Efficacy and Safety of Everolimus (RAD001) Compared to Placebo in Patients With Advanced Neuroendocrine Tumors

A Randomized Double-blind Phase III Study of RAD001 10 mg/d Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Pancreatic Neuroendocrine Tumor (NET)

Sponsors

Lead Sponsor: Novartis Pharmaceuticals

Source Novartis
Brief Summary

The purpose of this study was to evaluate progression free survival in those participants assigned everolimus 10 mg/day plus Best Supportive Care versus those assigned to placebo plus Best Supportive Care in Advanced Neuroendocrine Tumors of pancreatic origin.

Overall Status Completed
Start Date July 2007
Completion Date March 2014
Primary Completion Date February 2010
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Time to Progression Free Survival (PFS) Based as Per Investigator Using Kaplan-Meier Methodology Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
Secondary Outcome
Measure Time Frame
Percentage of Participants With Objective Response Rate ( CR {Complete Response} OR PR {Partial Response}) Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
Overall Survival Baseline, to death- no time limit
Progression Free Survival According to Ki-67 Levels Categorized as: Less Than or Equal to 2%, > 2% to Less Than or Equal to 5% and > 5% Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
Progression Free Survival According to Chromogramin A Tumor Marker (CgA) Baseline Level and According to CgA Early Response Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
Progression Free Survival According to Neuron Specific Enolase Tumor Marker (NSE) Baseline Level and According to NSE Early Response Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) on or after the start of double-blind study medication until no later than 28 days after double-blind study medication discontinuation
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) (Open-label Period) on or after the start of open-label study medication until no later than 28 days after open-label study medication discontinuation
Evaluation of Pharmacokinetics (PK) Parameter: AUC0-t Last Day 1 of every cycle (28 days/cycle) throughout the study
Evaluation of Pharmacokinetics (PK) Parameters: Cmax, Cmin Day 1 of every cycle (28 days/cycle) throughout the study
Evaluation of Pharmacokinetics (PK) Parameter: CL/F Day 1 of every cycle (28 days/cycle) throughout the study
Evaluation of Pharmacokinetics (PK) Parameter: Tmax -Time to Maximum (Peak) Drug Concentration Day 1 of every cycle (28 days/cycle) throughout the study
Analysis of Time to Definitive Deterioration of WHO Performance Status Using Kaplan-Meier 3 months, 6 months
Plasma Angiogenesis Marker: Basic Fibroblast Growth Factor (bFGF) Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Plasma Angiogenesis Marker: Placental Growth Factor (PLGF) Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1) Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Plasma Angiogenesis Marker: Vascular Endothelial Growth Factor (VEGF) Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Enrollment 410
Condition
Intervention

Intervention Type: Drug

Intervention Name: Everolimus

Description: A 10-mg dose of everolimus was given by continuous oral daily dosing of two 5-mg tablets.

Arm Group Label: Everolimus 10 mg/day

Other Name: RAD001

Intervention Type: Drug

Intervention Name: Everolimus Placebo

Description: a 10-mg dose of matching placebo to Everolimus was given by continuous oral daily dosing of two 5-mg tablets.

Arm Group Label: Placebo

Eligibility

Criteria:

Inclusion criteria:

1. Patients must have advanced (unresectable or metastatic) biopsy-proven pancreatic NET

2. Measurable disease by radiologic assessment

3. Adequate blood work

4. Performance Status 0-2 : Ability to be out of bed most of the time

5. Adult male or female patients ≥ 18 years of age

6. Women of childbearing potential must have a negative serum pregnancy test

7. Written informed consent from patients must be obtained in accordance to local guidelines

Exclusion criteria:

1. Patients with severe kind of (poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma) cancer are not eligible

2. Other chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to starting this trial

3. Hepatic artery procedure called embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/ radiofrequency ablation of hepatic metastasis within 2 months of enrollment

4. Prior therapy with the same kind of medication (mTOR inhibitors: sirolimus, temsirolimus, everolimus).

5. Uncontrolled diabetes mellitus Patients who have any severe and/or uncontrolled medical conditions such as:

6. Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent

7. Patients with a known history of HIV seropositivity

8. No other prior or concurrent cancer at the time enrolling to this trial

Other protocol defined inclusion/ exclusion criteria applied

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Novartis Pharmaceuticals Study Director Novartis Pharmaceuticals
Location
Facility:
University of South Alabama / Mitchell Cancer Institute Deptof Mitchell Cancer Inst(2) | Mobile, Alabama, 36688, United States
Pacific Cancer Medical Center, Inc. | Anaheim, California, 92801, United States
Cedars Sinai Medical Center SC-2 | Los Angeles, California, 90048, United States
University of California at Los Angeles UCLA (3) | Los Angeles, California, 90095, United States
University of California San Francisco Dept. of UCSF Comp. Cancer | San Francisco, California, 94143-0128, United States
Kaiser Permanente Northwest Franklin Medical Offices | Denver, Colorado, United States
H. Lee Moffitt Cancer Center & Research Institute Malignant Hematology Clinic | Tampa, Florida, 33612, United States
Indiana University Health Goshen Center for Cancer Dept. of Indiana Univ. Cancer | Indianapolis, Indiana, 46202, United States
University of Iowa Medical Center Dept. of Iowa Medical Center | Iowa City, Iowa, 52242, United States
University of Louisville / James Graham Brown Cancer Center SC | Louisville, Kentucky, 40202, United States
LSU HEALTH SCIENCES CENTER/ LSU SCHOOL OF MEDICINE Dept. of Neuroendocrine Clinic | New Orleans, Louisiana, 70115, United States
Boston Medical Center BMC | Boston, Massachusetts, 02118, United States
Wayne State University/Karmanos Cancer Institute Dept.of KarmanosCancerInst (4) | Detroit, Michigan, 48201, United States
Mayo Clinic - Rochester | Rochester, Minnesota, 55905, United States
Littleton Regional Hospital Dept. of Hematology/Oncology | Littleton, New Hampshire, 03561, United States
Columbia University Medical Center- New York Presbyterian Dept. of Columbia Med. Center | New York, New York, 10032, United States
Levine Cancer Institute | Charlotte, North Carolina, 28203, United States
Ohio State Comprehensive Cancer Center/James Cancer Hospital Dept. of OHSU Medical Center | Columbus, Ohio, 43210, United States
Oregon Health & Science University Dept. of OHSU (3) | Portland, Oregon, 97239, United States
St. Luke's Hospital and Health Network St. Luke's Cancer Network | Bethlehem, Pennsylvania, United States
Fox Chase Cancer Center | Philadelphia, Pennsylvania, 19111-2497, United States
University of Pittsburgh Medical Center Hillman Cancer Center | Pittsburgh, Pennsylvania, 15213, United States
The Center for Cancer and Blood Disorders | Fort Worth, Texas, 76104, United States
University of Texas/MD Anderson Cancer Center Dept of MD Anderson CancerCent | Houston, Texas, 77030-4009, United States
Novartis Investigative Site | Bruxelles, 1070, Belgium
Novartis Investigative Site | Bruxelles, 1200, Belgium
Novartis Investigative Site | Leuven, 3000, Belgium
Novartis Investigative Site | Fortaleza, CE, 60430-370, Brazil
Novartis Investigative Site | Calgary, Alberta, T2N 4N2, Canada
Novartis Investigative Site | Edmonton, Alberta, T6G 1Z2, Canada
Novartis Investigative Site | London, Ontario, N6A 4L6, Canada
Novartis Investigative Site | Montreal, Quebec, H1T 2M4, Canada
Novartis Investigative Site | Montreal, Quebec, H3A 1A1, Canada
Novartis Investigative Site | Besancon Cedex, 25030, France
Novartis Investigative Site | Clichy, 92110, France
Novartis Investigative Site | Dijon, 21079, France
Novartis Investigative Site | Lille Cedex, 59020, France
Novartis Investigative Site | Lyon, 69437, France
Novartis Investigative Site | Marseille cedex 05, 13385, France
Novartis Investigative Site | Montpellier Cedex 5, 34298, France
Novartis Investigative Site | Paris Cedex 13, 75651, France
Novartis Investigative Site | Paris, 75015, France
Novartis Investigative Site | Reims, 51092, France
Novartis Investigative Site | Strasbourg, 67098, France
Novartis Investigative Site | Toulouse Cedex 4, 31054, France
Novartis Investigative Site | Villejuif Cedex, 94805, France
Novartis Investigative Site | Bad Berka, 99438, Germany
Novartis Investigative Site | Berlin, 13353, Germany
Novartis Investigative Site | Mainz, 55131, Germany
Novartis Investigative Site | Marburg, 35033, Germany
Novartis Investigative Site | München, 81377, Germany
Novartis Investigative Site | Athens, GR, 115 27, Greece
Novartis Investigative Site | Athens, GR-115 22, Greece
Novartis Investigative Site | Bologna, BO, 40138, Italy
Novartis Investigative Site | Milano, MI, 20132, Italy
Novartis Investigative Site | Milano, MI, 20141, Italy
Novartis Investigative Site | Milano, MI, 20162, Italy
Novartis Investigative Site | Modena, MO, 41100, Italy
Novartis Investigative Site | Pisa, PI, 56124, Italy
Novartis Investigative Site | Kashiwa, Chiba, Japan
Novartis Investigative Site | Fukuoka-city, Fukuoka, 812-8582, Japan
Novartis Investigative Site | Chuo-ku, Tokyo, Japan
Novartis Investigative Site | Seoul, Korea, 110 744, Korea, Republic of
Novartis Investigative Site | Seoul, Korea, 120-752, Korea, Republic of
Novartis Investigative Site | Seoul, Korea, 135-710, Korea, Republic of
Novartis Investigative Site | Seoul, 738-736, Korea, Republic of
Novartis Investigative Site | Groningen, 9713 GZ, Netherlands
Novartis Investigative Site | Martin, Slovak Republic, 036 59, Slovakia
Novartis Investigative Site | Barcelona, Catalunya, 08035, Spain
Novartis Investigative Site | Hospitalet de LLobregat, Cataluña, 08907, Spain
Novartis Investigative Site | Uppsala, SE-751 85, Sweden
Novartis Investigative Site | Zurich, 8091, Switzerland
Novartis Investigative Site | Taipei, Taiwan, ROC, 112, Taiwan
Novartis Investigative Site | Kaohsiung, 807, Taiwan
Novartis Investigative Site | Lin-Ko, 33305, Taiwan
Novartis Investigative Site | Taipei, 10002, Taiwan
Novartis Investigative Site | Bangkok, 10400, Thailand
Novartis Investigative Site | Songkla, 90110, Thailand
Novartis Investigative Site | Withington, Greater Manchester, M20 4BX, United Kingdom
Novartis Investigative Site | Glasgow, G12 0YN, United Kingdom
Novartis Investigative Site | London, EC1A 7BE, United Kingdom
Novartis Investigative Site | London, SE5 9RS, United Kingdom
Location Countries

Belgium

Brazil

Canada

France

Germany

Greece

Italy

Japan

Korea, Republic of

Netherlands

Slovakia

Spain

Sweden

Switzerland

Taiwan

Thailand

United Kingdom

United States

Verification Date

June 2015

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Everolimus 10 mg/day

Type: Experimental

Description: Participants received 10 mg per day of Everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).

Label: Placebo

Type: Placebo Comparator

Description: Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).

Acronym RADIANT-3
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov