The incidence of new diagnosed patients with NET of the digestive tract including carcinoid and pancreatic islet cells tumors ranges from 2 to 10 per 100,000 in the western Countries (Kulke M, Mayer R. N Engl J Med 340:858-868, 1999). Despite of the low incidence, the prevalence of these tumors is high because of their relatively long survival estimated in 35% at 5 years for those patients with well or moderate differentiated tumors (Yao JC, et al. J Clin Oncol. 2008;26:3063-3072). In fact, digestive NETs are the second most prevalent tumors derived from the digestive tract after colorectal carcinoma.

NETs are characterized by abundant vasculature, moreover VEGFR and VEGFR are overexpressed in 60-84% of the carcinoids and pancreatic islet cells NETs (Zhang et al. Cancer 2007;109:1478-1486). Other pro-angiogenic factors like the platelet derived growth factor (PDGFR) have been also involved in NET progression and development (Chaudhry A, et al.Cancer Res 1992;52:1006-12).

Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, PDGFR and KIT with a dual activity both as an antiangiogenic and also and anti-tumoral agent (Kumar et al. Mol Cancer Ther2007;6:2012-2021, Hurwitz et al. Clin Cancer Res 2009;15:4220-4227). Pazopanib seems to have a better toxicity profile versus the other antiangiogenic tyrosine kinase inhibitors and has already shown activity in several tumor types like renal cell carcinoma (Sternberg et al. J Clin Oncol 2009;27:abst. 5021), soft tissue sarcomas (Sleijfer et al. J Clin Oncol 2009;27:3126-32), hepatocellular carcinoma (Yau et al. J Clin Oncol 2009;27:abst. 3561), colorectal cancer (Brady et al. J Clin Oncol 2009;27:abst.4133), and thyroid cancers (Bible et al. J Clin Oncol 2009;27:abst. 3521).

The Spanish Group for Research in Neuroendocrine Tumors (GETNE) group is an active Member inside of the GENET group and has a large tradition in clinical trials in NETs. The investigators hypothesize that pazopanib may have at least as good activity and better safety profile than other VEGFR inhibitors in progressive advanced or metastatic NET tumors derived from the digestive tract.

Inclusion Criteria:

1. Subjects must provide signed informed consent form prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow-up.

   Procedures conducted as part of the subject's clinical routine (e.g., blood count, imaging study) and obtained prior to signing the consent form might be used for screening or baseline purposes provided these procedures have been conducted as specified in the protocol.

2. Age ≥ 18 years.

3. Diagnosis of pancreatic islet cell tumors, well differentiated gastrointestinal NETs, pulmonary carcinoids and well differentiated thymic carcinoids. Locally-advanced or metastatic disease documented as progressive by CT scan, MRI, or Octreoscan at baseline and within 12 months prior to baseline. The previous scans will be used to classify the patient as having progressive disease at baseline according to RECIST criteria. Octreoscan results may be used to document progressive disease at baseline, but not for RECIST determination during the study.

4. ECOG performance status 0-1.

5. Disease not amenable to surgery, radiation or combined modality therapy with curative intent.

6. Presence of at least one dimensionally measurable target lesion for further evaluation according to RECIST 1.0 criteria (contrast enhancing lesion with the largest diameter > 1cm, based on CT or MRI scan done within 4 weeks before the start of treatment).

7. Patients could have received treatment with somatostatin analogs, chemotherapy, anti-VEGF, and anti-mTOR agents previously to the entrance into this study if the final toxicity was grade ≤ 1.

8. From patients who sign an informed consent form to donate biological samples: Tumor tissue must be provided for all available subjects at baseline and serum samples will be collected at baseline and at week 12 of treatment for biomarker analysis as defined at the biomarker section of this protocol.

9. Adequate organ system function as follows:

   9.1.Hematologic system:

   • Absolute neutrophil count (ANC) ≥ 1.5 X 10^9/L
   • Hemoglobin (1) ≥ 9 g/dL (5.6 mmol/L)
   • Platelets ≥ 100 X 10^9/L
   • Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.2 X upper limit of normal (ULN)
   • Partial thromboplastin time (PTT) ≤ 1.2 X ULN

   9.2.Hepatic system (2):

   • Total bilirubin ≤ 1.5 X ULN
   • AST and ALT ≤ 2.5 X ULN

   9.3.Renal system:

   • Serum creatinine ≤ 1.5 mg/dL (133 µmol/L),

   Or, if greater than 1.5 mg/dL:

   • Calculated creatinine clearance ≥ 50 mL/min

   (Note 1):"Subjects should not have had a transfusion within 7 days of screening assessment." (Note 2): "Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN are not permitted"

10. A female is eligible to enter and participate in this study if she is of:

    10.1.Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:

    • A hysterectomy
    • A bilateral oophorectomy (ovariectomy)
    • A bilateral tubal ligation
    • Is post-menopausal

    10.2.Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. GETNE acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow:

    • An intrauterine device with a documented failure rate of less than 1% per year.
    • Vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female.
    • Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product.
    • Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide).
    • Oral contraceptives
    • Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.

11. Life expectancy > 3 months.

12. Able to swallow oral compound.

13. Signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial prior to enrollment.

14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.

Exclusion Criteria:

1. Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri.

2. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 months prior to first dose of study drug. Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases.

3. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:

   3.1.Active peptic ulcer disease 3.2.Known intraluminal metastatic lesion/s with risk of bleeding 3.3.Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn's disease), or other gastrointestinal conditions with increased risk of perforation 3.4.History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.

4. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:

   4.1.Malabsorption syndrome 4.2.Major resection of the stomach or small bowel. 4.3.Active peptic ulcer disease 4.4.Known intraluminal metastatic lesion/s with risk of bleeding 4.5.Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn's disease), or other gastrointestinal conditions with increased risk of perforation 4.6.History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment.

5. Presence of uncontrolled infection.

6. Corrected QT interval (QTc) > 480 msecs using Bazett's formula.

7. History of any one or more of the following cardiovascular conditions within the past 6 months:

   7.1.Cardiac angioplasty or stenting 7.2.Myocardial infarction 7.3.Unstable angina 7.4.Coronary artery bypass graft surgery 7.5.Symptomatic peripheral vascular disease 7.6.Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)

8. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].

9. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

   Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.

10. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).

11. Evidence of active bleeding or bleeding diathesis.

12. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.

13. Hemoptysis in excess of 2.5ml within 8 weeks of first dose of study drug.

14. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.

15. Unable or unwilling to discontinue use of prohibited medications list in Concomitant Medication Section for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.

16. Treatment with any of the following anti-cancer therapies:

    • radiation therapy, surgery or tumor embolization within 28 days prior to the first dose of pazopanib, or
    • chemotherapy, immunotherapy, biological therapy, investigational therapy or hormonal therapy within 28 days prior to the first dose of pazopanib.

17. Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity, except alopecia.

4 years, 8 months

Small sample size, heterogeneous location and degree of differentiation of primary tumors, and lack of an appropriate control group. Additionally,response was evaluated by the investigator and not by an independent committee.