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)

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

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.

Study Overview

• Status: Completed
• Conditions: Carcinoma
• Intervention / Treatment: Drug: Everolimus; Other: Best Supportive Care (BSC); Drug: Everolimus Placebo

• Study Type: Interventional
• Enrollment (Actual): 546
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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.	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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	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.	When 454 OS events were observed

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Tumor Progression (TTP)	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.	Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient
Percentage of Participants With Disease Control Rate (DCR)	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.	Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient
Time to Definitive Deterioration of ECOG Performance Score (PS) Score	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	Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.
Time to Definitive Deterioration of EORTC QLQ-C30 Scores	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.	Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.
Pharmacokinetics Assessments - Cmin	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.	Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.
Pharmacokinetics Assessments - Cmax	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.	Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Zhu AX, Chen D, He W, Kanai M, Voi M, Chen LT, Daniele B, Furuse J, Kang YK, Poon RT, Vogel A, Chiang DY. Integrative biomarker analyses indicate etiological variations in hepatocellular carcinoma. J Hepatol. 2016 Aug;65(2):296-304. doi: 10.1016/j.jhep.2016.04.015. Epub 2016 Apr 27.
• Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, Poon RT, Blanc JF, Vogel A, Chen CL, Dorval E, Peck-Radosavljevic M, Santoro A, Daniele B, Furuse J, Jappe A, Perraud K, Anak O, Sellami DB, Chen LT. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014 Jul 2;312(1):57-67. doi: 10.1001/jama.2014.7189.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: December 17, 2009
• First Submitted That Met QC Criteria: December 17, 2009
• First Posted (Estimate): December 18, 2009

Study Record Updates

• Last Update Posted (Estimate): September 22, 2016
• Last Update Submitted That Met QC Criteria: August 16, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: randomized trial; placebo; Hepatocellular carcinoma; RAD001; medical treatment; Advanced Hepatocellular Carcinoma (HCC)
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CRAD001O2301; 2009-010196-25 (EudraCT Number)