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. * 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 a/an ECOG Status of 0-1 Refer to Appendix C; (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), activated partial thromboplastin time (aPTT) ≤ 1.2 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), activated partial thromboplastin time (aPTT) ≤ 1.2 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 POCBP and any of their partners with sperm-producing reproductive capability must agree to use a highly effective method of contraception (defined in Appendix E) 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. * 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 POCBP must agree to use a highly effective method of contraception (defined in Appendix E) 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. * 3.1.12 Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the study requirements. * 3.1.13 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 who have received ≥ 3 prior therapies in the advanced setting. * 3.2.4 Patients with prior Cabozantinib use. * 3.2.5 Patients who have had chemotherapy, cytotoxic, biologic, radiation, or other systemic anticancer (including investigational) therapy within 4 weeks prior to study Day 1 treatment. * 3.2.6 Patients who have received palliative radiation therapy for bone metastasis within 14 days or any other radiation therapy within 4 weeks days before first dose of study treatment. * 3.2.7 Patients who have undergone systemic treatment with radionuclides within 6 weeks (42 days) before first dose of study treatment. * 3.2.8 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. * 3.2.9 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 included only after consultation with the principal investigator. * 3.2.10 Patients with a known prior or concurrent malignancy that is progressing or requires active treatment within 2 years of first dose of study treatment. Note: The following exceptions may be made: 1)For patients with malignancies like basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer; or superficial skin cancers, localized low-grade tumors deemed cured and not treated with systemic therapy, and incidentally diagnosed prostate cancer if assessed as stage * 3.2.11 Patients with known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 28 days prior to first dose of study treatment. Note: Patients with an incidental finding of an isolated brain lesion \< 1 cm in diameter may be eligible after Principal Investigator approval if the lesion is radiographically stable for 28 days before first dose and does not require treatment per Investigator judgement. Note: Eligible patients must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment. Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed * 3.2.12 Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to zanzalintinib. * 3.2.13 Patients who are on concomitant anticoagulation therapy with oral anticoagulants (e.g., warfarin or direct thrombin inhibitors) and platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: a. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). b. Therapeutic doses of LMWH or anticoagulation with direct Factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in patients without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen. Note: Patients must have discontinued oral anticoagulants within 3 days or 5 halflives prior to first dose of study treatment, whichever is longer. * 3.2.14 Patients who are taking any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease under study with in 2 weeks prior to cycle 1 day 1. Note: Taking complementary medications to treat symptoms of the cancer is allowed. * 3.2.15 Patient has uncontrolled, significant intercurrent or recent illness. * 3.2.16 Patients with clinically significant hematuria, hematemesis, or hemoptysis of \>0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 84 days prior to registration. * 3.2.17 Patients with symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed). * 3.2.18 Patients with lesions invading major blood vessel including but not limited to inferior vena cava, pulmonary artery, or aorta. Note: Patients with intravascular tumor extension (e.g., tumor thrombus in renal vein or inferior vena cava) may be eligible following PI approval. Patients with lesions invading the hepatic portal vasculature are eligible * 3.2.19 Patients with other clinically significant disorders that would preclude safe study participation * 3.2.20 Patients with Recent surgery within the following parameters: • Major surgery (e.g., GI surgery or removal/biopsy of brain metastasis) within 8 weeks before first dose of study treatment. • Prior laparoscopic surgeries (i.e. nephrectomy) within 28 days prior to first dose of study treatment. Minor surgery (e.g., simple excision, tooth extraction) within 5 days before first dose of study treatment. • Complete wound healing from major surgery and from minor surgery (e.g., simple excision, tooth extraction) must have occurred at least prior to first dose of study treatment. • Patients with clinically relevant ongoing complications from prior surgery are not eligible. • Minor surgery (e.g., simple excision, tooth extraction) within 5 days prior to first dose of study treatment. Note: if a patient has had a recent surgery outside of the proscribed interval, complete wound healing from said surgery must have occurred prior to first dose of study treatment. Note: Fresh tumor biopsies should be performed at least 5 days prior to registration. Patients with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible. * 3.2.21 Patients with corrected QT interval calculated by the Fridericia formula (QTcF) \>480 ms within 14 days per electrocardiogram (ECG) prior to first dose of study treatment. Note: Triplicate ECG evaluations will be performed and the average of these 3 consecutive results for QTcF will be used to determine eligibility. * 3.2.22 Patients who are pregnant (positive serum or urine test within 72 hours prior to enrollment) or nursing. Pregnant people are excluded from this study because zanzalintinib is a next-generation TKI with potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the nursing parent with zanzalintinib , breastfeeding should be discontinued if the nursing parent is treated with zanzalintinib. POCBP are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes. In addition, POCBP \< 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. Note: If a urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required. * 3.2.23 Patients with psychiatric illness/social situations that would limit compliance with study requirements or give informed consent, per the opinion of the treating investigator. * 3.2.24 Patients with other conditions which, in the opinion of the Investigator, would compromise the safety of the patient or the patient's ability to complete the study. * 3.2.25 Patients with documented hepatic encephalopathy (HE) within 6 weeks before first dose of study treatment. Patients with clinically meaningful ascites (i.e., ascites requiring paracentesis or escalation in diuretics) within 2 weeks prior to registration, C1D1.