Clinical trial NCT01595009: 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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Neuroendocrine Tumors
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-05-09
Enrollment: 246
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number and Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths (Core)
timeFrame: from the day of first treatment up to 19 months
measure: Number and Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths During the Extension Phase (E1)
timeFrame: from the first day of treatment in the extension up to 4 years
Secondary outcomes:
measure: Investigator-assessed Progression Free Survival (PFS) (Core)
timeFrame: from the day of first treatment up to 19 months
measure: Mean European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Score (Core)
timeFrame: Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82
measure: Mean EORTC QLQ-G.I. NET21 Score (Core)
timeFrame: Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82
measure: Number and Percentage of Participants With Ratings of 'no Problem, 'Some Problem' and 'Extreme Problem' in the EuroQol Five Dimensions Questionnaire (EQ-5D) (Core)
timeFrame: Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82
measure: Mean EQ-5D Visual Analogue Scale (VAS) Score (Core)
timeFrame: Baseline, weeks 4, 8, 20, 32, 44, and end of treatment (EOT) up to week 82
measure: Investigator-assessed Best Overall Response (Core)
timeFrame: from the start of treatment, every 12 weeks for the first year and then every 6 months up to 19 months
measure: Investigator-assessed Progression Free Survival (PFS) (E1)
timeFrame: from first date of treatment in the extension up to 4 years
measure: 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)
timeFrame: baseline, every 12 weeks and up to 4 years
measure: Change in EORTC QLQ-G.I. NET21 Score at the End of Treatment From Baseline (Baseline = First Day of Treatment in the Extension) (E1)
timeFrame: baseline, every 12 weeks and up to 4 years
measure: 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)
timeFrame: baseline, every 12 weeks and up to 4 years
measure: Investigator-assessed Best Overall Response During the Extension Phase (E1)
timeFrame: from the start of treatment, every 12 weeks for the first year and then every 6 months up to 4 years
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Chemnitz
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Homburg
country: Germany
facility: Novartis Investigative Site
city: Kassel
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Osnabrück
country: Germany
facility: Novartis Investigative Site
city: Weiden
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: