neuroendocrine tumor
Conditions
Interventions
The dose RAD001 is 10 mg orally qd. continues. The dose will be reduced to 5 mg
qd in case of clinical relevant toxicities.
Patients randomized on placebo will take their medication likewise, ie 2
Sponsors
Novartis Pharma
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Pathologically confirmed, well-differentiated (G1 or G2), advanced (unresectable or metastatic), neuroendocrine tumor of GI or lung origin; 2. No history of and no active symptoms related to carcinoid syndrome; 3. In addition to treatment-naïve patients, patients previously treated with SSA, interferon (IFN), one prior line of chemotherapy, and/or PRRT are allowed into the study. Pretreated patients must have progressed on or after the last treatment. 4. Patients must have discontinued treatment prior to the day of randomization as follows: a. Prior SSA for at least 4 weeks b. Prior IFN for at least 4 weeks; c. Prior chemotherapy for at least 4 weeks; d. Prior PRRT for at least 6 months 5. Radiological documentation of disease progression within 3 months prior to randomization (i.e. 12 weeks from documentation of progression until randomization); 6. Measurable disease according to RECIST 1.0 (Appendix 1) determined by multiphasic Computer Tomography (CT) or Magnetic Resonance Imaging (MRI). Any lesions which have been subjected to percutaneous therapies, surgery, or radiotherapy should not be considered measurable, unless the lesion has clearly progressed since the procedure; 7. WHO performance status *1; 8. Adequate bone marrow function as shown by: ANC *1.5 x 109/L, Platelets *100 x 109/L, Hb >9 g/dL; 9. Adequate liver function as shown by: a. Total serum bilirubin *2.0 mg/dL, b. ALT and AST *2.5x ULN (*5x ULN in patients with liver metastases), c. INR *2; 10. Adequate renal function: serum creatinin *1.5x ULN; 11. Fasting serum cholesterol *300 mg/dL OR *7.75 mmol/L AND fasting triglycerides *2.5x ULN. 12. Adult male or female patients *18 years of age; 13. Written informed consent obtained prior to any screening procedures.
Exclusion criteria
Exclusion criteria: 1. Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, pancreatic islet cell carcinoma, insulinoma, glucagonoma, gastrinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma; 2. Patients with NET origins other than GI and lung; 3. Patients with history of or active symptoms of carcinoid syndrome; 4. More than one prior line of chemotherapy 5. Prior targeted therapy 6. Hepatic intra-arterial embolization within the last 6 months. Cryoablation or radiofrequency ablation of hepatic metastases within 2 months of randomization; 7. Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus); 8. Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus); 9. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus; 10. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary; 11. Patients who have any severe and/or uncontrolled medical conditions such as: a. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction *6 months prior to randomization, serious uncontrolled cardiac arrhythmia, b. active or uncontrolled severe infection, c. liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA), d. known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air), e. active, bleeding diathesis; 12. Chronic treatment with corticosteroids or other immunosuppressive agents; 13. Known history of HIV seropositivity; 14. Patients who have received live attenuated vaccines within 1 week of start of study drug and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines; 15. Patients who have a history of another primary malignancy, with the exceptions of non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for *3 years; 16. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study; 17. Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing; 18. Pregnant or nursing (lactating) women; 19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| PFS per modified RECIST 1.0 as defined in Appendix 1 and modified as per Section 7.2.1.1.1, assessed by central radiological assessment. PFS is defined as the time from randomization to the date of the first documented tumor progression or death from any cause, whichever comes first. PFS based on local radiology assessments will be used for supportive analysis of the primary endpoint. | — |
Secondary
| Measure | Time frame |
|---|---|
| OS is defined as the time from the date of randomization to date of death due to any cause. The assessment of safety will be based mainly on the frequency and type of treatment emergent adverse events and on the number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. vital signs) will be considered as appropriate. Time to definitive deterioration in FACT-G total score, where deterioration is defined as a decrease by at least 7 points compared to baseline ORR and DCR per modified RECIST 1.0 as defined in Appendix 1 and modified as per Section 7.2.1.1.1, according to central evaluation CgA and NSE levels Time to definitive deterioration in WHO Performance Status, where deterioration is defined as an increase of at least one category compared to baseline | — |
Countries
Netherlands
Outcome results
None listed