Back to resultsAn 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)
Primary Purpose
Neuroendocrine Tumors
Status
Completed
Phase
Phase 4
Locations
Germany
Study Type
Interventional
Intervention
Everolimus (RAD001)
Sponsored by
About this trial
This is an interventional treatment trial for Neuroendocrine Tumors
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
Sites / Locations
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Everolimus (RAD001)
Arm Description
Participants received Everolimus 10 mg orally once daily until documented tumor progression, unacceptable toxicity or any other reason.
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
NCT ID
NCT01595009
First Posted
May 7, 2012
Last Updated
November 26, 2018
Sponsor
Novartis Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT01595009
Brief 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)
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)
Study Type
Interventional
2. Study Status
Record Verification Date
March 2018
Overall Recruitment Status
Completed
Study Start Date
April 27, 2011 (undefined)
Primary Completion Date
August 9, 2016 (Actual)
Study Completion Date
August 9, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroendocrine Tumors
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
246 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Everolimus (RAD001)
Arm Type
Experimental
Arm Description
Participants received Everolimus 10 mg orally once daily until documented tumor progression, unacceptable toxicity or any other reason.
Intervention Type
Drug
Intervention Name(s)
Everolimus (RAD001)
Other Intervention Name(s)
Afinitor
Intervention Description
Everolimus was supplied as tablets of 5mg strength.
Primary Outcome Measure Information:
Title
Number and Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths (Core)
Description
The number of participants with AEs, SAEs and deaths were assessed.
Time Frame
from the day of first treatment up to 19 months
Title
Number and Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths During the Extension Phase (E1)
Description
The number of participants with AEs, SAEs and deaths were assessed.
Time Frame
from the first day of treatment in the extension up to 4 years
Secondary Outcome Measure Information:
Title
Investigator-assessed Progression Free Survival (PFS) (Core)
Description
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.
Time Frame
from the day of first treatment up to 19 months
Title
Mean European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Score (Core)
Description
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.
Time Frame
Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82
Title
Mean EORTC QLQ-G.I. NET21 Score (Core)
Description
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.
Time Frame
Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82
Title
Number and Percentage of Participants With Ratings of 'no Problem, 'Some Problem' and 'Extreme Problem' in the EuroQol Five Dimensions Questionnaire (EQ-5D) (Core)
Description
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.
Time Frame
Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82
Title
Mean EQ-5D Visual Analogue Scale (VAS) Score (Core)
Description
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.
Time Frame
Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82
Title
Investigator-assessed Best Overall Response (Core)
Description
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.
Time Frame
from the start of treatment, every 12 weeks for the first year and then every 6 months up to 19 months
Title
Investigator-assessed Progression Free Survival (PFS) (E1)
Description
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.
Time Frame
from first date of treatment in the extension up to 4 years
Title
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)
Description
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.
Time Frame
baseline, every 12 weeks and up to 4 years
Title
Change in EORTC QLQ-G.I. NET21 Score at the End of Treatment From Baseline (Baseline = First Day of Treatment in the Extension) (E1)
Description
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.
Time Frame
baseline, every 12 weeks and up to 4 years
Title
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)
Description
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.
Time Frame
baseline, every 12 weeks and up to 4 years
Title
Investigator-assessed Best Overall Response During the Extension Phase (E1)
Description
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.
Time Frame
from the start of treatment, every 12 weeks for the first year and then every 6 months up to 4 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
10098
Country
Germany
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Novartis Investigative Site
City
Chemnitz
ZIP/Postal Code
09113
Country
Germany
Facility Name
Novartis Investigative Site
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Facility Name
Novartis Investigative Site
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Novartis Investigative Site
City
Homburg
ZIP/Postal Code
66421
Country
Germany
Facility Name
Novartis Investigative Site
City
Kassel
ZIP/Postal Code
34125
Country
Germany
Facility Name
Novartis Investigative Site
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Facility Name
Novartis Investigative Site
City
Osnabrück
ZIP/Postal Code
49076
Country
Germany
Facility Name
Novartis Investigative Site
City
Weiden
ZIP/Postal Code
92637
Country
Germany
12. IPD Sharing Statement
Learn more about this trial
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)
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