Zanzalintinib Maintenance in Patients With High Grade Neuroendocrine Neoplasms (HG-NENs)

Inclusion Criteria:

• Histologically or cytologically confirmed high-grade poorly differentiated or welldifferentiated neuroendocrine tumor (with a Ki-67 of ≥20%), excluding small celllung cancer (SCLC) and Merkel cell cancer. High-grade includes any neuroendocrineneoplasm with a Ki-67 of >20% or with mitotic count of more than 20 mitoses per highpower field or any poorly differentiated neoplasm or any neoplasm lacking these thatis deemed high grade by pathology consensus, based on other markers (necrosis or IHCdemonstrating p53 or RB mutation). This includes:

• High-grade well-differentiated neuroendocrine neoplasms

• Transformed NENs from a lower to a higher grade (patient may have some lowgrade and some high grade NENs)

• High-grade neoplasms with significant expression of neuroendocrine markers suchas synaptophysin, chromogranin or INSM-1 or unknown origin neoplasms with geneexpression signatures consistent with neuroendocrine lineage (as per validatedtissue of origin testing, such as CancerType ID, after pathology consensus).

• Mixed neuroendocrine and non-neuroendocrine neoplasms (MiNEN), including MiNENper WHO and mixed neoplasms not fulfilling criteria of MiNEN. Theneuroendocrine component would need to be a high-grade neuroendocrine tumor asdocumented by pathology review.

• Note: For ambiguous cases, will consult with a designated expert pathologist.

• Measurable disease per RECIST 1.1.

• Current or prior somatostatin analogue therapy is allowed if clinically indicated.

• Patients must have received their initial course of chemotherapy and be eligible fora chemotherapy break with the most recent disease imaging assessment showing stabledisease (SD) or a partial response (PR) by RECIST 1.1. The imaging showing stabledisease or partial response should have occurred either during the chemotherapy orright after discontinuation of the chemotherapy treatment and before any othertreatment. Reasons for treatment break can include physician or patient preference,completion of pre-specified treatment cycles, or toxicity. Patients intolerant ofchemotherapy may also be eligible for the study, but they must have been treatedwith at least 2 cycles of chemotherapy and at least one imaging assessment ontreatment or right after treatment showing PR or SD per RECIST 1.1. There is nolimit for prior lines of non-chemotherapeutic regimens (including targeted agents,immunotherapy or radioligand treatment), but the most recent treatment prior tostudy initiation must contain chemotherapeutic agents.

• At least 18 years of age.

• ECOG performance status ≤ 2 (Karnofsky ≥ 80%).

• Adequate bone marrow and organ function as defined below:

• Absolute neutrophil count (ANC) ≥ 1.5 K/cumm without granulocytecolony-stimulating factor support within 2 weeks of screening laboratory samplecollection.

• Platelets ≥ 100 K/cumm without transfusion within 2 weeks prior to screeninglaboratory sample collection.

• Hemoglobin ≥ 9.0 g/dL without transfusion within 2 weeks prior to screeninglaboratory sample collection.

• International Normalized Ratio (INR) ≤ 1.5 and activated partial thromboplastintime (aPTT) ≤ 1.2 x IULN.

• Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease, totalbilirubin ≤ 3 x IULN).

• Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), and alkalinephosphatase (ALP) ≤ 3.0 x IULN. For subjects with documented bone metastasis,ALP ≤ 5.0 x IULN.

• Creatinine ≤ 1.5 x IULN OR calculated creatinine clearance ≥ 40 mL/min byCockcroft-Gault equation.

• Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤113.2 mg/mmol) creatinine.

• Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) 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 (eg,physiological replacement of corticosteroid). Low-grade or controlled toxicitiessuch as alopecia, ≤ Grade 2 hypomagnesemia, ≤ Grade 2 neuropathy are permitted.

• Sexually active fertile subjects and their partners must agree to use highlyeffective method of contraception during the course of the study and for thefollowing durations after the last dose of treatment (whichever is later). Anadditional contraceptive method, such as a barrier method (eg, condom), is requiredwith use of oral contraceptives. In addition, men must agree not to donate sperm andwomen must agree not to donate eggs (ova, oocyte) for the purpose of reproductionthrough 186 days after the last dose of zanzalintinib for women of childbearingpotential (WOCBP) or through 96 days after the last dose of zanzalintinib for men.

• Female subjects of childbearing potential must not be pregnant at screening. Femalesubjects are considered to be of childbearing potential unless one of the followingcriteria is met:

• permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateraloophorectomy) 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 stimulatinghormone [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.

• Ability to understand and willingness to sign an IRB approved written informedconsent document. Legally authorized representatives may sign and give informedconsent on behalf of study participants.

Exclusion Criteria:

• Prior treatment with zanzalintinib (XL092) or cabozantinib (XL184).

• Another malignancy that requires active therapy and in the opinion of theInvestigator would interfere with monitoring of radiologic assessments of responseto Investigational Product, within 2 years before C1D1, except for superficial skincancers, or localized, low-grade tumors deemed cured and not treated with systemictherapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤T2N0M0 and Gleason score ≤ 6.

• Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksbefore first dose of study treatment.

• Note: Eligible subjects must be neurologically asymptomatic and withoutcorticosteroid treatment at the time of first dose of study treatment.

• Note: Base of skull lesions without definitive evidence of dural or brainparenchymal involvement are allowed.

• Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 2 weeks before C1D1.

• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before C1D1.

• Radiation therapy for bone metastasis within 2 weeks, any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible.

• Any complementary medications (eg, herbal supplements or traditional Chinesemedicines) to treat the disease under study within 2 weeks before C1D1.

• Receipt of strong or moderate CYP3A4 inhibitors or inducers within 4 half-lives ofC1D1. (This includes cimetidine, because of its potential to interfere with CYP3A4mediated metabolism of zanzalintinib.)

• Use of concomitant medications that are known to prolong the QT interval within 4half-lives of C1D1.

• Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombininhibitors) and platelet inhibitors (eg, clopidogrel). Allowed anticoagulants arethe following:

• Prophylactic use of low-dose aspirin for cardioprotection (per local applicableguidelines) and low molecular weight heparins (LMWH).

• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitorsrivaroxaban, edoxaban, or apixaban in subjects without known brain metastaseswho are on a stable dose of the anticoagulant for at least 1 week before C1D1without clinically significant hemorrhagic complications from theanticoagulation regimen.

• Note: Subjects must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to C1D1, whichever is longer.

• A history of allergic reactions attributed to compounds of similar chemical orbiologic composition to zanzalintinib.

• 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 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) ≥ 140mm Hg systolic or ≥ 90 mm Hg diastolic despite optimal antihypertensivetreatment.

• Stroke (including transient ischemic attack [TIA]), myocardial infarction,or other clinically significant ischemic event within 6 months beforeC1D1.

• Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinicallysignificant venous or non-CVA/TIA arterial thromboembolic events within 3months before C1D1.

• Note: Subjects with a diagnosis of DVT within 6 months are allowed ifasymptomatic and stable at screening and are on a stable dose of theanticoagulant for at least 1 week before C1D1 without clinicallysignificant hemorrhagic complications from the anticoagulationregimen.

• Note: Subjects who don't require prior anticoagulation therapy may beeligible but must be discussed and approved by the PI.

• Prior history of myocarditis.

• Gastrointestinal (GI) disorders including those associated with a high risk ofperforation 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 acutepancreatitis

• Acute obstruction of the bowel, gastric outlet, or pancreatic or biliaryduct within 6 months unless cause of obstruction is definitively managedand subject is asymptomatic

• Abdominal fistula, gastrointestinal perforation, or intra-abdominalabscess within 6 months before first dose.

• Note: Complete healing of an intra-abdominal abscess must beconfirmed before C1D1.

• Known gastric or esophageal varices

• Ascites, pleural effusion, or pericardial fluid requiring drainage in thelast 4 weeks

• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5ml) of red blood, or other history of significant bleeding (eg, pulmonaryhemorrhage) within 12 weeks before C1D1.

• Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic orradiated lesions allowed).

• Lesions invading major blood vessel including, but not limited to, inferior venacava, pulmonary artery, or aorta.

• Note: Subjects with intravascular tumor extension (eg, tumor thrombus in renalvein or inferior V. cava) may be eligible following PI 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 followingcriteria: (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 bylocal regulation.

• Note: To be eligible, participants taking CYP inhibitors (eg, zidovudine,ritonavir, cobicistat, didanosine) or CYP3 inducers (efavirenz) mustchange to a different regimen not including these drugs 7 days prior toinitiation of study treatment. Anti-retroviral therapies (ART) must havebeen received for at least 4 weeks prior to the first dose.

• Note: CD4+ T cell counts, and viral load are monitored per standard ofcare by the local health care provider.

• Serious non-healing wound/ulcer/bone fracture.

• Note: non-healing wounds or ulcers are permitted if due totumor-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 (as defined in Appendix G; eg, GI surgery, removal or biopsy of brainmetastasis) within 8 weeks prior to C1D1. Prior laparoscopic surgeries (egnephrectomy) within 4 weeks prior to C1D1. Minor surgery (eg, simple excision, toothextraction) within 5 days before C1D1. Complete wound healing from major or minorsurgery must have occurred at least prior to C1D1.

• Note: Fresh tumor biopsies should be performed at least 5 days before the firstdose of study treatment. Subjects with clinically relevant ongoingcomplications from prior surgical procedures, including biopsies, are noteligible.

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms within 2weeks per electrocardiogram (ECG) before C1D1.

• Note: Triplicate ECG evaluations will be performed and the average of these 3consecutive results for QTcF will be used to determine eligibility.

• History of psychiatric illness likely to interfere with ability to comply withprotocol requirements or give informed consent.

• Inability to swallow tablets or ingest a suspension either orally or by anasogastric (NG) or gastrostomy (PEG) tube.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negativeserum or urine pregnancy test within 7 days of study entry.

• Other conditions, which in the opinion of the Investigator, would compromise thesafety of the patient or the patient's ability to complete the study.