| Eligibility |
Inclusion Criteria:
1. Patients with unresectable, progressive, histologically well-differentiated
neuroendocrine tumors of the fore-, mid-, or hindgut, including pancreas, or those
with an unknown primary with target lesions overexpressing somatostatin receptors
(Krenning 2, 3 or 4) on a SSTR PET.
2. Patients must have previously received one or more lines of systemic therapy including
somatostatin analogue therapy.
3. Prior PRRT therapy is permitted up to a maximum of 4 standard doses. Enrollment of
R-PRRT patients is permitted after initially 3 PRRT-naïve patients have been enrolled
on protocol and if the minimum progression free survival (PFS) with initial PRRT
therapy was = 18 months from day 1, cycle 1 of PRRT to progression.
4. ECOG 0-2.
5. Recovery to baseline or = Grade 1 (CTCAE v5.0) from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy.
6. Minimum 18 years or older.
7. Adequate organ and marrow function, based upon meeting all of 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). ALP = 5 x ULN with
documented bone metastases.
6. Total bilirubin = 1.5 x ULN (for patients 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 = 2.0 x ULN or estimated creatinine clearance = 30 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
8. Capable of understanding and complying with the protocol requirements and must have
signed the informed consent document.
9. Sexually active fertile participants and their partners must agree to use medically
accepted methods of contraception (e.g., barrier methods, including male condom,
female condom, or diaphragm with spermicidal gel) during the course of the study and
for 4 months after the last dose of study treatment.
10. Female participants of childbearing potential must not be pregnant at screening.
Female participants 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 therapy with cabozantinib.
2. Tumors with poorly differentiated or small cell histology.
3. Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks before first dose of study treatment.
4. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
(including investigational) within 4 weeks before first dose of study treatment.
5. 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. Participants with
clinically relevant ongoing complications from prior radiation therapy are not
eligible.
6. 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). Participants must have complete wound healing from major surgery or minor
surgery before first dose of study treatment. Eligible participants must be
neurologically asymptomatic and without corticosteroid treatment at the time of first
dose of study treatment.
7. 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.
8. The participant has uncontrolled, significant intercurrent or recent illness
including, but not limited to, the following conditions:
a. Cardiovascular disorders: i. Congestive heart failure New York Heart Association
Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
iii. 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. Participants with a diagnosis of incidental, subsegmental PE or 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 participant has evidence of tumor invading into the GI tract, active peptic
ulcer disease, inflammatory bowel disease (e.g., Crohn's disease), active
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.
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. 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).
12. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain
metastasis) within 2 weeks before first dose of study treatment. Minor surgeries
within 10 days before first dose of study treatment. Participants must have complete
wound healing from major surgery or minor surgery before first dose of study
treatment. Participants with clinically relevant ongoing complications from prior
surgery are not eligible.
13. 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.
14. Pregnant or lactating females.
15. Inability to swallow tablets.
16. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
17. 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.
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