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Global Study Looking at the Combination of RAD001 Plus Best Supportive Care (BSC) and Placebo Plus BSC to Treat Patients With Advanced Hepatocellular Carcinoma. (EVOLVE-1)

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ClinicalTrials.gov Identifier: NCT01035229
Recruitment Status : Completed
First Posted : December 18, 2009
Results First Posted : October 27, 2014
Last Update Posted : September 22, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this study is to compare treatment with RAD001 plus best supportive care (BSC) to placebo plus BSC in patients with advanced HCC whose disease progressed while on or after sorafenib treatment or who are intolerant to sorafenib.

Condition or disease Intervention/treatment Phase
Carcinoma Drug: Everolimus Drug: Everolimus Placebo Other: Best Supportive Care (BSC) Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 546 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Phase III, Double-blind, Placebo-controlled, Multi-center Study to Evaluate the Efficacy and Safety of Everolimus (RAD001) in Adult Patients With Advanced Hepatocellular Carcinoma After Failure of Sorafenib Treatment - The EVOLVE-1 Study
Study Start Date : April 2010
Actual Primary Completion Date : October 2013
Actual Study Completion Date : October 2013

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Everolimus + Best Supportice Care (BSC)
Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the investigational drug. In addition to taking Everolimus, all patients also received BSC as per normal local practice.
Drug: Everolimus
Everolimus (labeled as RAD001) was formulated as tablets of 2.5 mg strength and blisterpacked in units of 10 tablets.
Other Name: RAD001

Other: Best Supportive Care (BSC)
BSC was defined as drug or non-drug therapies, nutritional support, physical therapy or anything that the Investigator believed to be in the patient's best interest, but excluding other antineoplastic treatments. BSC administered to the patient throughout the study was to be reported on the Concomitant Medication/Significant Non-Drug Therapy electronic case report from (eCRF). Permitted BSC treatments during the study included, but were not limited to, the following: Pain medication to allow the patient to be as comfortable as possible, Bisphosphonates for bone metastases, Localized radiotherapy, for the treatment of pre-existing, painful bone metastases, Nutritional support or appetite stimulants (i.e. megestrol) as recommended by the Investigator, Oxygen therapy and blood products or transfusions

Placebo Comparator: Placebo + Best Supportive Care
Placebo Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placeb Everolimus, all patients also received BSC as per normal local practice.
Drug: Everolimus Placebo
Everolimus Placebo matched to the everolimus 2.5 mg tablet strength was blister-packed in units of 10 tablets. Matching placebo tablets were formulated to be indistinguishable from the everolimus tablets. Everolimus placebo was taken as a daily oral dose of 7.5 mg and was defined as the control drug.

Other: Best Supportive Care (BSC)
BSC was defined as drug or non-drug therapies, nutritional support, physical therapy or anything that the Investigator believed to be in the patient's best interest, but excluding other antineoplastic treatments. BSC administered to the patient throughout the study was to be reported on the Concomitant Medication/Significant Non-Drug Therapy electronic case report from (eCRF). Permitted BSC treatments during the study included, but were not limited to, the following: Pain medication to allow the patient to be as comfortable as possible, Bisphosphonates for bone metastases, Localized radiotherapy, for the treatment of pre-existing, painful bone metastases, Nutritional support or appetite stimulants (i.e. megestrol) as recommended by the Investigator, Oxygen therapy and blood products or transfusions




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: When 454 OS events were observed ]
    OS was defined as the time from the date of randomization to the date of death from any cause. The comparison of OS between the 2 arms was done using a stratified log-rank test at one-sided 2.5% level of significance.


Secondary Outcome Measures :
  1. Time to Tumor Progression (TTP) [ Time Frame: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient ]
    TTP was defined as the time from the date of randomization to the date of the first documented radiologic confirmation of disease progression. Since the study did not meet the primary objective, TTP was not formally tested.

  2. Percentage of Participants With Disease Control Rate (DCR) [ Time Frame: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient ]
    DCR is defined as the proportion of participants with a best objective response (BOR) of complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST. The BOR was the best response recorded from the start of the treatment until disease progression. CR is disappearance of all target lesions; PR is 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; SD is neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. PD is at least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.

  3. Time to Definitive Deterioration of ECOG Performance Score (PS) Score [ Time Frame: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient. ]
    Change in Eastern Cooperative Oncology Group (ECOG) were assessed by time to definitive performance status deterioration by at least one category on the ECOG scale. Deterioration was considered definitive if no improvement in the ECOG PS was observed at a subsequent measurement. ECOG PS: 0=Fully active, able to carry on all pre-disease performance without restriction, 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2=Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; 5=Dead

  4. Time to Definitive Deterioration of EORTC QLQ-C30 Scores [ Time Frame: Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient. ]
    The primary quality of life endpoint was the time to definitive 5% deterioration from baseline in the global health status/quality of life scale of the EORTC QLQ-C30 questionnaire. Definitive deterioration by at least 5% is defined as a decrease in score by at least 5% compared to baseline, with no later observed increase above this threshold. The EORTC quality of life questionnaire (QLQ) is an integrated system for assessing the healthrelated quality of life (QoL) of cancer patients participating in international clinical trials. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.

  5. Pharmacokinetics Assessments - Cmin [ Time Frame: Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient. ]
    Cmin is the pre-dose blood concentration at steady-state (ng/mL). Pre-dose (Cmin) blood samples were collected from all patients in both arms at Visit 3. Steady-state for the Cmin sample was defined as continuous administration of the same dose in the last 4 days prior to the collection of the Cmin sample. Steady-state for the 5 mg every other day regimen was defined as the state when the 5 mg dose was taken 2 days and 4 days before sampling. PK samples were only drawn at visit 3, and only analyzed for patients receiving everolimus at steady state (if patients had received the dose the previous 4 days). In addition summary statistics were only done for each everolimus dose when 3 samples were available. Only valid pre-dose (Cmin) everolimus samples were included in the analysis.

  6. Pharmacokinetics Assessments - Cmax [ Time Frame: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient. ]
    Cmax is the maximum (peak) blood drug concentration after dose administration (ng/mL) calculated as the maximum of C1h and C2h. C1h was 1 hour post-dose blood concentration (ng/mL) and C2h was 2 hour post-dose blood concentration (ng/mL). C1h and C2h post-dose samples were collected from all patients in both arms at Visit 3. Steady-state for the C1h and C2h samples was defined as continuous administration of the same dose in the previous 4 days and the day on which the C1h and C2h samples were collected. Steady-state for the 5 mg every other day regimen was defined as the state when the 5 mg dose was taken 2 days and 4 days before sampling. PK samples were only drawn at visit 3, and only analyzed for patients receiving everolimus at steady state (if patients had received the dose the previous 4 days). In addition summary statistics were only done for each everolimus dose when 3 samples were available. Only valid C1h and C2h everolimus samples were included in the analysis.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Advanced liver cancer
  • Prior systemic treatment with sorafenib for advanced HCC and for whom their disease progressed during or after sorafenib treatment, or were intolerant to sorafenib treatment. Specifically, this can be defined as:

    • Documented radiological confirmation (radiology scans or report) of disease progression during or after sorafenib treatment
    • Intolerance to sorafenib (at any dose and/or duration) is defined as documented sorafenib-related grade 3 or 4 adverse events that led to sorafenib discontinuation.

NOTE:

  • Sorafenib must be the last antineoplastic treatment before randomization
  • Prior local and/or hormonal therapy (e.g., tamoxifen) before sorafenib is allowed
  • One systemic chemotherapy regimen for advanced HCC is allowed before sorafenib treatment

    • ECOG performance status of ≤ 2
    • Child-Pugh A

Exclusion Criteria:

  • Active bleeding during the last 28 days
  • Prior therapy with mTOR inhibitors
  • Prior liver or other organ transplantation which mandates systemic immunosuppression

Other protocol-defined inclusion/exclusion criteria may apply


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01035229


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Locations
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United States, Arkansas
Highlands Oncology Group Dept of Highlands Oncology Grp
Fayetteville, Arkansas, United States, 72703
United States, California
Compassionate Cancer Care Medical Group CCCMG
Fountain Valley, California, United States, 92708
University of California San Diego - Moores Cancer Center SC - 3
La Jolla, California, United States, 92093-0658
California Pacific Medical Center California Pacific Med
San Francisco, California, United States, 94120-7999
United States, Colorado
Rocky Mountain Cancer Centers RMCC - Denver-Midtown (4)
Greenwood Village, Colorado, United States
United States, Hawaii
Queen's Medical Center Queens Cancer Center
Honolulu, Hawaii, United States, 96817
United States, Maryland
The Sidney Kimmel Cancer Center at Johns Hopkins Hospital Dept. of SKCC @ JHU
Baltimore, Maryland, United States, 21287-0013
United States, Massachusetts
Massachusetts General Hospital Dept. of Mass General Hospital
Boston, Massachusetts, United States, 02114
United States, Missouri
Midwest Cancer Care Physicians Research Medical Center
Kansas City, Missouri, United States, 64131
United States, Nevada
VA Sierra Nevada Health Care System Dept. of VA Sierra Nevada HCS
Reno, Nevada, United States, 89502
United States, New York
University of Rochester Medical Center Rochester
Rochester, New York, United States, 14642
United States, Oregon
Northwest Cancer Specialists Rose Quarter Cancer Center
Portland, Oregon, United States, 97210
United States, Pennsylvania
St. Luke's Hospital and Health Network St. Luke's Cancer Network (2)
Bethlehem, Pennsylvania, United States
United States, Texas
Texas Cancer Center - Abilene
Abilene, Texas, United States, 79606
Methodist Charlton Cancer Center Methodist
Dallas, Texas, United States, 75237
University of Texas Southwestern Medical Center DeptofSimmons Cancer Center(3)
Dallas, Texas, United States, 75390-8527
Cancer Care Centers of South Texas / HOAST CCC of So. TX- San Antonio
San Antonio, Texas, United States, 78229
United States, Virginia
Blue Ridge Research Center at Roanoke Neurological Center Blue Ridge Cancer Care
Roanoke, Virginia, United States, 24018
United States, Washington
University of Washington Cancer Care SC
Seattle, Washington, United States, 98109-1023
Australia, New South Wales
Novartis Investigative Site
Camperdown, New South Wales, Australia, 2050
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Kogarah, New South Wales, Australia, 2217
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Westmead, New South Wales, Australia, 2145
Australia, Victoria
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Heidelberg, Victoria, Australia, 3084
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Parkville, Victoria, Australia, 3050
Austria
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Graz, Austria, 8036
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Innsbruck, Austria, A-6020
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Wien, Austria, 1090
Belgium
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Bruxelles, Belgium, 1070
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Bruxelles, Belgium, 1200
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Edegem, Belgium, 2650
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Leuven, Belgium, 3000
Canada, Ontario
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London, Ontario, Canada, N6A 4L6
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Toronto, Ontario, Canada, M4N 3M5
Canada, Quebec
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Montreal, Quebec, Canada, H2X 1P1
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Montreal, Quebec, Canada, H3A 1A1
China, Jiangsu
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Nanjing, Jiangsu, China, 210002
China, Shanxi
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Xi'an, Shanxi, China, 710032
China, Sichuan
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Chengdu, Sichuan, China, 610041
China, Zhejiang
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Hangzhou, Zhejiang, China, 310016
China
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Beijing, China, 100039
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Guangzhou, China, 510060
France
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Amiens cedex 1, France, 80054
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Avignon Cedex, France, 84082
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Bordeaux Cedex, France, 33075
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Caen Cedex9, France, 14033
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Chambray-lès-Tours, France, 37170
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Clermont Ferrand cedex 1, France, 63003
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Clichy, France, 92110
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Dijon, France, 21079
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Lille Cedex, France, 59037
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Lyon Cedex 04, France, 69317
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Marseille Cédex 5, France, 13385
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Montpellier Cedex 5, France, 34298
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Nantes Cedex 1, France, 44093
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Nice Cedex 3, France, 06202
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Reims, France, 51092
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Rouen Cedex, France, 76031
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St Priest en Jarez Cedex, France, 42277
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Strasbourg, France, 67091
Germany
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Mannheim, Baden-Württemberg, Germany, 68305
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Berlin, Germany, 13353
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Essen, Germany, 45147
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Esslingen, Germany, 73730
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Frankfurt, Germany, 60590
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Goettingen, Germany, D-37075
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Hamburg, Germany, 20246
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Hannover, Germany, 30625
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Leipzig, Germany, 04103
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Muenchen, Germany, 81377
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Würzburg, Germany, 97080
Greece
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Athens, GR, Greece, 124 62
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Larissa, GR, Greece, 411 10
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Thessaloniki, Greece, 57001
Hong Kong
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Hong Kong, Hong Kong
Hungary
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Budapest, Hungary, H-1122
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Debrecen, Hungary, 4032
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Szeged, Hungary, H-6720
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Szombathely, Hungary, 9700
Israel
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Petach Tikva, Israel, 49100
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Ramat Gan, Israel, 5266202
Italy
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Benevento, BN, Italy, 82100
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Bologna, BO, Italy, 40138
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Foggia, FG, Italy, 71100
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Milano, MI, Italy, 20122
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Rozzano, MI, Italy, 20089
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Modena, MO, Italy, 41100
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Palermo, PA, Italy, 90127
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Padova, PD, Italy, 35128
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Aviano, PN, Italy, 33081
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Pavia, PV, Italy, 27100
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Roma, RM, Italy, 00128
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Roma, RM, Italy, 00168
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Frattamaggiore, Italy, 80020
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Napoli, Italy, 80131
Japan
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Nagoya, Aichi, Japan, 464-8681
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Chiba-city, Chiba, Japan, 260-8677
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Kashiwa, Chiba, Japan, 277-8577
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Matsuyama, Ehime, Japan, 791-0280
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Iizuka-city, Fukuoka, Japan, 820-8505
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Gifu-shi, Gifu, Japan, 500-8513
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Ogaki-city, Gifu, Japan, 503-8502
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Kanazawa-city, Ishikawa, Japan, 920-8641
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Yokohama-city, Kanagawa, Japan, 232-0024
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Kumamoto City, Kumamoto, Japan, 860-8556
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Sendai-city, Miyagi, Japan, 980-8574
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OsakaSayama, Osaka, Japan, 589-8511
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Chuo-ku, Tokyo, Japan, 104-0045
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Mitaka-city, Tokyo, Japan, 181-8611
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Shinagawa-ku, Tokyo, Japan, 141-8625
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Fukuoka, Japan, 810-8563
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Fukuoka, Japan, 811-1395
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Osaka, Japan, 537-8511
Korea, Republic of
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Seoul, Korea, Korea, Republic of, 03080
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Seoul, Korea, Korea, Republic of, 03722
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Seoul, Korea, Korea, Republic of, 05505
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Seoul, Korea, Korea, Republic of, 06351
Spain
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Cordoba, Andalucia, Spain, 14004
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Sabadell, Barcelona, Spain, 08208
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Barcelona, Catalunya, Spain, 08035
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Barcelona, Catalunya, Spain, 08036
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Pamplona, Navarra, Spain, 31008
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Madrid, Spain, 28034
Taiwan
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Taipei, Taiwan, ROC, Taiwan, 112
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Lin-Kou, Taiwan, 33305
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Liouying Township, Taiwan
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Niaosong Township, Taiwan, 83301
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Taichung, Taiwan, 40447
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Tainan, Taiwan, 70403
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Taipei, Taiwan, 10048
Thailand
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Bangkok, Thailand, 10400
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Bangkok, Thailand, 10700
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01035229     History of Changes
Other Study ID Numbers: CRAD001O2301
2009-010196-25 ( EudraCT Number )
First Posted: December 18, 2009    Key Record Dates
Results First Posted: October 27, 2014
Last Update Posted: September 22, 2016
Last Verified: August 2016

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Hepatocellular carcinoma
randomized trial
medical treatment
RAD001
placebo
Advanced Hepatocellular Carcinoma (HCC)

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents