Study of Cabozantinib Alone or in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors

• Dose Escalation Stage: to determine the schedule and maximum tolerated dose (MTD) and/or recommended Expansion Stage dose of cabozantinib when taken in combination with a standard dosing regimen of atezolizumab (1200 mg infusion, once every 3 weeks).
• Expansion Stage: to determine the preliminary efficacy (objective response rate [ORR] per RECIST 1.1) and safety of the recommended combination dose of cabozantinib with atezolizumab in eighteen tumor-specific cohorts including subjects with advanced UC, RCC, CRPC, NSCLC, TNBC, OC, EC, HCC, GC/GEJC/LEC, CRC, H&N, and DTC.
• Exploratory SAC Cohorts: Descriptive efficacy, safety, PK, and biomarker analyses of single-agent cabozantinib in UC, NSCLC, and CRPC subjects. Descriptive efficacy and safety analyses of combination therapy after progression on single-agent therapy
• Exploratory SAA Cohort: Descriptive efficacy, safety, PK, and biomarker analyses of single-agent atezolizumab in CRPC subjects. Descriptive efficacy and safety analyses of combination therapy after progression on single-agent therapy

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, 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:

• Inoperable locally advanced or metastatic solid tumor (UC, RCC, CRPC, NSCLC, TNBC, OC, EC, HCC, GC/GEJC/LEC, CRC, H&N cancer, and DTC as outlined above)
• Measurable disease per RECIST 1.1 as determined by the investigator.
• 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.
• Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception.
• Female subjects of childbearing potential must not be pregnant at screening.

Exclusion criteria

• Prior treatment with cabozantinib or immune checkpoint inhibitors including anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy except in Expansion Cohorts 5, 7, 9, 11, 17, 19 and 20. Other restrictions regarding prior therapy may apply.
• Known brain metastases or cranial epidural disease unless adequately treated and stable for at least 4 weeks before first dose of study treatment.
• Concomitant anticoagulation with oral anticoagulants.
• Subject is receiving systemic steroid therapy (>10 mg daily prednisone equivalent) or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment.
• 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, an active or history of autoimmune disease or immune deficiency; idiopathic pulmonary fibrosis, organizing pneumonia, pneumonitis; active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV), AIDS-related illness, acute or chronic hepatitis B or C infection, positive test for tuberculosis, moderate to severe hepatic impairment (Child-Pugh B or C).
• Pregnant or lactating females.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations.
• Diagnosis of another malignancy within 2 years before first dose of study treatment.