Zanzalintinib in Combination With Paclitaxel in Recurrent High Grade Uterine Cancer

Inclusion Criteria:

• Diagnosis of recurrent, FIGO grade 3 endometrioid, serous, or mixed high gradeuterine or endometrial cancer or uterine carcinosarcoma. Patients must haveexperienced either prior progression on a platinum-based therapy or intolerance toplatinum. Patients with dMMR or MSI-H tumors or targetable HER2 alterations arerequired to have received prior therapy with appropriate targeted agents.

• 1-2 prior lines of anti-cancer therapy are allowed.

• Subjects who have received prior treatment with trastuzumab, pembrolizumab, ordostarlimab can enroll in the study. Use of these agents together or as maintenancetherapy is considered 1 regimen.

• 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)

• Patients must have disease that cannot be managed by local therapy targeted at thetumor site (i.e. surgery, radiation therapy).

• Measurable disease by RECIST 1.1.

• At least 18 years of age.

• ECOG performance status ≤ 2.

• Adequate bone marrow and organ function within 14 days prior to first dose of studytreatment, as defined below:

• Absolute neutrophil count ≥ 1.5 K/cumm without granulocyte colony-stimulatingfactor support within 2 weeks of screening laboratory sample collection.

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

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

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

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkalinephosphatase (ALP) ≤ 3 x ULN. For subjects with documented bone metastasis ALP ≤ 5 x ULN. Serum creatinine < 1.5 x ULN OR calculated or measured creatinineclearance ≥ 40 mL/min (using Cockcroft-Gault equation)

• INR ≤ 1.5 x IULN

• aPTT ≤ 1.2 x IULN

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

• Female subjects of child-bearing 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, orbilateral oophorectomy) or documented postmenopausal status (defined as 12 months ofamenorrhea in a woman > 45 years-of-age in the absence of other biological orphysiological causes. In addition, females < 55 years-of-age must have a serumfollicle stimulating hormone [FSH] level > 40 mIU/mL to confirm menopause). Note:Documentation may include review of medical records, medical examination, or medicalhistory interview by study site staff. Should a patient become pregnant or suspectpregnancy while participating in this study, the treating physician must be informedimmediately.

• The effects of zanzalintinib on the developing human fetus are unknown. For thisreason and because chemotherapeutic agents are known to be teratogenic, patients ofchild-bearing potential must agree to use adequate contraception (hormonal orbarrier method of birth control, abstinence) prior to study entry and through 186days after last dose of zanzalintinib or paclitaxel for women of child-bearingpotential (WOCBP). An additional contraceptive method, such as a barrier method (eg,condom), is required. In addition, women must agree not to donate eggs (ova, oocyte)for the purpose of reproduction during these same periods.

• 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:

• Any prior treatment with zanzalintinib

• A history of other malignancy with the exception of malignancies for which alltreatment was completed at least 2 years before registration and the patient has noevidence of disease.

• Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 2 weeks before first dose of study treatment, or any priortreatment with any tyrosine kinase inhibitor (TKI) or any prior treatment withbevacizumab.

• Receipt of any other (non-study) cytotoxic chemotherapy, radiation, targetedtreatment, or immunotherapy (including investigational) within 4 weeks prior ofstart of study treatment.

• Receipt of any other investigational agents or has received an investigational agentwithin 4 weeks of start of study treatment.

• 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.

• 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 neurologicallyasymptomatic and without corticosteroid treatment at the time of enrollment. Note:Base of skull lesions without definitive evidence of dural or brain parenchymalinvolvement are allowed.

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

• Allowed anticoagulants are the following:

• Prophylactic use of low-dose aspirin for cardio-protection (per localapplicable guidelines) and low-dose low molecular weight heparins (LMWH).

• Therapeutic doses of LMWH or anticoagulation with direct factor Xainhibitors rivaroxaban, edoxaban, or apixaban in subjects without knownbrain metastases who are on a stable dose of the anticoagulant for atleast 1 week before first dose of study treatment without clinicallysignificant 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 (eg, herbal supplements or traditional Chinesemedicines) to treat the disease under study within 2 weeks before first dose ofstudy 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 2or higher, unstable angina pectoris, new-onset angina, serious cardiacarrhythmias (eg, ventricular flutter, ventricular fibrillation, Torsadesde 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 arterial thrombotic and/or ischemic eventwithin 6 months before first dose of study treatment.

• Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinicallysignificant venous events within 3 months before first dose of studytreatment. Note: Subjects with a diagnosis of DVT within 6 months areallowed if asymptomatic and stable at screening and are on a stable doseof the anticoagulant for at least 1 week before first dose of studytreatment without clinically significant hemorrhagic complications fromthe anticoagulation regimen. Note: Subjects who don't require prioranticoagulation therapy may be eligible but must be discussed and approvedby the Principal Investigator.

• 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 before first dose unless cause of obstruction isdefinitively managed and subject is asymptomatic

• Abdominal fistula, gastrointestinal perforation, bowel obstruction, orintra-abdominal abscess within 6 months before first dose. Note: Completehealing of an intra-abdominal abscess must be confirmed before first doseof study treatment.

• Known gastric or esophageal varices

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

• If tolerating PO, small bowel obstruction may be considered withInvestigator and Sponsor approval

• 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 first dose of study treatment.

• 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.

• Other clinically significant disorders that would preclude safe study participation.

• Active infection requiring systemic treatment. Note: Prophylactic antimicrobialtreatments (antibiotics, antimycotic, antiviral) are allowed.

• Known infection with acute or chronic hepatitis B or C, known humanimmunodeficiency 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 performedat 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 notincluding these drugs 7 days prior to initiation of study treatment.Anti-retroviral therapies (ART) must have been received for at least 4 weeksprior to the first dose. Note: CD4+ T cell counts, and viral load are monitoredper standard of care by the local health care provider.

• Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds orulcers 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 within 8 weeks prior to first dose of study treatment. Priorlaparoscopic surgeries (ie nephrectomy) within 4 weeks prior to first dose of studytreatment. Minor surgery (eg, simple excision, tooth extraction) within 5 daysbefore first dose of study treatment. Complete wound healing from major or minorsurgery must have occurred at least prior to first dose of study treatment. Note:Subjects with clinically relevant ongoing complications from prior surgicalprocedures, including biopsies, are not eligible.

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms within 14days per electrocardiogram (ECG) before first dose of study treatment. Note:Triplicate ECG evaluations will be performed and the average of these 3 consecutiveresults 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.

• Pregnant or lactating females.

• Inability to swallow tablets

• Previously identified allergy or hypersensitivity to components of the studytreatment formulations.

• 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 first dose of study treatment,except for superficial skin cancers, or localized, low-grade tumors deemed cured andnot treated with systemic therapy.

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