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)

Phase 4

Completed

Conditions: Neuroendocrine Tumors

Interventions: Drug: Everolimus (RAD001)

Registration Number: NCT01595009

Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 246

Inclusion Criteria

Not provided

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Everolimus (RAD001)	Everolimus (RAD001)	Participants received Everolimus 10 mg orally once daily until documented tumor progression, unacceptable toxicity or any other reason.

Primary Outcome Measures

Name	Time	Method
Number and Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths (Core)	from the day of first treatment up to 19 months	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)	from the first day of treatment in the extension up to 4 years	The number of participants with AEs, SAEs and deaths were assessed.

Secondary Outcome Measures

Name	Time	Method
Investigator-assessed Progression Free Survival (PFS) (Core)	from the day of first treatment up to 19 months	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 EORTC QLQ-G.I. NET21 Score (Core)	Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82	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)	Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82	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 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Score (Core)	Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82	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.
Investigator-assessed Best Overall Response (Core)	from the start of treatment, every 12 weeks for the first year and then every 6 months up to 19 months	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.
Mean EQ-5D Visual Analogue Scale (VAS) Score (Core)	Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82	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 Progression Free Survival (PFS) (E1)	from first date of treatment in the extension up to 4 years	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)	baseline, every 12 weeks and up to 4 years	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)	baseline, every 12 weeks and up to 4 years	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)	baseline, every 12 weeks and up to 4 years	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)	from the start of treatment, every 12 weeks for the first year and then every 6 months up to 4 years	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.