Zanzalintinib in Second Line and Beyond for the Treatment of Advanced Liver Cancer

Inclusion Criteria: * 3.1.1 Patients with confirmed diagnosed HCC who are not amendable to curative treatments. * 3.1.2 Patients must have documented objective radiographic progression during or after treatment with any first or second line therapy, or intolerance to any first or second line therapy, which include immunotherapy-based combination, or non-immunotherapy-based treatment, except cabozantinib. Note: Patients who have progressed on up to two prior lines therapy (not including cabozantinib) in the advanced metastatic setting are eligible * 3.1.3 Patients must have a Child-Pugh class A or Child-Pugh class B (B7 or B8) score for cirrhosis mortality. Child-Pugh class B, B9 is excluded. See Appendix A for Child-Pugh Class Scores. * 3.1.4 Patients must have measurable disease according to RECIST v1.1. See Section 7 for the evaluation of measurable disease. See Appendix B for RECIST v1.1 criteria. * 3.1.5 Patients may have had up to two prior lines therapy (not including cabozantinib) in the advanced metastatic setting. Palliative radiation or locoregional therapies are not considered a line of therapy. * 3.1.6 Patients must be age ≥ 18 years. * 3.1.7 Patients must exhibit /an ECOG Status of 0-1 Refer to Appendix C; OR Karnofsky ≥ 60%. See Appendix D. * 3.1.8 Patients must have adequate organ and bone marrow function as defined below in Table 2 (Child-Pugh Class A): Absolute neutrophil count (ANC) ≥ 1,500/mcL, Hemoglobin (Hgb) ≥ 9 g/dL, Platelets (PLT) ≥ 75,000/mcL, International Normalized Ratio (INR) ≤ 1.7 x upper limit of normal (ULN), Total bilirubin ≤ 3.0 mg/dl, Albumin ≥ 2.5 (g/dL), AST (SGOT) ≤ 5 x institutional ULN, ALT (SGPT) ≤ 5 x institutional ULN, ALP ≤ 5.0 x institutional ULN, Creatinine Clearance \> 40 mL/ minute if serum creatinine is elevated above 1.5 X ULN, Urine protein-to-creatinine ratio (UPCR) ≤ 1.5 mg/mg (≤ 169.8 mg/mmol) creatinine. * 3.1.8 Patients must have adequate organ and bone marrow function as defined below in Table 2 (Child-Pugh Class B): Absolute neutrophil count (ANC) ≥ 1,200/mcL, Hemoglobin (Hgb) ≥ 8.5 g/dL, Platelets (PLT) ≥ 60,000/mcL, International Normalized Ratio (INR) ≤ 2.3 x upper limit of normal (ULN), Total bilirubin ≤ 3.0 mg/dl, Albumin ≥ 2.5 (g/dL), AST (SGOT) ≤ 5 x institutional ULN, ALT (SGPT) ≤ 5 x institutional ULN, ALP ≤ 5.0 x institutional ULN, Creatinine Clearance \> 40 mL/ minute if serum creatinine is elevated above 1.5 X ULN, Urine protein-to-creatinine ratio (UPCR) ≤ 1.5 mg/mg (≤ 169.8 mg/mmol) creatinine.3.1.9 FOCBP and any of their partners with sperm-producing reproductive capability (PWSPRC) must agree to use a highly effective method of contraception (hormonal or barrier method of birth control; abstinence; defined in Appendix E) from the time of informed consent, throughout the course of the study and for 186 days after the last dose of treatment. Additional contraceptive method, such as a barrier method (e.g., condom) is also required. Should a female patient become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy , Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months) * 3.1.10 Patients with sperm-producing reproductive capacity (PWSPRC) treated or enrolled on this protocol must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence), refer to Appendix E, with partners of childbearing potential from time of informed consent, for the duration of study participation, and for 96 days following completion of therapy. * 3.1.11 Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the study requirements. * 3.1.12 Patients must have the ability to swallow, retain, and absorb oral medications or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube. Exclusion Criteria: * 3.2.1 Patients with prior treatment with zanzalintinib. * 3.2.2 Patients who have received any type of small-molecule kinase inhibitor (including an investigational kinase inhibitor) within 14 days prior to study Day 1 treatment. * 3.2.3 Patients with prior Cabozantinib use. * 3.2.4 Patients who have had chemotherapy, cytotoxic, biologic, radiation, or other systemic anticancer (including investigational) therapy within 4 weeks prior to study Day 1 treatment. * 3.2.5 Patients who have received palliative radiation therapy for bone metastasis within 14 days or any other radiation therapy within 4 weeks before first dose of study treatment. * 3.2.6 Patients who have undergone systemic treatment with radionuclides within 6 weeks (42 days) before first dose of study treatment. * 3.2.7 Patients who have received any local anticancer therapy including surgery, PEI, RFA, MWA, transarterial chemoembolization (TACE), or trans arterial radioembolization (TARE) within 28 days prior to first dose of study treatment. * 3.2.8 Patients with any unresolved toxicity NCI Common Terminology Criteria for Adverse Event (CTCAE 5.0) Grade \>1 at baseline, including immune-related adverse events (irAEs), related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (eg, physiological replacement of corticosteroid, from a previous anticancer therapy, with the following exceptions: Alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the treating physician. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with zanzalintinib may be incl