Inclusion Criteria:

• Age ≥ 18 years. As no dosing or adverse event data are currently available in participants < 18 years of age, children and adolescents are excluded from this study.

• Documentation of Disease

  • Histologic Documentation: Histologically-proven advanced (metastatic or unresectable primary) pheochromocytoma or paraganglioma.
  • Stage: Advanced (metastatic or unresectable primary) disease
  • Tumor Site: Histologically-proven pheochromocytoma or paraganglioma
  • Radiographic Evaluation: Radiographic evidence of disease progression by RECIST v1.1 criteria in the 12 months prior to registration.

• Measurable disease

  • Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 1 cm with CT or MRI (or ≥ 1.5 cm for lymph nodes). Non-measurable disease includes disease smaller than these dimensions or lesions considered truly non-measurable including: leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung.

• Prior Treatment

  • Prior treatment with other somatostatin analog, chemotherapy, radiotherapy (including peptide radionuclide receptor therapy [PRRT]), or surgery is permitted.

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.

• Organ and marrow function and laboratory values as follows within 4 days prior to the first dose of zanzalintinib:

  • Absolute neutrophil count (ANC) ≥ 1500/mm3without colony stimulating factor support
  • Platelets ≥ 100,000/mm3
  • Hemoglobin ≥ 9 g/dL
  • Bilirubin ≤ 1.5 the upper limit of normal (ULN). For subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL
  • Serum albumin ≥ 2.8 g/dl
  • Serum creatinine ≤ 1.5 ULN or creatinine clearance (CrCl) ≥ 50 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used:

Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72) Female: Multiply above result by 0.85

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 ULN

• Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis

• Urine protein/creatinine ratio (UPCR) ≤ 1

• Serum phosphorus, calcium, potassium ≥ LLN and magnesium ≥ 1.2 mg/dL

  • Capable of understanding and complying with the protocol requirements and has signed the informed consent document.
  • Sexually active patients (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).
  • Women of childbearing potential must have a negative pregnancy test at screening. Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post-menopause is defined as amenorrhea ≥ 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason.

Exclusion Criteria:

• Received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment.

• Prior treatment with zanzalintinib

• Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.

• Received radionuclide treatment (i.e. I 131 meta-iodo- benzyl guanidine) within 6 months of the first dose of study treatment

• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before the first dose of study treatment.

• Receipt of any other type of investigational agent within 28 days before the first dose of study treatment.

• The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia, fatigue, and other non-clinically significant AEs.

• Prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test ≥ 1.3 the laboratory ULN within 7 days before the first dose of study treatment.

• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 81 mg/day), , prophylactic low molecular weight heparin (LMWH), and or specified direct Fxa inhibitors rivaroxaban, edoxaban, or apixabanare permitted in subjects without known brain metastases.

• Subjects must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer.

• The subject requires chronic concomitant treatment of strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort).

• 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.

• 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.

• The subject has experienced any of the following: clinically significant gastrointestinal bleeding within 6 months before the first dose of study treatment hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment

  ·any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment

• Radiographic evidence of cavitating pulmonary lesion(s)

• Tumor invading or encasing > 180 degrees any major blood vessels

• Evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of zanzalintinib.

  ·Uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

• Cardiovascular disorders including

  • Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening
  • Concurrent uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
  • Any history of congenital long QT syndrome
  • Any of the following within 6 months before the first dose of study treatment:
  • unstable angina pectoris
  • clinically-significant cardiac arrhythmias
  • stroke (including TIA, or other ischemic event)
  • myocardial infarction
  • thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)

• Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

Any of the following within 28 days before the first dose of study treatment

• intra-abdominal tumor/metastases invading GI mucosa
• known gastric or esophageal varices, ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks
• active peptic ulcer disease; patients must be completely recovered
• acute flare of inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis; patients must be completely recovered from these conditions
• malabsorption syndrome

Any of the following within 6 months before the first dose of study treatment:

• abdominal fistula

• gastrointestinal perforation

• bowel obstruction or gastric outlet obstruction

• intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with zanzalintinib even if the abscess occurred more than 6 months before the first dose of study treatment.

• Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy

  -Other clinically significant disorders such as:

• Active infection requiring systemic treatment within 28 days before the first dose of study treatment.

• 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) on stable anti-retroviral therapy; (2) CD4+ T cell count ≥ 200/µL; and (3) 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 (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. Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment

  • History of organ transplant
  • Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
  • Major surgery within 12 weeks before the first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment. Minor surgery within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
  • Unable to swallow tablets
  • A corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before first dose of study treatment. Three ECGs must be performed. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard.
  • Pregnant or breastfeeding.
  • A previously identified allergy or hypersensitivity to components of the study treatment formulation.
  • Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
  • Evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment except for cured nonmelanoma skin cancer or cured in situ cervical carcinoma
  • Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality which, in the judgment of the investigator, would have made the patient inappropriate for entry into this study.
  • Moderate to severe hepatic impairment (Child-Pugh B or C).
  • Requirement for hemodialysis or peritoneal dialysis.

Inclusion of Women and Minorities

Both men and women of all races and ethnic groups are eligible for this trial.

NIH policy requires that women and members of minority groups and their subpopulations be included in all NIH-supported biomedical and behavioral research projects involving NIH-defined clinical research unless a clear and compelling rationale and justification establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Exclusion under other circumstances designated by the Director, NIH, upon the recommendation of an IC Director based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of childbearing potential should not be routinely excluded from participation in clinical research. Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf.