Inclusion Criteria:
1. Pathologically confirmed G1 or G2 NET of GEP origin with locally advanced or
metastatic stage who failed to one line or more than one line of small molecular
kinase inhibitor (mTOR inhibitor or other targeted kinase inhibitor) or W-D G3 NET of
GEP origin with locally advanced or metastatic stage who failed to one line or more
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 prior
treatments, unless AE(s) are clinically non-significant and/or stable on supportive
therapy.
4. Age≥ 20 years old and ECOG Performance Status ≤ 1.
5. Adequate organ and marrow function, based upon meeting all the following laboratory
criteria within 14 days before first dose of study treatment:
1. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony- stimulating
factor support.
2. White blood cell count ≥ 2500/µL.
3. Platelets ≥ 100,000/µL without transfusion.
4. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP) ≤ 3 x upper limit of normal (ULN). If there is liver
metastasis, AST, ALT ≤ 5 x ULN. ALP ≤ 5 x ULN with documented bone metastases.
6. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN).
7. Serum albumin ≥ 2.8 g/dl. 8. (PT)/INR or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN. 9. 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-h urine
protein ≤ 1 g. 6. At least one measurable lesion according to RECIST 1.1 over non-locally treated site,
such as RT, TAE (TACE), or RFA.
7. Life expectancy greater than 12 weeks.
8. Capable of understanding and complying with the protocol requirements and must have
signed informed consent document.
9. Female subjects of childbearing potential (i.e. less than or equal to 2 years
post-menopause and not surgically sterile) and their partners must agree to use highly
effective methods of contraception (that alone or in combination result in a failure
rate of less than 1% per year when used consistently and correctly during the 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 a
barrier method;
- intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) plus a
barrier method;
- bilateral tubal occlusion (females);
- vasectomized partner (males).
10. Female subjects of childbearing potential must not be pregnant at screening. Female
subjects are considered to be of childbearing potential unless one of the following
criteria are met: documented permanent sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) 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 stimulating (FSH) level > 40 mIU/mL to confirm menopause). Note:
Documentation may include review of medical records, medical examinations, 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 investigational
kinase 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) or
systemic chemotherapy within 4 weeks before first dose of study treatment.
4. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation
therapy within 4 weeks before first dose of study treatment. Systemic treatment with
radionuclides within 6 weeks before first dose of study treatment. Subjects with
clinically relevant ongoing complications from prior radiation therapy are not
eligible.
5. Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to
first dose of study treatment after major surgery (e.g., removal or biopsy of brain
metastasis). Subjects must have complete wound healing from major surgery or minor
surgery before first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of first dose of study
treatment.
6. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH).
2. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
are on a stable dose of the anticoagulant for at least 1 week before first dose
of study treatment without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor.
7. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
a. Cardiovascular disorders:
1. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina
pectoris, serious cardiac arrhythmias.
2. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
3. 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.
1. Subjects with a diagnosis of incidental, subsegmental PE or deep vein thrombosis
(DVT) within 6 months are allowed if stable, asymptomatic, and treated with a
stable dose of permitted anticoagulation (see exclusion criterion #6) for at
least 1 week before first dose of study treatment.
2. Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation:
i. The subject has evidence of tumor invading the GI tract, active peptic ulcer
disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute
obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.
ii. Abdominal fistula, GI perforation, bowel obstruction, or intra- abdominal abscess
within 6 months before first dose of study treatment.
iii. Note: Complete healing of an intra-abdominal abscess must be confirmed before
first dose of study treatment.
8. Major surgery within 4 weeks prior to study enrolment. Complete wound healing within 2
weeks before treatment.
9. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (e.g., pulmonary
hemorrhage) within 12 weeks before first dose of study treatment.
10. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation.
11. Lesions invading or encasing any major blood vessels.
12. Other clinically significant disorders that would preclude safe study participation.
1. Serious non-healing wound/ulcer/bone fracture.
2. Uncompensated/symptomatic hypothyroidism.
3. Moderate to severe hepatic impairment (Child-Pugh B or C).
13. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain
metastasis) within 4 weeks before first dose of study treatment. Minor surgeries
within 2 weeks before first dose of study treatment. Subjects must have complete wound
healing from major surgery or minor surgery before first dose of study treatment.
Subjects with clinically relevant ongoing complications from prior surgery are not
eligible.
14. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment [add
reference for Fridericia formula].
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional
ECGs at intervals of approximately 3 min must be performed within 30 min after the
initial ECG, and the average of these three consecutive results for QTcF will be used
to determine eligibility.
15. Pregnant or lactating females.
16. Inability to swallow tablets.
17. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
18. Any other active malignancy at time of first dose of study treatment or diagnosis of
another malignancy within 3 years prior to first dose of study treatment that requires
active treatment, except for locally curable cancers that have been apparently cured,
such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma
in situ of the prostate, cervix, or breast, or stage 0-I colon or breast cancer
treated by surgery only and without evidence of relapsed tumor.
19. Mental status is not fit for clinical trial
