RAMSETE: RAD001 in Advanced and Metastatic Silent Neuro-endocrine Tumors in Europe

Study Overview
=================
Brief Summary
-----------------
To evaluate the preliminary efficacy and safety of RAD001 as monotherapy for first-line treatment of patients with metastatic papillary carcinoma of the kidney.

Official Title
-----------------
A Single Arm, Multicenter Single Stage Phase II Trial of RAD001 as Monotherapy in the Treatment of Metastatic Non Syndromic Neuro-endocrine Tumors

Conditions
-----------------
Advanced and Metastatic Silent Neuro-Endocrine Tumors, Carcinoma, Neuroendocrine, Non Functioning Neuroendocrine Tumors (NETs), Non Syndromic Neuroendocrine Tumors, Carcinoids, Non Functioning

Intervention / Treatment
-----------------
* Drug: Everolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: ≥ 18 years old Patients with advanced (unresectable or metastatic) biopsy proven non-syndromic neuro-endocrine carcinoma, low or intermediate grade Radiological documentation of disease progression within 12 months prior to study entry. If patients received anti-tumor therapy during the past 12 months, they must have radiological documentation of progressive disease (PD) while on or after receiving the therapy Patients may have received previous treatments (chemotherapy, biotherapy, peptide-receptor radionuclide therapy); an overall maximum of 3 systemic treatment is allowed Patients with at least one measurable lesion Patients with an ECOG (Eastern Cooperative Oncology Group) Performance Status 0-2 Adequate bone marrow function Adequate liver function Adequate renal function Adequate lipid profile Exclusion criteria: Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma Patients with carcinoid with hormone related symptoms (diarrhea ≥ 4 stools per day and/or flushes) Patients with Islet cell carcinomas or pancreatic NET Patients who received prior therapy with Vascular Endothelial Growth Factor (VEGF) pathway inhibitor within 4 weeks prior to study entry Patients who entered peptide receptor radionuclide therapy (PRRT) within 3 months prior to study entry Patients who received CT, biotherapy or radiotherapy within 4 weeks prior to study entry Patients who have previously received systemic (mammalian target of rapamycin) mTOR inhibitors Patients with a known hypersensitivity to everolimus or other rapamycins or to its excipients Patients with uncontrolled central nervous system (CNS) metastases Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent Patients with a known history of HIV seropositivity Patients with autoimmune hepatitis Patients with an active, bleeding diathesis Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study Patients who have a history of another primary malignancy and off treatment ≤ 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study treatment start Patients unwilling to or unable to comply with the protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus<br>Everolimus | Drug: Everolimus<br>* Everolimus 5 mg tablets were supplied in blister packs<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP) | Overall response rate (ORR) was based on RECIST central assessment and defined as the percentage of patients with best overall response (BOR) of a confirmed complete response (CR) or partial response (PR). The BOR was calculated on basis of the tumor of overall lesion response evaluated at each visit. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments obtained within 4 weeks after the criteria for response were first met. Assessments was based on RECIST criteria 1.0. Measurable disease lesions had to be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). PR required at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. CR required disappearance of all target and non-target lesions. | baseline up to approximately 12 months | 
| Percentage of Participants With Objective Response Rate at 12 Months - Per Protocol Set (PP) | Overall Response Rate (ORR) was calculated for total PP population based on central review as confirmatory, primary analysis as well as for ITT population as sensitivity analysis. It was presented with relative frequencies and the exact 2-sided 80% confidence limit (CI) computed using the Clopper-Pearson method). If the lower limit of the CI did not include p0=5%, the hypothesis that p ≤ 5% was rejected. The primary analysis was based on the PP Set | baseline up to approximately 12 months | 
| Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set | The best overall response (BOR) was calculated on basis of the tumor of overall lesion response evaluated at each visit. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed not less than 4 weeks after the criteria for response were first met. Assessments was based on RECIST criteria 1.0. Measurable disease lesions had to be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). PR required at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. CR required disappearance of all target and non-target lesions. | baseline up to approximately 12 months | 
| Percentage of Participants With Objective Response Rate at 12 Months ITT Set | Overall Response Rate (ORR) was presented for ITT population as sensitivity analysis. It was presented with relative frequencies and the exact 2-sided 80% confidence limit (CL; computed using the Clopper-Pearson method). If the lower limit of the CI did not include p0=5%, the hypothesis that p ≤ 5% was rejected. | baseline up to approximately 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Disease Control Rate (DCR) at 12 Months for Per Protocol (PP) and ITT Sets | DCR was based on central radiologic review and is defined as the percentage of patients with a best overall response of 'Complete response' (CR), 'Partial response' (PR) or 'Stable disease' (SD). Relative frequencies together with their exact 2-sided 80% confidence intervals were presented | baseline up to approximately 12 months | 
| Percentage of Participants' Biochemical Response Rate Based on the Tumor Marker Chromogranin A (CgA) | Biochemical response was defined as level and change from baseline in CgA during the course of the trial. The resulting values showed a high variation and were not interpretable, as different methodology was used for the assessment of CgA at the individual centers. | baseline up to approximately 12 months | 
| Duration of Progression Free Survival (PFS) for Per Protocol (PP) and ITT Sets | Duration of PFS was defined as the time from first study drug administration to objective tumor progression or death from any cause. Observations from patients not experiencing tumor progression or death at date of database closure were censored with the date of their last adequate tumor assessment. Progression was either 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline or 2) the appearance of a new lesion or 3) the unequivocal progression of non-target lesions. | baseline up to approximately 12 months | 
| Overall Survival (OS) for Per Protocol (PP) and ITT Sets | OS was defined as the time from first study drug administration to death from any cause. If a patient was not known to have died at date of database closure, overall survival was censored at the date of last contact. | baseline up to approximately 15 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neuroendocrine tumors, non functioning neuroendocrine tumors, Non syndromic neuroendocrine tumors, carcinoids, non-functioning carcinoids, adults, everolimus, NET, RAMSETE, CRAD001, non-functioning neuroendocrine tumors carcinoids