Clinical trial NCT01524783: Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin)
Official title: A Randomized, Double-blind, Multicenter, Phase III Study of Everolimus (RAD001) Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced NET of GI or Lung Origin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Advanced NET of GI Origin
Advanced NET of Lung Origin
Neuroendocrine Tumors
Keywords: Neuroendocrine tumor
NET
progressive
advanced
gastrointestinal
GI or lung origin
nonfunctional
everolimus
Advanced NET of GI origin
Advanced NET of lung origin
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-02-02
Enrollment: 302
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment
timeFrame: From date of randomization to progression or death, whichever comes first, assessed up to 27 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From date of randomization to date of death, assessed up to approximately 8 years
measure: Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation
timeFrame: From randomization until end of treatment, assessed up to approximately 2.5 years
measure: Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment
timeFrame: From randomization until end of treatment, assessed up to approximately 2.5 years
measure: Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score
timeFrame: From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years
measure: Change From Baseline in Chromogranin A (CgA) Levels
timeFrame: From baseline (every 4 weeks) up to 116 weeks
measure: Change From Baseline in Neuron Specific Enolase (NSE) Levels
timeFrame: From baseline (every 4 weeks) up to Week 116
measure: Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change
timeFrame: From randomization to definitive deterioration of WHO performance status, assessed up to approximately 3 years
measure: Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29
timeFrame: Pre-dose at Day 29.
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego - Moores Cancer Center Regulatory
state: California
city: La Jolla
country: United States
facility: Scripps Clinic Regulatory
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center SC
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Centre SC
state: Colorado
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute HLM
state: Florida
city: Chicago
country: United States
facility: University of Chicago UC SC
state: Illinois
city: Indianapolis
country: United States
facility: Goshen Center for Cancer Care IU Health SC
state: Indiana
city: Boston
country: United States
facility: Dana Farber Cancer Institute SC
state: Massachusetts
city: Bronx
country: United States
facility: Montefiore Medical Center MMC
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering MSkCC SC
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University OH&SU
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University Medical Center Vanderbilt Med Ctr
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology P A Texas Oncology Amarillo
state: Texas
city: Dallas
country: United States
facility: Texas Oncology P A TX Oncology Baylor
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center UT MD Anderson Cancer Ctr
state: Texas
city: Madison
country: United States
facility: University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc
state: Wisconsin
city: Innsbruck
country: Austria
facility: Novartis Investigative Site
state: Tyrol
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Edegem
country: Belgium
facility: Novartis Investigative Site
state: Antwerpen
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Halifax
country: Canada
facility: Novartis Investigative Site
state: Nova Scotia
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Beijing
country: China
facility: Novartis Investigative Site
state: Beijing
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Bogotá
country: Colombia
facility: Novartis Investigative Site
state: Cundinamarca
city: Brno
country: Czechia
facility: Novartis Investigative Site
city: Olomouc
country: Czechia
facility: Novartis Investigative Site
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Bad Berka
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: BS
city: Viagrande
country: Italy
facility: Novartis Investigative Site
state: CT
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Osaka-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Chuo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Ashrafieh
country: Lebanon
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Gliwice
country: Poland
facility: Novartis Investigative Site
state: Slaskie
city: Poznan
country: Poland
facility: Novartis Investigative Site
city: Rostov-na-Donu
country: Russian Federation
facility: Novartis Investigative Site
city: Riyadh
country: Saudi Arabia
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Parktown
country: South Africa
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan, ROC
city: Kuei-Shan Chiang
country: Taiwan
facility: Novartis Investigative Site
state: Taoyuan/ Taiwan ROC
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Chiang Mai
country: Thailand
facility: Novartis Investigative Site
city: Gaziantep
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
state: Scotland
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Southampton
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Chan DL, Yao JC, Carnaghi C, Buzzoni R, Herbst F, Ridolfi A, Strosberg J, Kulke MH, Pavel M, Singh S. Markers of Systemic Inflammation in Neuroendocrine Tumors: A Pooled Analysis of the RADIANT-3 and RADIANT-4 Studies. Pancreas. 2021 Feb 1;50(2):130-137. doi: 10.1097/MPA.0000000000001745.
citation: Buzzoni R, Carnaghi C, Strosberg J, Fazio N, Singh S, Herbst F, Ridolfi A, Pavel ME, Wolin EM, Valle JW, Oh DY, Yao JC, Pommier R. Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4. Onco Targets Ther. 2017 Oct 16;10:5013-5030. doi: 10.2147/OTT.S142087. eCollection 2017.
citation: Fazio N, Buzzoni R, Delle Fave G, Tesselaar ME, Wolin E, Van Cutsem E, Tomassetti P, Strosberg J, Voi M, Bubuteishvili-Pacaud L, Ridolfi A, Herbst F, Tomasek J, Singh S, Pavel M, Kulke MH, Valle JW, Yao JC. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis. Cancer Sci. 2018 Jan;109(1):174-181. doi: 10.1111/cas.13427. Epub 2017 Nov 9.
citation: Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, Carnaghi C, Tomasek J, Wolin E, Raderer M, Lahner H, Valle JW, Pommier R, Van Cutsem E, Tesselaar MET, Fave GD, Buzzoni R, Hunger M, Eriksson J, Cella D, Ricci JF, Fazio N, Kulke MH, Yao JC. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1411-1422. doi: 10.1016/S1470-2045(17)30471-0. Epub 2017 Aug 30.
citation: Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. doi: 10.1016/S0140-6736(15)00817-X. Epub 2015 Dec 17.