An Open-label, Multi-center, Expanded Access Study of Everolimus in Participants With Advanced Neuroendocrine Tumors (NETs) (Core Study) and an Extension Study to the Open-label, Multi-center, Expanded Access Study of Everolimus in Patients With Advanced NETs (E1)

Study Overview
=================
Brief Summary
-----------------
This record combines the results of CRAD001K24133 and CRAD001K24133E1. The purpose of the CRAD001K24133 study was to evaluate the safety profile of everolimus in patients with advanced neuroendocrine tumors of pancreatic origin (pNETs) and to provide access of everolimus to this patient population. Everolimus was taken by participants until disease progression, unacceptable toxicity, death, discontinuation from the trial for any other reason, or when it became commercially available for this indication, or until May 30, 2012, whichever came first. Prior to amendment 1, the study enrolled participants with NET of the lung (L-NETs) and gastrointestinal (GI) (GI-NETs) origin. The core study was stopped (per protocol) because everolimus was approved for pNETs. All ongoing patients with pNETs were switched to commercially available everolimus. For GI and lung NETs, everolimus was not approved at the time the core study was stopped. Therefore, patients with GI or lung NETs were not able to switch to commercial drug. To provide study medication access to these patients beyond 30 May 2012, the open label extension study, CRAD001K24133E1, was conducted. In the extension study, RAD001K24133E1, participants with GI or lung NETs who had not progressed during therapy with everolimus in the core study and who had not suffered from intolerable toxicity, were enrolled and treated with everolimus in order to provide data on long-term safety and efficacy. Patients were treated until it became commercially available in the respective indication or until documented tumor progression, unacceptable toxicity, any other reason or until study end on 31 May 2017, whichever came first.

Official Title
-----------------
An Open-label, Multi-center, Expanded Access Study of Everolimus in Participants With Advanced Neuroendocrine Tumors (NETs) (Core Study) and an Extension Study to the Open-label, Multi-center, Expanded Access Study of Everolimus in Patients With Advanced NETs (E1)

Conditions
-----------------
Neuroendocrine Tumors

Intervention / Treatment
-----------------
* Drug: Everolimus (RAD001)


Participation Criteria
=================
Eligibility Criteria
-----------------
Core Inclusion: Age ≥ 18 years old Advanced (unresectable or metastatic) biopsy-proven NETs of pancreatic origin World health organization (WHO) Performance status of 0-2 Adequate bone marrow function as shown by: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Hemoglobin >9 g/dL Adequate liver function as shown by: Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN. Patients with known liver metastases with an AST and ALT ≤ 5 x ULN International normalized ratio (INR) <1.3 (INR <3 in patients treated with anticoagulants) Adequate renal function as shown by: Serum creatinine ≤ 1.5 x ULN Fasting serum cholesterol ≤ 300 mg/dL or ≤ 7.75 mmol/L and fasting triglycerides ≤ 2.5 x ULN Written informed consent obtained before any trial related activity and according to local guidelines. Core Exclusion: Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma were not eligible. Following Amendment 1, patients with neuroendocrine tumors of GI or lung origin Cytotoxic chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to enrollment Hepatic artery embolization within the last two months or cryoablation or radiofrequency ablation of hepatic metastasis within two months of enrollment Prior therapy with mTOR inhibitors (for example sirolimus, temsirolimus, everolimus) Patients with a known hypersensitivity to everolimus or other rapamycin analogs (sirolimus, temsirolimus) or to its excipients Patients receiving chronic treatment with immunosuppressives Uncontrolled diabetes mellitus as defined by fasting serum glucose >1.5 x ULN Patients who had any severe and/or uncontrolled medical conditions such as: Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia Active or uncontrolled severe infection A history of invasive fungal infections Severe hepatic impairment (Child Pugh class C) Severely impaired lung function Active bleeding diathesis Patients with a known history of Human immunodeficiency virus (HIV) seropositivity No other prior or concurrent malignancy was allowed except for, adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient had been disease free for ≥ 3 years Patients within four weeks post-major surgery, open-biopsy, or significant traumatic injury to avoid wound healing complications. Minor procedures and percutaneous biopsies or placement of vascular access device required seven days prior to study entry Female patients who were pregnant or nursing Adults who were of reproductive potential who were not using effective birth control methods. Adequate contraceptives were to be used throughout the trial and for eight weeks after last study drug administration in female patients. Women of child bearing potential must have had a negative serum pregnancy test within seven days prior to first administration of study drug Patients who were unwilling to or unable to comply with the protocol Extension Inclusion and Exclusion Criteria: The patient must provide a signed Informed Consent Form (ICF) for the extension study prior to any study related procedures Age ≥18 years old Completion of the whole treatment period in the CRAD001K24133 study Neuroendocrine tumor of gastrointestinal or pulmonary origin (pancreatic neuroendocrine tumors are excluded) No tumor progression during therapy with everolimus during CRAD001K24133 study (checked via radiologically assessment) No intolerable toxicity during therapy everolimus, or during combination therapy of everolimus and somatostatin analogues

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 (RAD001)<br>Participants received Everolimus 10 mg orally once daily until documented tumor progression, unacceptable toxicity or any other reason. | Drug: Everolimus (RAD001)<br>* Everolimus was supplied as tablets of 5mg strength.<br>* Other names: Afinitor;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths (Core) | The number of participants with AEs, SAEs and deaths were assessed. | from the day of first treatment up to 19 months | 
| Number and Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths During the Extension Phase (E1) | The number of participants with AEs, SAEs and deaths were assessed. | from the first day of treatment in the extension up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed Progression Free Survival (PFS) (Core) | PFS was defined as the time from the date of the first dose to the date of the first radiologically documented disease progression or death due to any cause. If a participant had not progressed or died at the study end date or when he/she received any further anti-neoplastic therapy, PFS was censored at the time of the last tumor assessment before the end of study date. Progression was defined,using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | from the day of first treatment up to 19 months | 
| Mean European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Score (Core) | The EORTC QLQ-C30 contains 30 questions assessed by the participant. There are 9 multiple-item scales: 5 scales that assess aspects of functioning (physical, role functioning, cognitive, emotional, and social); 3 symptom scales (Fatigue, Pain, and Nausea and Vomiting); and a global health status/Quality of Life (QOL) scale. There are 5 single-item measures assessing additional symptoms (i.e., dyspnea, loss of appetite, insomnia, constipation, and diarrhea) and a single item concerning perceived financial impact of the disease. All but two questions have 4-point scales ranging from Not at all to Very much. The two questions concerning global health status/ QOL have 7 point scales with ratings ranging from Very poor to Excellent. For each of the 14 domains, final scores are transformed such that they range from 0-100, where higher scores indicate improvement. | Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82 | 
| Mean EORTC QLQ-G.I. NET21 Score (Core) | The EORTC QLQ-G.I. NET21 contains 21 questions and has three defined multi-item symptom scales (endocrine - 3 questions, gastrointestinal - 5 questions, and treatment related side effects - 3 questions), two single item symptoms (bone/muscle pain and concern about weight loss), two psychosocial scales (social function - 3 questions and disease-related worries - 3 questions) and two other single items (sexuality and communication). For each of the 9 domains, final scores are transformed such that they range from 0-100, where higher scores indicate worsening. | Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82 | 
| Number and Percentage of Participants With Ratings of 'no Problem, 'Some Problem' and 'Extreme Problem' in the EuroQol Five Dimensions Questionnaire (EQ-5D) (Core) | The EQ-5D is divided into two distinct sections. The first section includes one item addressing each of five dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression). Patients rate each of these items from no problem, some problem, or extreme problem. A composite health index is then defined by combining the levels for each dimension. The second section of the questionnaire measures self-rated (global) health status utilizing a vertically oriented visual analogue scale where 100 represents the best possible health state and 0 represents the worst possible health state. Respondents are asked to rate their current health by placing a mark along this continuum. The scores from each section are then transformed into a single health utility score. Overall scores range from 0 to 1 with lower scores representing a higher level of dysfunction. | Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82 | 
| Mean EQ-5D Visual Analogue Scale (VAS) Score (Core) | The EQ-5D is divided into two distinct sections. The first section includes one item addressing each of five dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression). Patients rate each of these items from no problem, some problem, or extreme problem. A composite health index is then defined by combining the levels for each dimension. The second section of the questionnaire measures self-rated (global) health status utilizing a vertically oriented visual analogue scale where 100 represents the best possible health state and 0 represents the worst possible health state. Respondents are asked to rate their current health by placing a mark along this continuum. The scores from each section are then transformed into a single health utility score. Overall scores range from 0 to 1 with lower scores representing a higher level of dysfunction. | Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82 | 
| Investigator-assessed Best Overall Response (Core) | Best overall response was determined from the sequence of investigator overall lesions responses according to Response Evaluation Criteria in Solid Tumors (RECIST). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Progression, a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | from the start of treatment, every 12 weeks for the first year and then every 6 months up to 19 months | 
| Investigator-assessed Progression Free Survival (PFS) (E1) | PFS was defined as the time from the date of the start of therapy in the extension study to the date of the first radiologically documented disease progression or death due to any cause. If a participant had not progressed or died at the analysis cut-off date or when he/she received any further anti-neoplastic therapy, PFS was censored at the time of the last adequate tumor evaluation before the cut-off date or the anti-neoplastic therapy start date. | from first date of treatment in the extension up to 4 years | 
| Change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Score at the End of Treatment From Baseline (Baseline = First Day of Treatment in the Extension) (E1) | The EORTC QLQ-C30 contains 30 questions assessed by the participant. There are 9 multiple-item scales: 5 scales that assess aspects of functioning (physical, role, cognitive, emotional, and social); 3 symptom scales (Fatigue, Pain, and Nausea and Vomiting); and a global health status and QOL scale. There are 5 single-item measures assessing additional symptoms (i.e., dyspnea, loss of appetite, insomnia, constipation, and diarrhea) and a single item concerning perceived financial impact of the disease. All but two questions have 4-point scales ranging from Not at all to Very much. The two questions concerning global health status and QOL have 7 point scales with ratings ranging from Very poor to Excellent. For each of the 14 domains, changes are calculated as value at later time point minus value at baseline, and final scores are transformed such that they range from 0-100, where higher scores indicate better outcomes. A positive change from baseline indicates improvement. | baseline, every 12 weeks and up to 4 years | 
| Change in EORTC QLQ-G.I. NET21 Score at the End of Treatment From Baseline (Baseline = First Day of Treatment in the Extension) (E1) | The EORTC QLQ-G.I. NET21 contains 21 questions and has three defined multi-item symptom scales (endocrine - 3 questions, gastrointestinal - 5 questions, and treatment related side effects - 3 questions), two single item symptoms (bone/muscle pain and concern about weight loss), two psychosocial scales (social function - 3 questions, disease-related worries - 3 questions) and two other single items (sexuality and communication). For each of the 9 domains, final scores are transformed such that they range from 0-100, where higher scores indicate worsening outcomes. A positive change from baseline indicates worsening. | baseline, every 12 weeks and up to 4 years | 
| Change in EuroQol Five Dimensions Questionnaire (EQ-5D) Score at the End of Treatment From Baseline (Baseline = First Day of Treatment in the Extension) (E1) | The EQ-5D contains 2 sections:1st section has 1 item addressing each of 5 dimensions (mobility, self-care, usual activity, pain/discomfort, anxiety/depression). Each dimension has 3 levels: no problems, some problems, extreme problems, 1-3, respectively. A health state is defined by combining 1 level from each dimension. 243 health states are possible. Each state is referred to in a 5 digit code. E.g., state 11111 indicates no problems on any dimension, while state 11223 indicates no problems with mobility and self-care, some problems with performing usual activities, moderate pain or discomfort and extreme anxiety or depression. The 2nd section measures self-rated health status using a visual analogue scale (VAS) where 100 represents best possible health and 0 represents worst possible health. Patients are asked to rate their current health by placing a mark on the VAS. Scores from each section are then transformed into an overall score of 0 or 1, with 0= higher level of dysfunction. | baseline, every 12 weeks and up to 4 years | 
| Investigator-assessed Best Overall Response During the Extension Phase (E1) | Best overall response was determined from the sequence of investigator overall lesions responses according to Response Evaluation Criteria in Solid Tumors (RECIST). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Progression, a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | from the start of treatment, every 12 weeks for the first year and then every 6 months up to 4 years |