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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01524783
Other study ID # CRAD001T2302
Secondary ID 2011-002887-26
Status Completed
Phase Phase 3
First received
Last updated
Start date March 30, 2012
Est. completion date August 7, 2020

Study information

Verified date July 2021
Source Novartis
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The purpose of this study is to compare the antitumor activity of everolimus plus best supportive care versus placebo plus best supportive care in patients with progressive nonfunctional neuroendocrine tumor (NET) of gastrointestinal (GI) or lung origin without a history of, or current symptoms of carcinoid syndrome.


Description:

This was a prospective, multi-center, randomized, double-blind, parallel-group, placebo-controlled, two-arm Phase III study comparing the efficacy and safety of everolimus 10 mg daily to placebo in patients with advanced NET of GI or lung origin without a history of, or current symptoms of carcinoid syndrome. After assessment of eligibility, participants qualifying for the study were randomized in a 2:1 ratio to receive either everolimus or matching placebo. Participants received daily oral doses of 10 mg everolimus or matching placebo as study drug. In both arms, the study drug was combined with best supportive care and treatment cycles were defined as 28 days. Participants were treated until disease progression as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0, intolerable toxicity, death, lost to follow-up or consent withdrawal. Regardless of the reason for study drug discontinuation, participants had a safety follow-up visit scheduled 30 days after the last dose of the study drug. Per data monitoring committee recommendation, all participants on treatment with placebo were allowed to crossover to open-label treatment with everolimus. This change was implemented through protocol amendment 3 (issued on 06-May-2016) after which remaining participants entered into open-label phase of the study.


Recruitment information / eligibility

Status Completed
Enrollment 302
Est. completion date August 7, 2020
Est. primary completion date November 28, 2014
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Pathologically confirmed, well differentiated (G1 or G2), advanced (unresectable or metastatic), neuroendocrine tumor of GI or lung origin - No history of and no active symptoms related to carcinoid syndrome - In addition to treatment-naive patients, patients previously treated with SSA, Interferon (IFN), one prior line of chemotherapy, and/or PRRT were allowed into the study. Pretreated patients had to have progressed on or after the last treatment - Radiological documented disease progression within 6 months prior to randomization - Measurable disease - WHO performance status =1 - Adequate bone marrow, liver and renal function Exclusion Criteria: - Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, pancreatic islet cell carcinoma, insulinoma, glucagonoma, gastrinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma - Patients with pancreatic NET or NET of origins other than GI or Lung - Patients with history of or active symptoms of carcinoid syndrome (e.g. flushing, diarrhea) - Patients with more than one line of prior chemotherapy - Prior targeted therapy - Hepatic intra-arterial embolization within the last 6 months. Cryoablation or radiofrequency ablation of hepatic metastases within 2 months of randomization - Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus) - Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus) - Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus - Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy - 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 randomization, serious uncontrolled cardiac arrhythmia - active or uncontrolled severe infection - liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA) - Chronic treatment with corticosteroids or other immunosuppressive agents - Known history of HIV seropositivity - Pregnant or nursing (lactating) women Other protocol-defined inclusion/exclusion criteria might apply.

Study Design


Intervention

Drug:
Everolimus
Participants were treated with everolimus 10 mg (two 5 mg tablets) once daily orally taken
Placebo
Participants were treated with two tablets of matching placebo once daily orally taken.
Other:
Best suportive care (BSC)
Best supportive care includes all care provided to participants deemed necessary by the treating physician, such as but not restricted to anti-diarrheals and analgesics. The optimal care of the patient is based on the treating physician's best medical judgment.

Locations

Country Name City State
Austria Novartis Investigative Site Innsbruck Tyrol
Austria Novartis Investigative Site Wien
Belgium Novartis Investigative Site Bruxelles
Belgium Novartis Investigative Site Edegem Antwerpen
Belgium Novartis Investigative Site Gent
Belgium Novartis Investigative Site Leuven
Canada Novartis Investigative Site Calgary Alberta
Canada Novartis Investigative Site Halifax Nova Scotia
Canada Novartis Investigative Site London Ontario
Canada Novartis Investigative Site Montreal Quebec
Canada Novartis Investigative Site Ottawa Ontario
Canada Novartis Investigative Site Toronto Ontario
Canada Novartis Investigative Site Vancouver British Columbia
China Novartis Investigative Site Beijing Beijing
China Novartis Investigative Site Beijing
China Novartis Investigative Site Beijing
China Novartis Investigative Site Beijing
China Novartis Investigative Site Beijing
Colombia Novartis Investigative Site Bogotá Cundinamarca
Czechia Novartis Investigative Site Brno
Czechia Novartis Investigative Site Olomouc
Czechia Novartis Investigative Site Praha
Germany Novartis Investigative Site Bad Berka
Germany Novartis Investigative Site Berlin
Germany Novartis Investigative Site Essen
Germany Novartis Investigative Site Frankfurt
Germany Novartis Investigative Site Hannover
Germany Novartis Investigative Site Magdeburg
Germany Novartis Investigative Site Mainz
Greece Novartis Investigative Site Athens
Hungary Novartis Investigative Site Budapest
Hungary Novartis Investigative Site Budapest
Italy Novartis Investigative Site Bologna BO
Italy Novartis Investigative Site Brescia BS
Italy Novartis Investigative Site Firenze FI
Italy Novartis Investigative Site Milano MI
Italy Novartis Investigative Site Milano MI
Italy Novartis Investigative Site Modena MO
Italy Novartis Investigative Site Napoli
Italy Novartis Investigative Site Napoli
Italy Novartis Investigative Site Roma RM
Italy Novartis Investigative Site Roma RM
Italy Novartis Investigative Site Rozzano MI
Italy Novartis Investigative Site Verona VR
Italy Novartis Investigative Site Viagrande CT
Japan Novartis Investigative Site Chuo ku Tokyo
Japan Novartis Investigative Site Fukuoka city Fukuoka
Japan Novartis Investigative Site Osaka-city Osaka
Korea, Republic of Novartis Investigative Site Seoul Korea
Korea, Republic of Novartis Investigative Site Seoul Seocho Gu
Korea, Republic of Novartis Investigative Site Seoul
Korea, Republic of Novartis Investigative Site Seoul
Korea, Republic of Novartis Investigative Site Seoul
Lebanon Novartis Investigative Site Ashrafieh
Lebanon Novartis Investigative Site Beirut
Netherlands Novartis Investigative Site Amsterdam
Poland Novartis Investigative Site Gliwice Slaskie
Poland Novartis Investigative Site Poznan
Russian Federation Novartis Investigative Site Rostov-na-Donu
Saudi Arabia Novartis Investigative Site Riyadh
Slovakia Novartis Investigative Site Bratislava Slovak Republic
South Africa Novartis Investigative Site Parktown
Spain Novartis Investigative Site Barcelona Catalunya
Spain Novartis Investigative Site Hospitalet de LLobregat Catalunya
Spain Novartis Investigative Site Sevilla Andalucia
Taiwan Novartis Investigative Site Kaohsiung
Taiwan Novartis Investigative Site Kuei-Shan Chiang Taoyuan/ Taiwan ROC
Taiwan Novartis Investigative Site Taichung
Taiwan Novartis Investigative Site Taipei
Taiwan Novartis Investigative Site Taipei Taiwan, ROC
Thailand Novartis Investigative Site Bangkok THA
Thailand Novartis Investigative Site Chiang Mai
Turkey Novartis Investigative Site Gaziantep
Turkey Novartis Investigative Site Istanbul
United Kingdom Novartis Investigative Site Cambridge
United Kingdom Novartis Investigative Site Glasgow Scotland
United Kingdom Novartis Investigative Site London
United Kingdom Novartis Investigative Site London
United Kingdom Novartis Investigative Site Manchester
United Kingdom Novartis Investigative Site Southampton
United States University of Colorado Cancer Centre SC Aurora Colorado
United States Dana Farber Cancer Institute SC Boston Massachusetts
United States Montefiore Medical Center MMC Bronx New York
United States University of Chicago UC SC Chicago Illinois
United States Texas Oncology P A Texas Oncology Amarillo Dallas Texas
United States Texas Oncology P A TX Oncology Baylor Dallas Texas
United States University of Texas Southwestern Medical Center Dallas Texas
United States University of Texas MD Anderson Cancer Center UT MD Anderson Cancer Ctr Houston Texas
United States Goshen Center for Cancer Care IU Health SC Indianapolis Indiana
United States Scripps Clinic Regulatory La Jolla California
United States University of California San Diego - Moores Cancer Center Regulatory La Jolla California
United States Cedars Sinai Medical Center SC Los Angeles California
United States University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc Madison Wisconsin
United States Vanderbilt University Medical Center Vanderbilt Med Ctr Nashville Tennessee
United States Memorial Sloan Kettering MSkCC SC New York New York
United States Oregon Health and Science University OH&SU Portland Oregon
United States H Lee Moffitt Cancer Center and Research Institute HLM Tampa Florida

Sponsors (1)

Lead Sponsor Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  China,  Colombia,  Czechia,  Germany,  Greece,  Hungary,  Italy,  Japan,  Korea, Republic of,  Lebanon,  Netherlands,  Poland,  Russian Federation,  Saudi Arabia,  Slovakia,  South Africa,  Spain,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment PFS is defined as the time from randomization to the date of the first documented tumor progression or death from any cause, whichever comes first.
Progression was defined using modified RECIST 1.0 and as per central radiology assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Progression was assessed by cat scan (CT) and/or magnetic resonance imaging (MRI).
For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown.
The percentage event-free probability estimate is the estimated probability that a patient will remain event-free in PFS up to the specified time point.
From date of randomization to progression or death, whichever comes first, assessed up to 27 months
Secondary Overall Survival (OS) OS is defined as the time from the date of randomization to date of death due to any cause. If a death had not been observed by the date of analysis cut-off, then OS was censored at the date of last contact. All participants randomized to placebo arm who crossed over to everolimus were censored. From date of randomization to date of death, assessed up to approximately 8 years
Secondary Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to central evaluation and as per modified RECIST 1.0.
CR: disappearance of all target lesions. PR: 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.
From randomization until end of treatment, assessed up to approximately 2.5 years
Secondary Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment DCR is defined as the proportion of subjects with best overall response of CR or PR or stable disease based on modified RECIST 1.0 and as per central radiology assessment.
CR: disappearance of all target lesions. PR: 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.
Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression.
From randomization until end of treatment, assessed up to approximately 2.5 years
Secondary Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score FACT-G is a self-assessed health-related quality of life questionnaire. The questionnaire is comprised of 27 questions examining physical, social/family, emotional, and functional well-being. Participants responded to the items on a five-point scale, ranging from 0: "Not at all" to 4: "Very much." The total score ranges from 0 to 108, with higher scores indicating a better patient-reported outcome/quality of life.
Definitive deterioration is defined as a decrease in the total score by at least 7 points compared to baseline with no further improvement.
Death was considered as worsening of the FACT-G total score if it occurred close to the last available assessment, where "close" was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment.
From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years
Secondary Change From Baseline in Chromogranin A (CgA) Levels CgA is a potential biomarker for tumor response. Blood samples were collected for assessment of CgA levels. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline. From baseline (every 4 weeks) up to 116 weeks
Secondary Change From Baseline in Neuron Specific Enolase (NSE) Levels NSE is a potential biomarker for tumor response. Blood samples were collected for assessment of NSE levels. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline. From baseline (every 4 weeks) up to Week 116
Secondary Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change WHO PS is a scale rated from 0 (fully active) to 5 (death) by a healthcare professional to assess the overall status of a patient: a lower score represents a higher ability to perform daily tasks. Deterioration is defined as an increase of at least one point compared to baseline. Deterioration is considered definitive if no improvements in the WHO PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. Death was considered as worsening of the WHO PS if it occurred close to the last available assessment, where "close" was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment. From randomization to definitive deterioration of WHO performance status, assessed up to approximately 3 years
Secondary Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29 A pre-dose blood sample at day 29 was collected to determine the exposure of everolimus at the steady-state pre-dose concentration (Cmin). Cmin is provided for participants randomized to everolimus+BSC who received 10mg of everolimus daily and also for participants randomized to everolimus+BSC who received 5mg of everolimus daily which was required for a number of participants in the study experiencing adverse events requiring dose modifications Pre-dose at Day 29.
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