Phase II Randomized Double-blind Study of Sandostatin LAR in Combination With Axitinib Versus Placebo in Patients With Progressive Advanced Well-differentiated Neuroendocrine Carcinomas of Non-pancreatic Origin
1. Histologically confirmed well differentiated neuroendocrine carcinoma of
3. Metastatic or locally advanced disease not amenable to treatment with curative intent
4. Progressive disease documented in the prior 12 months (RECIST criteria)
5. Measurable disease
6. Prior treatment with somatostatin analogues permitted
7. Prior interferon therapy allowed
8. One prior systemic chemotherapy allowed
9. No prior VEGF- or VEGFR-targeted therapy allowed
10. Adequate organ function as defined by the following criteria:
- absolute neutrophil count (ANC) ≥1500 cells/mm3;
- platelets ≥75,000 cells/mm3;
- hemoglobin ≥9.0 g/dL;
- AST and ALT ≤2.5 x upper limit of normal (ULN), unless there are liver
metastases in which case AST and ALT ≤5.0 x ULN;
- total bilirubin ≤1.5 x ULN;
- serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min;
- urinary protein <2+ by urine dipstick. If dipstick is ≥2+ then a 24-hour urine
collection can be done and the patient may enter only if urinary protein is <2 g
per 24 hours.
11. Male or female, age ≥18 years.
12. ECOG performance status of 0-2.
13. Life expectancy of ≥12 weeks.
14. At least 4 weeks since the end of prior systemic treatment, radiotherapy, or surgical
procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 3.0
grade ≤1 or back to baseline except for alopecia or hypothyroidism.
15. No evidence of preexisting uncontrolled hypertension as documented by 2 baseline
blood pressure readings taken at least 1 hour apart. The baseline systolic blood
pressure readings must be ≤150 mm Hg, and the baseline diastolic blood pressure
readings must be ≤90 mm Hg. Patients whose hypertension is controlled by
antihypertensive therapies are eligible.
16. Women of childbearing potential must have a negative serum or urine pregnancy test
within 3 days prior to treatment.
17. Signed and dated informed consent document indicating that the patient (or legally
acceptable representative) has been informed of all pertinent aspects of the trial
prior to enrollment.
18. Willingness and ability to comply with scheduled visits, treatment plans and study
1. The following endocrine tumor types may not be included: paraganglioma, adrenal,
thyroid, parathyroid or pituitary endocrine tumors.
2. Major surgery in <4 weeks or radiation therapy <2 weeks prior to starting the study
treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted,
provided there is at least one measurable lesion that has not been irradiated.
3. Gastrointestinal abnormalities including:
- inability to take oral medication;
- requirement for intravenous alimentation;
- prior surgical procedures affecting absorption including total gastric
- treatment for active peptic ulcer disease in the past 6 months;
- active gastrointestinal bleeding, unrelated to cancer, as evidenced by
hematemesis, hematochezia or melena in the past 3 months without evidence of
resolution documented by endoscopy or colonoscopy;
- malabsorption syndromes.
4. Current use or anticipated need for treatment with drugs that are known potent CYP3A4
inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir,
nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine).
5. Current use or anticipated need for treatment with drugs that are known CYP3A4 or
CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole,
phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin,
and St.John's wort).
6. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose
anticoagulants for maintenance of patency of central venous access devise or
prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular
weight heparin is allowed.
7. Active seizure disorder or evidence of brain metastases, spinal cord compression, or
8. A serious uncontrolled medical disorder or active infection that would impair their
ability to receive study treatment.
9. Any of the following within the 12 months prior to study drug administration:
myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft,
symptomatic congestive heart failure, cerebrovascular accident or transient ischemic
attack and 6 months for deep vein thrombosis or pulmonary embolism.
10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
11. History of a malignancy (other than renal cell cancer) except those treated with
curative intent for skin cancer (other than melanoma), in situ breast or in situ
cervical cancer, or those treated with curative intent for any other cancer with no
evidence of disease for 5 years.
12. Dementia or significantly altered mental status that would prohibit the understanding
or rendering of informed consent and compliance with the requirements of this
13. Female patients who are pregnant or lactating, or men and women of reproductive
potential not willing or not able to employ an effective method of birth
control/contraception to prevent pregnancy during treatment and for 6 months after
discontinuing study treatment The definition of effective contraception should be in
agreement with local regulation and based on the judgment of the principal
investigator or a designated associate.
14. Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and
in the judgment of the investigator would make the patient inappropriate for entry
into this study.