Advanced NET of GI OriginPhase 3RADIANT-4NCT01524783
Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin)
A Phase 3 study testing Everolimus and Best suportive care (BSC) in people with Advanced NET of GI Origin and Advanced NET of Lung Origin, run by Novartis Pharmaceuticals at 97 sites in 25 countries.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced NET of GI Origin, Advanced NET of Lung Origin, Neuroendocrine Tumors
- What is being tested?
- Everolimus and Best suportive care (BSC)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 302 participants
- Where
- 97 sitesin 25 countries
- Study dates
- 30 Mar 2012to 7 Aug 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 18Show fewer
- 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.
Trial locations and contacts
97 sites in 25 countries.
97 sites in 25 countries
United States17 sites
University of Colorado Cancer Centre SC
Aurora, Colorado, 80045
Dana Farber Cancer Institute SC
Boston, Massachusetts, 02215
University of Chicago UC SC
Chicago, Illinois, 60637
Texas Oncology P A Texas Oncology Amarillo
Dallas, Texas, 75251
Texas Oncology P A TX Oncology Baylor
Dallas, Texas, 75251
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
University of Texas MD Anderson Cancer Center UT MD Anderson Cancer Ctr
Houston, Texas, 77030
Goshen Center for Cancer Care IU Health SC
Indianapolis, Indiana, 46202
University of California San Diego - Moores Cancer Center Regulatory
La Jolla, California, 92093-0658
Scripps Clinic Regulatory
La Jolla, California, 92121
Cedars Sinai Medical Center SC
Los Angeles, California, 90048
University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc
Madison, Wisconsin, 53792-6164
Vanderbilt University Medical Center Vanderbilt Med Ctr
Nashville, Tennessee, 37232
Memorial Sloan Kettering MSkCC SC
New York, New York, 10017
Oregon Health and Science University OH&SU
Portland, Oregon, 97239
H Lee Moffitt Cancer Center and Research Institute HLM
Tampa, Florida, 33612
Montefiore Medical Center MMC
The Bronx, New York, 10467
Italy13 sites
Novartis Investigative Site
Bologna, BO, 40138
Novartis Investigative Site
Brescia, BS, 25123
Novartis Investigative Site
Florence, FI, 50134
Novartis Investigative Site
Milan, MI, 20133
Novartis Investigative Site
Milan, MI, 20141
Novartis Investigative Site
Modena, MO, 41124
Novartis Investigative Site
Naples, 80131
Novartis Investigative Site
Naples, 80132
Novartis Investigative Site
Roma, RM, 00168
Novartis Investigative Site
Roma, RM, 00189
Novartis Investigative Site
Rozzano, MI, 20089
Novartis Investigative Site
Verona, VR, 37126
Novartis Investigative Site
Viagrande, CT, 95029
Canada7 sites
Novartis Investigative Site
Calgary, Alberta, T2N 4N2
Novartis Investigative Site
Halifax, Nova Scotia, B3H 1V7
Novartis Investigative Site
London, Ontario, N6A 4L6
Novartis Investigative Site
Montreal, Quebec, H1T 2M4
Novartis Investigative Site
Ottawa, Ontario, K1H 8L6
Novartis Investigative Site
Toronto, Ontario, M4N 3M5
Novartis Investigative Site
Vancouver, British Columbia, V5Z 4E6
Germany7 sites
Novartis Investigative Site
Bad Berka, 99438
Novartis Investigative Site
Berlin, 13353
Novartis Investigative Site
Essen, 45147
Novartis Investigative Site
Frankfurt, 60590
Novartis Investigative Site
Hanover, 30625
Novartis Investigative Site
Magdeburg, 39120
Novartis Investigative Site
Mainz, 55131
United Kingdom6 sites
Novartis Investigative Site
Cambridge, CB2 2QQ
Novartis Investigative Site
Glasgow, Scotland, G12 0YN
Novartis Investigative Site
London, SE1 9RT
Novartis Investigative Site
London, W12 0HS
Novartis Investigative Site
Manchester, M20 2BX
Novartis Investigative Site
Southampton, SO16 6YD
China5 sites
Novartis Investigative Site
Beijing, Beijing Municipality, 100730
Novartis Investigative Site
Beijing, 100021
Novartis Investigative Site
Beijing, 100029
Novartis Investigative Site
Beijing, 100036
Novartis Investigative Site
Beijing, 100039
South Korea5 sites
Novartis Investigative Site
Seoul, Korea, 05505
Novartis Investigative Site
Seoul, Seocho Gu, 06591
Novartis Investigative Site
Seoul, 03080
Novartis Investigative Site
Seoul, 03722
Novartis Investigative Site
Seoul, 06351
Taiwan5 sites
Novartis Investigative Site
Kaohsiung City, 833
Novartis Investigative Site
Kuei-Shan Chiang, Taoyuan/ Taiwan ROC, 33305
Novartis Investigative Site
Taichung, 40705
Novartis Investigative Site
Taipei, Taiwan, ROC, 11217
Novartis Investigative Site
Taipei, 10048
Belgium4 sites
Novartis Investigative Site
Brussels, 1200
Novartis Investigative Site
Edegem, Antwerpen, 2650
Novartis Investigative Site
Ghent, 9000
Novartis Investigative Site
Leuven, 3000
Czechia3 sites
Novartis Investigative Site
Brno, 65653
Novartis Investigative Site
Olomouc, 775 20
Novartis Investigative Site
Prague, 12808
Japan3 sites
Novartis Investigative Site
Chuo Ku, Tokyo, 104 0045
Novartis Investigative Site
Fukuoka, Fukuoka, 812-8582
Novartis Investigative Site
Osaka, Osaka, 553-0003
Spain3 sites
Novartis Investigative Site
Barcelona, Catalonia, 08035
Novartis Investigative Site
L'Hospitalet de Llobregat, Catalonia, 08907
Novartis Investigative Site
Seville, Andalusia, 41009
Austria2 sites
Novartis Investigative Site
Innsbruck, Tyrol, 6020
Novartis Investigative Site
Vienna, A-1090
Hungary2 sites
Novartis Investigative Site
Budapest, 1062
Novartis Investigative Site
Budapest, 1085
Lebanon2 sites
Novartis Investigative Site
Beirut, 1107 2020
Novartis Investigative Site
El Achrafiyé, 166830
Poland2 sites
Novartis Investigative Site
Gliwice, Silesian Voivodeship, 44-101
Novartis Investigative Site
Poznan, 60-355
Thailand2 sites
Novartis Investigative Site
Bangkok, THA, 10330
Novartis Investigative Site
Chiang Mai, 50200
Turkey (Türkiye)2 sites
Novartis Investigative Site
Gaziantep, 27310
Novartis Investigative Site
Istanbul, 34303
Slovakia1 site
Novartis Investigative Site
Bratislava, Slovak Republic, 833 10
About this study
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
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.
Read the 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.
- Being tested
- Everolimus, Placebo, Best suportive care (BSC)
- Keywords
- Neuroendocrine tumor, NET, progressive, advanced, gastrointestinal, GI or lung origin, nonfunctional, everolimus, Advanced NET of GI origin, Advanced NET of lung origin
- Medical subject headings
- Neuroendocrine Tumors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EverolimusDrug
Also called RAD001
Participants were treated with everolimus 10 mg (two 5 mg tablets) once daily orally taken
PlaceboDrug
Participants were treated with two tablets of matching placebo once daily orally taken.
Best suportive care (BSC)Other
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.
| Study group | Role | What they receive |
|---|---|---|
| Everolimus + BSC | Experimental | Participants received everolimus 10 mg once daily plus best supportive care (BSC) throughout the study Receives: Drug: Everolimus; Other: Best suportive care (BSC) |
| Placebo + BSC | Placebo comparator | Participants received matching placebo once daily plus best supportive care (BSC) during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period. Receives: Drug: Placebo; Other: Best suportive care (BSC) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From date of randomization to progression or death, whichever comes first, assessed up to 27 months
Secondary outcomes (8)
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.
Measured: From date of randomization to date of death, assessed up to approximately 8 years
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.
Measured: From randomization until end of treatment, assessed up to approximately 2.5 years
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.
Measured: From randomization until end of treatment, assessed up to approximately 2.5 years
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.
Measured: From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years
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.
Measured: From baseline (every 4 weeks) up to 116 weeks
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.
Measured: From baseline (every 4 weeks) up to Week 116
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.
Measured: From randomization to definitive deterioration of WHO performance status, assessed up to approximately 3 years
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
Measured: Pre-dose at Day 29.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2012 (estimated)
- Study start30 Mar 2012
- Primary completion28 Nov 2014
- Study completion7 Aug 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Advanced NET of GI OriginStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 302 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01524783
- Sponsor's protocol ID
- CRAD001T2302
- Other IDs
- 2011-002887-26
- Acronym
- RADIANT-4
- Status last verified
- Jul 2021
- First submitted
- 22 Dec 2011
- Last updated
- 5 Aug 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Publications
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.
PubMed 33560090Buzzoni 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.
PubMed 29081664Fazio 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.
PubMed 29055056Pavel 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.
PubMed 28838862Yao 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.
PubMed 26703889
Study at a glance
From the registry record, last updated by the sponsor on 5 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01524783
- Acronym / sponsor ID
- RADIANT-4 / CRAD001T2302
- Keywords
- Neuroendocrine tumor, NET, progressive, advanced, gastrointestinal, GI or lung origin, nonfunctional, everolimus
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 302 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 30 Mar 2012 (actual)
- Primary completion
- 28 Nov 2014 (actual)
- Study completion
- 7 Aug 2020 (actual)
- First posted
- 2 Feb 2012 (estimated)
- Results
- Posted 28 Dec 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Everolimus + BSC | Experimental | Drug: Everolimus, Other: Best suportive care (BSC)Participants received everolimus 10 mg once daily plus best supportive care (BSC) throughout the study |
| Placebo + BSC | Placebo comparator | Drug: Placebo, Other: Best suportive care (BSC)Participants received matching placebo once daily plus best supportive care (BSC) during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (18 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EverolimusAlso: RAD001Participants were treated with everolimus 10 mg (two 5 mg tablets) once daily orally taken | Drug | Everolimus + BSC |
| PlaceboParticipants were treated with two tablets of matching placebo once daily orally taken. | Drug | Placebo + BSC |
| 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. | Other | Everolimus + BSC, Placebo + BSC |
Primary outcome
Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment
Time frame: From date of randomization to progression or death, whichever comes first, assessed up to 27 months
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.
8 secondary outcomes
Overall Survival (OS)
Time frame: From date of randomization to date of death, assessed up to approximately 8 years
Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation
Time frame: From randomization until end of treatment, assessed up to approximately 2.5 years
Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment
Time frame: From randomization until end of treatment, assessed up to approximately 2.5 years
Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score
Time frame: From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years
Change From Baseline in Chromogranin A (CgA) Levels
Time frame: From baseline (every 4 weeks) up to 116 weeks
Change From Baseline in Neuron Specific Enolase (NSE) Levels
Time frame: From baseline (every 4 weeks) up to Week 116
Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change
Time frame: From randomization to definitive deterioration of WHO performance status, assessed up to approximately 3 years
Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29
Time frame: Pre-dose at Day 29.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Aug 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33560090Chan 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.
- Derived from this study: PubMed 29081664Buzzoni 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.
- Derived from this study: PubMed 29055056Fazio 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.
- Derived from this study: PubMed 28838862Pavel 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.
- Derived from this study: PubMed 26703889Yao 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.
- Individual participant dataSharing planned: Yes. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
97 sites in 25 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Everolimus and Best suportive care (BSC) in people with Advanced NET of GI Origin and Advanced NET of Lung Origin, run by Novartis Pharmaceuticals at 97 sites in 25 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 97 sites in United States, Italy, Canada, Germany, United Kingdom and 20 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Dec 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment (time frame: From date of randomization to progression or death, whichever comes first, assessed up to 27 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01524783, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2021.