The goal of this clinical research study is to learn if zanzalintinib can help to control recurrent/metastatic ONB. The safety of zanzalintinib will also be studied.

Primary Objectives:

• To assess the efficacy of Zanzalintinib in patients with R/M ONB

Endpoint

ORR, defined as the proportion of patients who achieve a complete response (CR) or partial response (PR) as measured by response evaluation criteria in solid tumors (RECIST), version 1.1, as determined by investigator radiologist assessment.

Secondary Objectives:

• To assess the metabolic response of Zanzalintinib in patients with R/M ONB

Endpoint

Objective Metabolic Response Rate (OMRR), defined as the proportion of patients who achieve a complete metabolic response (CMR) or partial metabolic response (PMR), as measured by PERCIST v.1.0 using DOTATATE-PET imaging, based on investigator assessment by radiology and/or nuclear medicine.

• To estimate the median duration of response (DOR)

Endpoint

DOR, defined as time from first documentation of CR or PR to the earliest date of documented disease progression or death from any cause, or last follow-up without disease progression or death, whichever occurs first.

• Duration of metabolic response (DOMR)

Endpoint

DOMR, defined as time from first documentation of CMR or PMR to the earliest date of documented metabolic disease progression or death from any cause, or last follow-up without disease progression or death, whichever occurs first.

• Time to response

Endpoint

Among objective responders (CR and PR), the time between the date treatment was started (C1D1) and first radiological evidence of CR or PR.

• To estimate the median progression-free survival (PFS) and 12-months PFS rate

Endpoint

PFS, defined as the time from the date of dose initiation to the earliest date of documented disease progression, or death from any cause, or last follow-up without disease progression or death, whichever occurs first.

To estimate the median overall survival (OS) and 12-months OS

Endpoint

OS, defined as time from date of dose initiation to death from any cause or last follow-up without death.

• To assess safety of Zanzalintinib

Endpoint

Safety will be measured as the incidence of adverse events (AEs) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

Tertiary/Exploratory Objectives

• To explore biomarkers that may predict response to therapy

Endpoint

Correlation of clinical response with biomarkers at baseline and/or on treatment. Correlatives analysis may include, but are not limited to, genomic (tumor molecular profiling, RNAseq) and proteomics (mIF or IMC) profiling.

Inclusion Criteria:

All subjects must meet all the following inclusion criteria to be eligible for participation in this study:

1. Subjects ≥18 years with histology-proven R/M ONB.

2. Not amenable to curative intent surgery or radiotherapy

3. Measurable disease per RECIST 1.1

4. Performance status ECOG of 0 or 1

5. VEGFR-inhibitor naïve (R/M ONB never treated with VEGFR inhibitors including Zanzalintinib)

6. Adequate organ and marrow function, based upon meeting all the following laboratory criteria within 14 days before first dose of study treatment

   1. Hemoglobin ≥ 9 g/dL without transfusion within 2 weeks prior to screening laboratory sample collection.
   2. Absolute neutrophil count ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocyte colony-stimulating factor support within 2 weeks of screening laboratory sample collection.
   3. Platelets ≥ 100 x 109/mL without transfusion within 2 weeks of screening laboratory sample collection.

7. Laboratory measurements, renal function:

   1. Creatinine clearance ≥ 40 mL/min as assessed by the Cockcroft-Gault equation
   2. Urine protein creatinine ration (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol creatinine)

8. Laboratory measurements, hepatic function:

   1. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x ULN. For subjects with documented bone metastasis ALP ≤ 5 x ULN.

      For subjects with CRPC and bone metastasis ALP ≤ 10 x ULN if predominantly bone-specific ALP.

   2. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN ).

   3. International Normalized Ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.2 x upper limit of normal (ULN ).

9. Sexually active fertile subjects and their partners must agree to use highly effective method of contraception (defined in Appendix A) 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 (eg, 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.

   a. 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

10. 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.

11. Capable of understanding and complying with protocol requirement and must have signed informed consent.

Exclusion Criteria:

All Patients

Patients who meet any of the following exclusion criteria are not eligible to be enrolled in this study:

1. Prior radiation therapy for bone metastasis within 2 weeks and any other radiation therapy within 4 weeks, or systemic treatment with radionuclide within 6 weeks before first dose of study treatment; ongoing relevant complications from prior radiation therapy are not eligible.

2. Active CNS disease (subjects with asymptomatic and stable, treated CNS lesions who have been off corticosteroids, radiation, or other CNS-directed therapy for at least 4 weeks are not considered active)

3. Red blood cell transfusion dependence, defined as requiring more than 2 units of packed red blood cell transfusions during the 4-week period prior to screening. Red blood cell transfusions are permitted during the screening period and prior to enrollment to meet the hemoglobin inclusion criterion.

4. Receipt of any type of small molecule kinase inhibitor (including Zanzalintinib) within 2 weeks before first dose of study treatment.

5. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.

6. Current participation in another interventional clinical study

7. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin inhibitors) and platelet inhibitors (eg, clopidogrel).

   Allowed anticoagulants are the following:

   1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
   2. 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.

8. History of previous malignancy other than malignancy treated with curative intent within less than 5 years. Subjects with the following diagnoses represents an exception and may enroll if ≥ 1 year with no evidence of active disease before the first dose of the study drug.:

   1. Non-melanoma skin cancers with no current evidence of disease
   2. Melanoma in situ with no current evidence of disease
   3. Localized cancer of the prostate with prostate-specific antigen of <1 ng/mL
   4. Treated or localized well-differentiated thyroid cancer
   5. Treated cervical carcinoma in situ
   6. Treated ductal/lobular carcinoma in situ of the breast

9. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

   1. Unstable of 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 (eg, 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
      • 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.

   2. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation, and malabsorption syndrome.

      • 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
      • Moderate to severe hepatic impairment (CHILD-PUGH B or C).

   3. Genitourinary bleeding: Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary haemorrhage) within 12 weeks before first dose of study treatment.

   4. Urine protein ≥ ++ or 24 h urine protein > 1.0 g as indicated by urinalysis. Requirement for haemodialysis or peritoneal dialysis.

   5. Symptomatic cavitating pulmonary lesions or endobronchial disease (asymptomatic or radiated lesions allowed)

   6. Lesions invading or encasing any major blood vessels

10. Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions.

11. Presence of multiple factors affecting oral medications (such as inability to swallow, chronic diarrhea, and intestinal obstruction, which significantly affect drug administration and absorption);

12. Female subjects who are pregnant or breast-feeding

13. Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient

14. Any complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment.

15. Major surgery (as defined in Appendix 1; eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to first dose of study treatment. Prior laparoscopic surgeries (ie nephrectomy) within 4 weeks prior to first dose of study treatment. Minor surgery (eg, 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.

16. Other clinically significant disorders:

    1. active infections requiring systemic treatment (prophylactic antibiotics is allowed).

    2. Pharmacologically uncompensated, symptomatic hypothyroidism

    3. Pregnant or lactating females

    4. 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:

       • On stable retroviral therapy
       • CD4+ T cells > 200 per microliters
       • Undetectable viral load. Note: HIV testing will be performed at screening if and as is required by local regulation Note: To be eligible, participants taking CYP inhibitors (eg, 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.

17. History of solid organ or allogeneic stem cell transplant

18. History of psychiatric illness likely to interfere with ability to comply with protocol requirement or give informed consent.

19. Other conditions, which in the opinion of the investigator would compromise the safety of the patient or the patient's ability to comply with study