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

NCT01524783 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: CRAD001T23022011-002887-26
• Study Type: interventional
• Target: 302
• Locations: 25 countries
• Sites: 97

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.

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Overall Survival (OS)

  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

  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

  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

  From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years

• Change From Baseline in Chromogranin A (CgA) Levels

  From baseline (every 4 weeks) up to 116 weeks

Study Arms (2)

Everolimus + BSC

EXPERIMENTAL

Participants received everolimus 10 mg once daily plus best supportive care (BSC) throughout the study

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.

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

Interventions

Everolimus DRUG

Participants were treated with everolimus 10 mg (two 5 mg tablets) once daily orally taken

Also known as: RAD001

Everolimus + BSC

Placebo DRUG

Participants were treated with two tablets of matching placebo once daily orally taken.

Placebo + BSC

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.

Everolimus + BSC; Placebo + BSC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (97)

University of California San Diego - Moores Cancer Center Regulatory

La Jolla, California, 92093-0658, United States

Location

Scripps Clinic Regulatory

La Jolla, California, 92121, United States

Location

Cedars Sinai Medical Center SC

Los Angeles, California, 90048, United States

Location

University of Colorado Cancer Centre SC

Aurora, Colorado, 80045, United States

Location

H Lee Moffitt Cancer Center and Research Institute HLM

Tampa, Florida, 33612, United States

Location

University of Chicago UC SC

Chicago, Illinois, 60637, United States

Location

Goshen Center for Cancer Care IU Health SC

Indianapolis, Indiana, 46202, United States

Location

Dana Farber Cancer Institute SC

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering MSkCC SC

New York, New York, 10017, United States

Location

Montefiore Medical Center MMC

The Bronx, New York, 10467, United States

Location

Oregon Health and Science University OH&SU

Portland, Oregon, 97239, United States

Location

Vanderbilt University Medical Center Vanderbilt Med Ctr

Nashville, Tennessee, 37232, United States

Location

Texas Oncology P A Texas Oncology Amarillo

Dallas, Texas, 75251, United States

Location

Texas Oncology P A TX Oncology Baylor

Dallas, Texas, 75251, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

University of Texas MD Anderson Cancer Center UT MD Anderson Cancer Ctr

Houston, Texas, 77030, United States

Location

University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc

Madison, Wisconsin, 53792-6164, United States

Location

Novartis Investigative Site

Innsbruck, Tyrol, 6020, Austria

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Novartis Investigative Site

Vienna, A-1090, Austria

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Novartis Investigative Site

Edegem, Antwerpen, 2650, Belgium

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Novartis Investigative Site

Brussels, 1200, Belgium

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Novartis Investigative Site

Ghent, 9000, Belgium

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Novartis Investigative Site

Leuven, 3000, Belgium

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Novartis Investigative Site

Calgary, Alberta, T2N 4N2, Canada

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Novartis Investigative Site

Vancouver, British Columbia, V5Z 4E6, Canada

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Novartis Investigative Site

Halifax, Nova Scotia, B3H 1V7, Canada

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London, Ontario, N6A 4L6, Canada

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Ottawa, Ontario, K1H 8L6, Canada

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Toronto, Ontario, M4N 3M5, Canada

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Montreal, Quebec, H1T 2M4, Canada

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Novartis Investigative Site

Beijing, Beijing Municipality, 100730, China

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Novartis Investigative Site

Beijing, 100021, China

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Novartis Investigative Site

Beijing, 100029, China

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Novartis Investigative Site

Beijing, 100036, China

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Novartis Investigative Site

Beijing, 100039, China

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Bogotá, Cundinamarca, Colombia

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Brno, 65653, Czechia

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Olomouc, 775 20, Czechia

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Prague, 12808, Czechia

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Bad Berka, 99438, Germany

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Berlin, 13353, Germany

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Essen, 45147, Germany

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Frankfurt, 60590, Germany

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Hanover, 30625, Germany

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Magdeburg, 39120, Germany

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Mainz, 55131, Germany

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Athens, 115 27, Greece

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Budapest, 1062, Hungary

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Budapest, 1085, Hungary

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Bologna, BO, 40138, Italy

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Brescia, BS, 25123, Italy

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Viagrande, CT, 95029, Italy

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Florence, FI, 50134, Italy

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Milan, MI, 20133, Italy

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Milan, MI, 20141, Italy

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Rozzano, MI, 20089, Italy

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Modena, MO, 41124, Italy

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Roma, RM, 00168, Italy

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Roma, RM, 00189, Italy

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Verona, VR, 37126, Italy

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Novartis Investigative Site

Napoli, 80131, Italy

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Novartis Investigative Site

Napoli, 80132, Italy

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Novartis Investigative Site

Fukuoka, Fukuoka, 812-8582, Japan

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Novartis Investigative Site

Osaka, Osaka, 553-0003, Japan

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Novartis Investigative Site

Chuo Ku, Tokyo, 104 0045, Japan

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Novartis Investigative Site

Beirut, 1107 2020, Lebanon

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Novartis Investigative Site

El Achrafiyé, 166830, Lebanon

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Amsterdam, 1066 CX, Netherlands

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Gliwice, Silesian Voivodeship, 44-101, Poland

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Poznan, 60-355, Poland

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Rostov-on-Don, 344037, Russia

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Riyadh, 11211, Saudi Arabia

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Bratislava, Slovak Republic, 833 10, Slovakia

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Parktown, 2193, South Africa

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Seoul, Korea, 05505, South Korea

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Novartis Investigative Site

Seoul, Seocho Gu, 06591, South Korea

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Novartis Investigative Site

Seoul, 03080, South Korea

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Novartis Investigative Site

Seoul, 03722, South Korea

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Novartis Investigative Site

Seoul, 06351, South Korea

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Novartis Investigative Site

Seville, Andalusia, 41009, Spain

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Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

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Novartis Investigative Site

L'Hospitalet de Llobregat, Catalonia, 08907, Spain

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Novartis Investigative Site

Taipei, Taiwan, ROC, 11217, Taiwan

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Novartis Investigative Site

Kuei-Shan Chiang, Taoyuan/ Taiwan ROC, 33305, Taiwan

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Novartis Investigative Site

Kaohsiung City, 833, Taiwan

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Novartis Investigative Site

Taichung, 40705, Taiwan

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Novartis Investigative Site

Taipei, 10048, Taiwan

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Novartis Investigative Site

Bangkok, THA, 10330, Thailand

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Novartis Investigative Site

Chiang Mai, 50200, Thailand

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Novartis Investigative Site

Gaziantep, 27310, Turkey (Türkiye)

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Istanbul, 34303, Turkey (Türkiye)

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Glasgow, Scotland, G12 0YN, United Kingdom

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Novartis Investigative Site

Cambridge, CB2 2QQ, United Kingdom

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Novartis Investigative Site

London, SE1 9RT, United Kingdom

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Novartis Investigative Site

London, W12 0HS, United Kingdom

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Novartis Investigative Site

Manchester, M20 2BX, United Kingdom

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Novartis Investigative Site

Southampton, SO16 6YD, United Kingdom

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Related Publications (5)

• 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.

  PMID: 33560090 DERIVED

• 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.

  PMID: 29081664 DERIVED

• 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.

  PMID: 29055056 DERIVED

• 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.

  PMID: 28838862 DERIVED

• 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.

  PMID: 26703889 DERIVED

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2011
• First Posted: February 2, 2012
• Study Start: March 30, 2012
• Primary Completion: November 28, 2014
• Study Completion: August 7, 2020
• Last Updated: August 5, 2021
• Results First Posted: December 28, 2016

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will share

Locations

NL (1); PL (2); BE (4); CA (7); CZ (3); RU (1); SA (1); HU (2); US (17); ZA (1); SL (1); CN (5); JP (3); DE (7); TH (2); GR (1); TU (2); ES (3); AU (2); CO (1); IT (13); LE (2); KR (5); TW (5); GB (6)