SUNLAND

randomized, double blind trial

Primary

To evaluate the efficacy of the combination of sunitinib malate with lanreotide acetate and of placebo with lanreotide acetate regarding progression-free-survival (PFS) as assessed by the investigator, in patients suffering from progressive, advanced/metastatic midgut carcinoid tumors.

Secondary

• To evaluate overall survival (OS) in sunitinib- and placebo- treated patients.
• To evaluate duration of response (DR) in sunitinib- and placebo- treated patients achieving a response.
• To evaluate objective response (OR) in sunitinib- and placebo- treated patients.
• To assess time to tumor response (TTR) in sunitinib- and placebo- treated patients.
• To assess Health related Quality of life (EORTC QLQ C-30).
• To evaluate the symptomatic effects of sunitinib in subjects with carcinoid syndrome.
• To evaluate the best biological response by assessing serum hromogranin A and urine 5HIAA.
• To evaluate plasma levels of VEGF-A, VEGF-C, sKIT, and sVEGFR2 by Elisa assay.
• To assess the safety and tolerability of sunitinib in the study population.

1. Patients with midgut well-differentiated Grade 1-2 endocrine tumor (ENETS guidelines). Pathological confirmation might have been obtained from primary tumor (surgical resection), or lymph node/liver metastases. Histologically documented endocrine liver metastases with unknown primary are eligible if the patient has history of carcinoid syndrome with elevated serum chromogranin A and urinary 5HIAA levels.
2. Local, locally advanced or metastatic disease documented as progressive by RECIST v1.1. on CT-scan or MRI 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 v1.1 criteria. Octreoscan results may be used to document progressive disease at baseline, but not for RECIST v1.1 determination during the study. Locally advanced liver metastasis, corresponding to >50% liver involvement as documented on baseline CT-scan or MRI by the local investigator, are eligible regardless prior progression.
3. 5HIAA levels >1.5ULN as measured in each individual centre.
4. Disease that is not amenable to surgery with curative intent.
5. Presence of at least one measurable target lesion for further evaluation according to RECIST v1.1 (contrast enhancing lesion with the largest diameter ≥20 mm, based on conventional CT or MRI scan (or ≥10 mm with spiral CT scan) done within 4 weeks before the start of treatment).
6. Adequate organ function as defined by the following:
   • Serum aspartate aminotransferase (AST; serum glutamate-oxalate transferase [SGOT]) and serum alanine aminotransferase (ALT; serum glutamate-pyruvate transferase [SGPT]) 2.5 x upper limit of normal (ULN). If liver function abnormalities are due to underlying malignancy, then AST and ALT may be 5 x ULN
   • Total serum bilirubin 1.5 x ULN
   • Prothrombin time (PT) and partial thromboplastin time (PTT) 1.5 x ULN
   • Serum albumin 3.0 g/dL
   • Absolute neutrophil count (ANC) 1500/L
   • Platelets 100,000/L
   • Hemoglobin 9.0 g/dL
   • Serum creatinine 1.5 x ULN
   • kaliemia ≥ lower limit and ≤ upper limit of normal of the local laboratory
7. ECOG Performance status 0 or 1.
8. Life expectancy  3 months.
9. Age > 18 years.
10. Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) within 7 days prior to enrollment. Breast feeding is not allowed. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate.
11. Able to swallow oral compound.
12. Signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial prior to enrolment.
13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.
14. Registration in a national health care system (CMU included).

1. Patients with undifferentiated, poorly differentiated gastrointestinal neuroendocrine tumors, pancreatic neuroendocrine tumors, bronchial carcinoid tumors (WHO 2010 classification).
2. Patients with carcinoid tumors with the presence of an obstructive intestinal tumor.
3. Patients with uncontrolled cardiac complication as part of their carcinoid syndrome.
4. Current treatment with any chemotherapy, chemoembolization therapy, immunotherapy, or investigational anticancer agent
5. Current treatment with dose ≥ 120 mg per month of lanreotide
6. Prior treatment with any tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors (such as bevacizumab, sorafenib, or sunitinib). Prior treatment with non-VEGF-targeted angiogenic inhibitors such as everolimus or temsirolimus is permitted.
7. Patients who stopped everolimus treatment was less than 4 weeks prior to randomization.
8. Patients with concomitant treatment with interferon.
9. Patients previously treated with chemotherapy, loco-regional therapy (e.g., chemoembolization) or interferon with last administration less than 6 weeks prior to randomization or with toxicity not resolved to ≤ grade 1 at randomization.
10. 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.
11. Treatment with potent CYP3A4 inhibitors and inducers within 7 and 12 days, respectively prior to study drug administration.
12. Concomitant treatment with therapeutic doses of anticoagulants (low dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).
13. Concomitant treatment with a drug having proarrhythmic potential (terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide and flecainide).
14. Unstable systemic diseases including uncontrolled hypertension (>150/100 mmHg despite optimal medical therapy) or active uncontrolled infections.
15. Current treatment on another clinical trial.
16. Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
17. Ongoing cardiac dysrhythmias of NCI CTC grade 2, atrial fibrillation of any grade, or prolongation of the QTc interval to >450 msec for males or >470 msec for females.
18. Symptomatic brain metastases, spinal cord compression, or new evidence of brain or leptomeningeal disease.
19. Left ventricular ejection fraction (LVEF) ≤50% as measured by either multigated acquisition (MUGA) scan or echocardiogram (ECHO).
20. Positive test for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.
21. Patients with complicated, untreated lithiasis of the bile ducts.
22. 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

For each patient, the participation will last approximately 14 months, i.e. a 3-week screening period, a treatment period until disease progression, then a 1-month follow-up period. Sunitinib will be administered orally from Day 1 at the starting dose of 37.5 mg daily in a continuous daily regimen. Lanreotide acetate will be supplied in strengths of 120mg designed for subcutaneous injection from day 1, then every 28 days.

Date of beginning of study: 3Q 2012 (First patient in). Last patient in 1Q2015 (2.5 year recruitment period in relatively rare malignancy). Date of end of study: 1Q 2016 (Last patient out).

Sponsor : GERCOR Study Coordinating Investigator : Prf. P. Hammel, Hôpital Beaujon, Clichy, France Coordinating Investigator in Belgium: Pr. E. Van Cutsem, UZ Leuven

BGDO, ENETS, RENATEN

1) UZ Leuven, Prof. E. Van Cutsem 2) UZ Antwerpen, Prof. M. Peeters 3) UCL St-Luc, Prof. I. Borbath 4) ULB Erasme, Prof. J-L. Van Laethem 5) UZ Gent, Prof. K. Geboes 6) Institut Jules Bordet, Dr; A. Hendilsz