Zanzalintinib Combined With Eribulin in Advanced Liposarcoma and Leiomyosarcoma

Inclusion Criteria:

• Pathologically proven diagnosis of unresectable or metastatic leiomyosarcoma oradipocytic sarcoma.

• Progressed on at least 1 line of prior therapy and have received no more than 4lines of prior therapy.

• Measurable disease per RECIST 1.1.

• At least 18 years of age.

• ECOG performance status ≤ 1

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

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

• Platelets ≥ 100 K/cumm without transfusion within 2 weeks of collection

• Hemoglobin ≥ 9.0 g/dL without transfusion within 2 weeks of collection

• INR ≤ 1.5 x ULN and aPTT ≤ 1.2 x ULN; for subjects on Factor Xa inhibitors,this criterion does not apply.

• Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease, ≤ 3.0 xIULN)

• AST(SGOT)/ALT(SGPT)/alkaline phosphatase (ALP) ≤ 3.0 x IULN (for subjects withdocumented bone metastasis, ALP ≤ 5.0 x IULN)

• Serum albumin ≥ 2.8 g/dL

• Serum creatine ≤ 1.5 x IULN or calculated creatinine clearance ≥ 40 mL/min byCockcroft-Gault

• UPCR ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine

• Recovery to baseline or ≤ grade 1 from AEs, including immune-related AEs related toany prior treatments, unless AEs are clinically nonsignificant and/or stable onsupportive therapy (e.g., physiological replacement of corticosteroid). Low-grade orcontrolled toxicities such as alopecia, ≤ grade 2 hypomagnesemia, ≤ grade 2neuropathy are permitted.

• The effects of zanzalintinib on the developing human fetus are unknown. For thisreason, women of childbearing potential and men must agree to use adequatecontraception prior to study entry, for the duration of study participation, and for 186 days after last dose of zanzalintinib (for women) or 96 days after last dose ofzanzalintinib (for men). Should a woman become pregnant or suspect she is pregnantwhile participating in this study or should a man suspect he has fathered a child,s/he must inform her treating physician immediately.

• 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:

• Pure well-differentiated liposarcoma or low grade leiomyosarcoma.

• Prior or concurrent malignancy whose natural history has the potential to interferewith the safety or efficacy assessment of the investigational regimen. Patients withprior or concurrent malignancy that does NOT meet that definition are eligible forthis trial.

• Prior treatment with zanzalintinib.

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

• 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 before first dose of studytreatment; any other radiation therapy within 4 weeks before first dose of studytreatment. Systemic treatment with radionuclides within 6 weeks before first dose ofstudy treatment. Subjects with clinically relevant ongoing complications from priorradiation therapy are not eligible.

• Currently receiving any other investigational agents.

• Patients with untreated brain metastases. Patients with treated brain metastases areallowed if post-treatment brain-imaging after CNS-directed therapy shows no evidenceof progression and disease is stable for at least 4 weeks before first dose of studytreatment.

• Note: eligible subjects must be neurologically asymptomatic and withoutcorticosteroid treatment at the time of enrollment.

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

• A history of allergic reactions attributed to compounds of similar chemical orbiologic composition to zanzalintinib or eribulin or other agents used in the study.

• Concomitant anticoagulation with warfarin or other vitamin-K antagonists, directthrombin inhibitors, or antiplatelet agents (e.g. clopidogrel). Allowedanticoagulants 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 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 firstdose of study treatment without clinically significant hemorrhagiccomplications from the anticoagulation regimen.

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

• Any complementary medications (e.g. herbal supplements or traditional Chinesemedicines) to treat the disease under study within 2 weeks before first dose ofstudy treatment.

• Uncontrolled, significant intercurrent or recent illness including, but not limitedto:

• Unstable or deteriorating cardiovascular disorders:

• Congestive heart failure NYHA Class 3 or 4, or Class 2 or higher unstableangina pectoris, new-onset angina, serious cardiac arrhythmias (e.g.ventricular flutter, ventricular fibrillation, Torsades de pointes).

• Uncontrolled hypertension defined as sustained blood pressure > 140 mmHgsystolic or > 90 mmHg diastolic despite optimal antihypertensivetreatment.

• Stroke (including transient ischemic attack), myocardial infarction, orother clinically significant arterial thrombotic and/or ischemic eventwithin 6 months before first dose of study treatment.

• Pulmonary embolism or deep vein thrombosis or prior clinically significantvenous events within 3 months before first dose of study treatment.

• 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 first dose of studytreatment without clinically significant hemorrhagic complicationsfrom the anticoagulation regimen.

• 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 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: complete healing of an intra-abdominal abscess must beconfirmed 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 (2.5mL) of red blood, or other history of significant bleeding (e.g. 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.

• Note: subjects with intravascular tumor extension (e.g. tumor thrombus in renalvein on inferior vena 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, antimycotics,antivirals) are allowed.

• Known infection with acute or chronic hepatitis B or C, known HIV orAIDS-related illness except for subjects meeting all of the following criteria:

• On stable anti-retroviral therapy

• CD4+ T cell count ≥ 200/μL

• Undetectable viral load.

• Note: HIV testing will be performed at screening if and as requiredby local regulation.

• Note: to be eligible, participants taking strong or moderate CYPinhibitors (e.g. zidovudine, ritonavir, cobicistat, didanosine) orstrong or moderate CYP3 inducers (efavirenz) must change to adifferent regimen not including these drugs 7 days prior toinitiation of study treatment. Anti-retroviral therapies 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 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 (e.g. GI surgery, removal or biopsy of brain metastasis) within 8weeks prior to first dose of study treatment. Prior laparoscopic surgeries (e.g.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 studytreatment. Complete wound healing from major or minor surgery must have occurred atleast prior to first dose of study treatment.

• 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 14days per ECG before first dose of study treatment.

• 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.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negativepregnancy test within 14 days of study entry.

• Inability to swallow tablets or ingest a suspension either orally or by a NG or PEGtube.

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