Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin) (RADIANT-4)

• ClinicalTrials.gov Identifier: NCT01524783
• Recruitment Status: Completed
• First Posted: February 2, 2012
• Results First Posted: December 28, 2016
• Last Update Posted: August 5, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: December 22, 2011
• First Posted Date: February 2, 2012
• Results First Submitted Date: March 26, 2016
• Results First Posted Date: December 28, 2016
• Last Update Posted Date: August 5, 2021
• Actual Study Start Date: March 30, 2012
• Actual Primary Completion Date: November 28, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 13, 2021)

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.

Original Primary Outcome Measures (submitted: February 1, 2012)

Time to Progression free survival (PFS) [ Time Frame: From date of randomization to the date of death ]

The estimated average duration from randomization date is at least 5-8.5 months until disease progression. PFS is defined as the time from randomization to the date of the first documented tumor progression as per modified RECIST 1.0 or death from any cause, whichever comes first. Progression is assessed by CT and/or MRI.

Current Secondary Outcome Measures (submitted: July 13, 2021)

• Overall Survival (OS) [ Time Frame: From date of randomization to date of death, assessed up to approximately 8 years ]
  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.
• 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 ]
  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.
• 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 ]
  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.
• 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 ]
  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.
• Change From Baseline in Chromogranin A (CgA) Levels [ Time Frame: From baseline (every 4 weeks) up to 116 weeks ]
  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.
• Change From Baseline in Neuron Specific Enolase (NSE) Levels [ Time Frame: From baseline (every 4 weeks) up to Week 116 ]
  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.
• 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 ]
  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.
• Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29 [ Time Frame: Pre-dose 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

Original Secondary Outcome Measures (submitted: February 1, 2012)

• Time to Overall survival (OS) [ Time Frame: From date of randomization to the date of death ]
  The estimated average survival duration is at least 30 to 46 months from randomization date. OS is defined as the time from the date of randomization to date of death due to any cause.
• Overall safety evaluation of everolimus versus placebo [ Time Frame: Each visit from randomization up to 5 years ]
  The estimated average survival duration is at least 30 to 46 months from randomization date.The assessment of safety will be based mainly on the frequency and type of treatment emergent adverse events and on the number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. vital signs) will be considered as appropriate. Safety events will be graded using the CTCAE V4.03 (Common Terminology Criteria for Adverse Events) which defines the severity of adverse events from Grade 0 (None) to Grade 4 (life-threatening consequences) and Grade 5 (Death due to AE).
• Time to definitive deterioration in FACT-G total score over the duration of the study [ Time Frame: Every 2 - 3 months up to 5 years ]
  The estimated average duration is at least 5-8.5 months until disease progression. FACT-G is a self-assessed health-related quality of life questionnaire. The questionnaire is comprised of 27 questions, scored 0 to 4, examining physical, social/family, emotional, and functional well-being. Deterioration is defined as a decrease by at least 7 points compared to baseline.
• Time to Objective response rate (ORR) [ Time Frame: 5 years ]
  The estimated average duration is at least 5-8.5 months until disease progression. ORR will be assessed per modified RECIST 1.0. ORR is the proportion of patients with a best overall response of complete response (CR) or partial response (PR).
• Disease control rate (DCR) [ Time Frame: 5 years ]
  The estimated average treatment duration is at least 5-8.5 months until disease progression. DCR will be assessed per modified RECIST 1.0. DCR is the proportion of patients with best overall response of CR, PR or stable disease (SD).
• Change in Chromogranin A (CgA) and Neuron specific enolase (NSE) levels during the study [ Time Frame: Every visit from baseline up to 5 years ]
  The estimated average treatment duration is at least 5-8.5 months until disease progression. CgA and NSE are potential biomarkers for tumor response. Change from baseline will be noted and correlated with tumor response.
• Time to definitive deterioration inWHO Performance Status change during the study [ Time Frame: Every visit up from randomization to 5 years ]
  The estimated average duration is at least 5-8.5 months until disease progression. WHO Performance Status is a scale rated from 0 (normal) to 5 (dead) by a healthcare professional to assess the overall status of a patient. Deterioration is defined as an increase of at least one category compared to baseline.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• 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
  Other Name: RAD001
• Drug: 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.

Study Arms

• Experimental: Everolimus + BSC
  Participants received everolimus 10 mg once daily plus best supportive care (BSC) throughout the study
  Interventions:

  • Drug: Everolimus
  • Other: Best suportive care (BSC)
• Placebo Comparator: Placebo + 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.
  Interventions:

  • Drug: Placebo
  • Other: Best suportive care (BSC)

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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 1, 2016): 302
• Original Estimated Enrollment (submitted: February 1, 2012): 279
• Actual Study Completion Date: August 7, 2020
• Actual Primary Completion Date: November 28, 2014 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: 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, United States
• Removed Location Countries: Czech Republic, Norway, Peru

Administrative Information

• NCT Number: NCT01524783
• Other Study ID Numbers: CRAD001T2302; 2011-002887-26 ( Registry Identifier: EudraCT )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: July 2021