Cabozantinib and Lanreotide as Treatment for Gastroenteropancreatic Neuroendocrine Tumors

Inclusion Criteria:

1. Pathologically confirmed G1 or G2 NET of GEP origin with locally advanced ormetastatic stage who failed to one line or more than one line of small molecularkinase inhibitor (mTOR inhibitor or other targeted kinase inhibitor) or W-D G3 NETof GEP origin with locally advanced or metastatic stage who failed to one line ormore than one line of chemotherapy or small molecule kinase inhibitor.

2. Radiologic progression within 12 months of entry

3. Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any priortreatments, unless AE(s) are clinically non-significant and/or stable on supportivetherapy.

4. Age≥ 20 years old and ECOG Performance Status ≤ 1.

5. Adequate organ and marrow function, based upon meeting all the following laboratorycriteria within 14 days before first dose of study treatment:

6. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating factor support.

7. White blood cell count ≥ 2500/µL.

8. Platelets ≥ 100,000/µL without transfusion.

9. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).

10. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkalinephosphatase (ALP) ≤ 3 x upper limit of normal (ULN). If there is livermetastasis, AST, ALT ≤ 5 x ULN. ALP ≤ 5 x ULN with documented bone metastases.

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

12. Serum albumin ≥ 2.8 g/dl

13. (PT)/INR or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN

14. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation:Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72) Females: [(140

• age) x weight (kg)/(serum creatinine [mg/dL] ×72)] × 0.85

10. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-hurine protein ≤ 1 g

11. At least one measurable lesion according to RECIST 1.1 over non-locally treatedsite, such as RT, TAE (TACE), or RFA.

12. Life expectancy greater than 12 weeks.

13. Capable of understanding and complying with the protocol requirements and must havesigned informed consent document.

14. Female subjects of childbearing potential (i.e. less than or equal to 2 yearspost-menopause and not surgically sterile) and their partners must agree to usehighly effective methods of contraception (that alone or in combination result in afailure rate of less than 1% per year when used consistently and correctly duringthe course of the study and for 4 months after the last dose of study treatment.

• Effective methods of birth control include:

• Hormonal contraception (oral, injectable, implantable, transdermal) plus abarrier method;

• intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) plus abarrier method;

• bilateral tubal occlusion (females);

• vasectomized partner (males).

10. Female subjects of childbearing potential must not be pregnant at screening. Femalesubjects are considered to be of childbearing potential unless one of the followingcriteria are met: documented permanent sterilization (hysterectomy, bilateralsalpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence ofother biological or physiological causes. In addition, females < 55 years-of-agemust have a serum follicle stimulating (FSH) level > 40 mIU/mL to confirmmenopause). Note: Documentation may include review of medical records, medicalexaminations, or medical history interview by study site.

Exclusion Criteria:

1. Prior use of cabozantinib. (prior use of lanreotide is acceptable)

2. Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer,before first dose of study treatment.

3. Receipt of any type of anticancer antibody (including investigational antibody) orsystemic chemotherapy within 4 weeks before first dose of study treatment.

4. Receipt of radiation therapy for bone metastasis within 2 weeks or any otherradiation therapy within 4 weeks before first dose of study treatment. Systemictreatment with radionuclides within 6 weeks before first dose of study treatment.Subjects with clinically relevant ongoing complications from prior radiation therapyare not eligible.

5. Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksprior to first dose of study treatment after radiotherapy or at least 4 weeks priorto first dose of study treatment after major surgery (e.g., removal or biopsy ofbrain metastasis). Subjects must have complete wound healing from major surgery orminor surgery before first dose of study treatment. Eligible subjects must beneurologically asymptomatic and without corticosteroid treatment at the time offirst dose of study treatment.

6. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombininhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or plateletinhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

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

8. 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 or the tumor.

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

10. Congestive heart failure New York Heart Association Class 3 or 4, unstableangina pectoris, serious cardiac arrhythmias.

11. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hgsystolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.

12. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis,pulmonary embolism) within 6 months before first dose of study treatment.

13. Subjects with a diagnosis of incidental, subsegmental PE or deep veinthrombosis (DVT) within 6 months are allowed if stable, asymptomatic, andtreated with a stable dose of permitted anticoagulation (see exclusioncriterion #6) for at least 1 week before first dose of study treatment.

14. Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation: i. The subject has evidence of tumor invading the GI tract, active peptic ulcerdisease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acuteobstruction of the pancreatic duct or common bile duct, or gastric outletobstruction. ii. Abdominal fistula, GI perforation, bowel obstruction, or intra- abdominalabscess within 6 months before first dose of study treatment. iii. Note: Complete healing of an intra-abdominal abscess must be confirmed beforefirst dose of study treatment.

15. Major surgery within 4 weeks prior to study enrolment. Complete wound healing within 2 weeks before treatment.

16. 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.

17. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation.

18. Lesions invading or encasing any major blood vessels.

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

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

21. Uncompensated/symptomatic hypothyroidism.

22. Moderate to severe hepatic impairment (Child-Pugh B or C).

23. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy ofbrain metastasis) within 4 weeks before first dose of study treatment. Minorsurgeries within 2 weeks before first dose of study treatment. Subjects must havecomplete wound healing from major surgery or minor surgery before first dose ofstudy treatment. Subjects with clinically relevant ongoing complications from priorsurgery are not eligible.

24. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 14 days before first dose of study treatment [addreference for Fridericia formula]. Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additionalECGs at intervals of approximately 3 min must be performed within 30 min after theinitial ECG, and the average of these three consecutive results for QTcF will beused to determine eligibility.

25. Pregnant or lactating females.

26. Inability to swallow tablets.

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

28. Any other active malignancy at time of first dose of study treatment or diagnosis ofanother malignancy within 3 years prior to first dose of study treatment thatrequires active treatment, except for locally curable cancers that have beenapparently cured, such as basal or squamous cell skin cancer, superficial bladdercancer, or carcinoma in situ of the prostate, cervix, or breast, or stage 0-I colonor breast cancer treated by surgery only and without evidence of relapsed tumor.

29. Mental status is not fit for clinical trial