Zanzalintinib and MO-03 for the Treatment of Metastatic Renal Cell Cancer After Progression on Immunotherapy

Inclusion Criteria: * Capable of understanding and complying with the protocol requirements and must have signed the informed consent document * Agreement to allow the use of archival tissue from diagnostic tumor biopsies * If unavailable, exceptions may be granted with study principal investigator (PI) approval * Age: ≥ 18 years * Gender: Males and females are eligible * Any ethnicity or race * Eastern Cooperative Oncology Group (ECOG) ≤ 2 * Histologically confirmed renal cell carcinoma with a clear-cell histology * Patients must have received one or two prior lines of systemic therapy for metastatic disease, which must include prior treatment with a checkpoint inhibitor and cabozantinib (not necessarily in the same line). Prior use of hypoxia-inducible factor (HIF) inhibitors or other tyrosine kinase inhibitors (TKIs) other than cabozantinib are not allowed * Measurable metastatic disease by RECIST v 1.1 criteria * Recovery to baseline or ≤ grade 1 severity (CTCAE v 6.0) from adverse events (AEs), including immune-related adverse events (irAEs), related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (e.g., physiological replacement of corticosteroid). Low-grade or controlled toxicities such as alopecia, ≤ grade 2 hypomagnesemia, ≤ grade 2 neuropathy are permitted) * White blood cell (WBC) \> 2,000/mm\^3 (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * NOTE: Growth factor is not permitted within 14 days of absolute neutrophil count (ANC) assessment unless cytopenia is secondary to disease involvement * Neutrophils ≥ 1,500/mm\^3 (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * NOTE: Growth factor is not permitted within 14 days of absolute neutrophil count (ANC) assessment unless cytopenia is secondary to disease involvement * Platelets ≥ 100,000/mm\^3 (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement * Hemoglobin ≥ 9g/dL (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment unless cytopenia is secondary to disease involvement * Total bilirubin ≤ 1.5 X upper limit of normal (ULN) (except for subjects with Gilbert Syndrome, who may have total bilirubin up to 3.0 mg/dL) (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * Aspartate aminotransferase (AST) ≤ 3.0 x ULN (except for subjects with Gilbert Syndrome, who may have total bilirubin up to 3.0 mg/dL) (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * Alkaline phosphatase (ALP) ≤ 3.0 x ULN. For subjects with documented bone metastasis ALP ≤ 5 x ULN (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * Creatinine clearance ≥ 40 mL/min the Cockcroft-Gault formula (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN. If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.2 x ULN, INR ≤ 1.5. If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants (to be performed within 14 days prior to day 1 of protocol therapy unless otherwise stated) * QT interval corrected by Bazett's formula (QTcB) ≤ 480 ms * Note: To be performed within 28 days prior to day 1 of protocol therapy * If seropositive for HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), nucleic acid quantitation must be performed. Viral load must be undetectable. HIV-infected, chronic carriers of HBV, and chronic carriers of HCV on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * Meets other institutional and federal requirements for infectious disease titer requirements * Note: Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy * Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Sexually active fertile subjects and their partners must agree to use highly effective method of contraception during the course of the study and for the following durations after the last dose of treatment (whichever is later). An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods, through 186 days after the last dose of zanzalintinib for women of childbearing potential (WOCBP) or through 96 days after the last dose of zanzalintinib for men * 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 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, females \< 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 zanzalintinib * Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment * Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. 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 * Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of enrollment. * Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed * Known medical condition (e.g., chronic diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results * Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin inhibitors ) and platelet inhibitors (e.g., clopidogrel).Allowed anticoagulants are the following: * Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). * Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects 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: Subjects must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer * Any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment * The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Unstable or deteriorating cardiovascular disorders: * Congestive heart failure New York Heart Association Class 3 or 4, class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (e.g., ventricular flutter, ventricular fibrillation, Torsades de pointes). * 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, or other clinically significant arterial thrombotic and/or ischemic event within 6 months before first dose of study treatment. * Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before first dose of study treatment. * Note: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and 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: Subjects who don't require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator * Prior history of myocarditis. * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: * Tumors invading the GI-tract from external viscera. * Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis. * Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months before first dose unless cause of obstruction is definitively managed and subject is asymptomatic. * Abdominal fistula, gastrointestinal 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 of study treatment * Known gastric or esophageal varices * Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks * 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 12 weeks before first dose of study treatment * Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed) * Lesions invading major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta. * Note: Subjects with intravascular tumor extension (e.g., tumor thrombus in renal vein or inferior V. cava) may be eligible following Principal Investigator approval * Other clinically significant disorders that would preclude safe study participation * Active infection requiring systemic treatment. Note: Prophylactic antimicrobial treatments (antibiotics, antimycotic, antiviral) are allowed. * Known infection with acute or chronic hepatitis B or C, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness except for subjects meeting all of the following criteria: * (1) Chronic carriers of HBV infection (hepatitis B surface antigen \[HBsAg\]-positive, anti-hepatitis B core antibody \[anti-HBc\]-positive) who have undetectable HBV deoxyribonucleic acid (DNA) and are on stable suppressive antiviral therapy. * (2) Individuals with prior HCV infection who have completed curative antiviral treatment and achieved undetectable HCV viral load. * (3) Chronic carriers of HCV infection who are on stable suppressive antiviral therapy and have undetectable HCV viral load. * (4) HIV-infected patients on stable anti-retroviral therapy with CD4+ T cell count ≥ 200/µL; and) an undetectable viral load. \*\*\* Note: HIV testing will be performed at screening if and as required by local regulation. * Note: To be eligible, participants taking CYP inhibitors (e.g., zidovudine, ritonavir, cobicistat, didanosine) or CYP3 inducers (efavirenz) must change to a different regimen not including these drugs 7 days prior to initiation of study treatment. Anti-retroviral therapies (ART) must have been received for at least 4 weeks prior to the first dose. * Note: CD4+ T cell counts, and viral load are monitored per standard of care by the local health care provider. * Serious non-healing wound/ulcer/bone fracture. * Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions. * Malabsorption syndrome. * Pharmacologically uncompensated, symptomatic hypothyroidism. * Moderate to severe hepatic impairment (Child-Pugh B or C). * Requirement for hemodialysis or peritoneal dialysis. * History of solid organ or allogeneic stem cell transplant * Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to first dose of study treatment. Prior laparoscopic surgeries (i.e. nephrectomy) within 4 weeks 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 or minor surgery must have occurred at least prior to first dose of study treatment * Note: Fresh tumor biopsies should be performed at least 5 days before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible * Corrected QT interval calculated by the Fridericia formula (QTcF) \> 480 ms within 14 days per electrocardiogram (ECG) before 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 * History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent * Women who are pregnant or breastfeeding * Inability to swallow tablets or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube * Previously identified allergy or hypersensitivity to components of the study treatment formulations * Another malignancy that requires active therapy and in the opinion of the Investigator would interfere with monitoring of radiologic assessments of response to Investigational Product, 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 * 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 * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)