLA-4 targeting antibody is permitted within 4 weeks before first dose of study treatment.
• Radiation therapy for bone metastasis within 2 weeks, any other local radiation therapy within 4 weeks before first dose of study treatment. Subjects who have received systemic treatment with radionuclides within 6 weeks before first dose of study treatment are not eligible. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
• Concomitant anticoagulation with oral anticoagulants except for those specified below.
  • Allowed anticoagulants are:
    • Prophylactic use of low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
    • Therapeutic doses of LMWH or specified direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects (excluding HCC subjects) without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatent and without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor. Note: Subjects with HCC may be treated with therapeutic LMWH but must have a screening platelet count > 100,000/μL. Direct inhibitors of thrombin or factor Xa are not permitted in subjects with HCC.
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment. Inhaled and topical corticosteroids and mineralocorticoids are allowed.
• Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
  • Cardiovascular disorders:
    • Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
    • Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
    • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT], pulmonary embolism) within 6 months before first dose. Subjects with a diagnosis of DVT within 6 months are allowed if stable, asymptomatic, and treated with LMWH for at least 6 weeks before first dose.
  • Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
    • Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction.  Presence of primary GI tumor is not excluded.
    • Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose
    • Gastric or esophageal varices that are untreated or incompletely treated with bleeding or high risk for bleeding. Subjects treated with adequate endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months prior to study entry are eligible.
  • Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose.
  • Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
  • Lesion invading a major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta. HCC subjects with lesions invading the hepatic portal vasculature are eligible.
  • Other clinically significant disorders such as:
    • Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple sclerosis. Subjects with the following conditions are eligible for the study:
      • A history of autoimmune-related hypothyroidism and on thyroid replacement hormone therapy
      • Controlled Type 1 diabetes mellitus and on an insulin regimen
      • Asthma
      • Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only provided all of following are true:
      • Rash covers < 10% of body surface area
      • Disease is well controlled at baseline and requires only low-potency topical corticosteroids
      • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months
    • Active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, acute or chronic hepatitis B or C infection in non-HCC tumor cohorts, or positive test for tuberculosis.  Subjects with history of COVID-19 must have recovered from the disease at least 30 days prior to enrollment.
    • History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
    • Serious non-healing wound/ulcer/bone fracture.
    • Malabsorption syndrome.
    • For all subjects except Cohort 18 (DTC): Free thyroxine (FT4) outside the laboratory normal reference range. Asymptomatic subjects with FT4 abnormalities can be eligible after sponsor approval.
    • Moderate to severe hepatic impairment (Child-Pugh B or C; Appendix K).
    • Requirement for hemodialysis or peritoneal dialysis.
    • History of solid organ or allogenic stem cell transplant.
• Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 4 weeks or minor surgery (eg, simple excision, tooth extraction) within 10 days before first dose of study treatment. Complete wound healing from surgery must have occurred before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment (see Section 5.6.4 for Fridericia formula).
  • Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these  three consecutive results for QTcF will be used to determine eligibility (ie, if the average is ≤ 500 ms the subject is eligible).
• Pregnant or lactating females.
• Inability to swallow tablets.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations. Subjects with a history of infusion-related reaction to prior therapy with atezolizumab may be eligible by sponsor approval if the reaction was considered mild and manageable with appropriate supportive care (eg, use of premedication according to standard of care).
• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6.