Phase III Prospective Randomized Comparison of Depot Octreotide Plus Interferon Alpha Versus Depot Octreotide Plus Bevacizumab (NSC #704865) in Advanced, Poor Prognosis Carcinoid Patients

Inclusion Criteria:

- Diagnosis of unresectable metastatic or locally advanced, low- or intermediate-grade
neuroendocrine carcinoma, including the following subtypes:

- Carcinoid tumor, low-grade or well differentiated neuroendocrine carcinoma

- Atypical carcinoid tumor, intermediate-grade or moderately differentiated
neuroendocrine carcinoma

- High-risk disease as defined by at least one of the following:

- Progressive disease

- Refractory carcinoid syndrome while receiving octreotide acetate (i.e., defined
by > 2 flushing episodes/day or > 4 bowel movements/day)

- Atypical histology and more than 6 lesions

- Metastatic colorectal carcinoid tumor

- Patients with metastatic cecal or appendiceal carcinoid tumor are not
eligible unless they fit other mentioned high-risk features

- Metastatic gastric carcinoid tumor

- Measurable disease

- Patients with poorly differentiated neuroendocrine carcinoma, high-grade
neuroendocrine carcinoma, adenocarcinoid tumor, or goblet cell carcinoid tumor are
not eligible

- Osseous metastasis as only site of disease

- Medullary thyroid carcinoma or islet cell carcinoma

- History of primary brain tumor or metastatic cancer to the brain

- Zubrod performance status 0-2

- Platelet count > 100,000/mm³

- ANC > 1,500/mm³

- Hemoglobin > 8 g/dL

- Serum bilirubin < 1.5 times upper limit of normal (ULN)

- SGOT and SGPT ≤ 2.5 times ULN

- Serum creatinine < 1.5 mg/dL

- 24-hour urine protein < 1,000 mg if urine protein:creatinine ratio > 0.5

- PT and PTT ≤ 1.1 times ULN

- History of hypertension must be well controlled (i.e., blood pressure < 150/90 mm Hg)
on a stable regimen of antihypertensive therapy

- Not pregnant or nursing

- Fertile patients must use effective barrier method contraception during and for 6
months after completion of study treatment

- History or evidence of clinically significant peripheral vascular disease (e.g.,
non-healing peripheral ulcers or claudication)

- Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 28 days

- Bleeding diathesis or coagulopathy that results in spontaneous bleeding (in the
absence of trauma) requiring red blood cell transfusion within the past 5 years

- Serious (i.e., requiring active medical therapy with medication or medical device
under the supervision of a physician) non-healing wound, ulcer, or bone fracture

- Recent history (i.e., within the past 6 months) of any of the following arterial
thromboembolic events:

- Transient ischemic attack

- Cerebrovascular accident

- Unstable angina

- Myocardial infarction

- New York Heart Association class II or higher congestive heart failure

- Hemoglobinopathies (e.g., Thalassemia) or any other cause of hemolytic anemia

- Pregnant or nursing

- Any other prior malignancy within the past 5 years except for adequately treated
basal cell or squamous cell skin cancer, or other adequately treated in situ cancer

- Any immunologically mediated disease, including any of the following:

- Inflammatory bowel disease (Crohn disease, ulcerative colitis)

- Rheumatoid arthritis

- Idiopathic thrombocytopenia purpura

- Systemic lupus erythematosus

- Autoimmune hemolytic anemia

- Scleroderma

- Severe psoriasis

- Any serious intercurrent infections or nonmalignant medical illnesses that are
uncontrolled or whose control may be jeopardized by the complications of this
treatment

- Psychiatric disorders rendering patient incapable of complying with the requirements
of the protocol

- Recovered from all prior therapy

- At least 28 days since and no more than 1 prior regimen of cytotoxic chemotherapy

- At least 28 days since prior hepatic artery embolization provided there is residual
measurable disease

- Chemoembolization is considered as 1 prior chemotherapy regimen

- No prior interferon, bevacizumab, or any other therapy targeting VEGF or VEGF
receptors (e.g., SU11248, PTK/ZK, sorafenib tosylate, or pazopanib hydrochloride)

- Prior therapy targeting c-kit, abl, PDGFR, mTOR, and somatostatin receptors allowed

- At least 28 days since prior radiotherapy

- Target lesions must have shown disease progression if therapy included peptide
receptor radiotherapy

- At least 1 week since prior minor surgery

- At least 4 weeks since prior major surgery

- At least 21 days since prior octreotide acetate therapy

- Concurrent full-dose anticoagulation (warfarin or low molecular weight heparin)
allowed provided the following criteria are met:

- In-range INR (e.g., between 2 and 3) on a stable dose of oral anticoagulant or
on a stable dose of low molecular weight heparin

- No active bleeding or pathological condition that carries a high risk of
bleeding (e.g., varices)

- No concurrent interferon to control carcinoid syndrome for patients receiving
bevacizumab

- Other supportive care medication (e.g., short acting octreotide acetate) allowed

- No other concurrent chemotherapy, immunotherapy, radiotherapy, hepatic artery
embolization, hepatic artery chemoembolization, radiofrequency ablation, or other
tumor ablative procedure

- No other investigational or commercial agents