Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin)

Neuroendocrine Tumors Clinical Trial

— RADIANT-4  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01524783
• Other study ID #: CRAD001T2302
• Secondary ID: 2011-002887-26
• Status: Completed
• Phase: Phase 3
• 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
• 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.

Related Conditions & MeSH terms

• Advanced NET of GI Origin
• Advanced NET of Lung Origin
• Neuroendocrine Tumors

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.