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CarcinomaPhase 3EVOLVE-1NCT01035229

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

A Phase 3 study testing Everolimus in people with Carcinoma, run by Novartis Pharmaceuticals at 131 sites in 18 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Carcinoma
What is being tested?
Everolimus
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
546 participants
Where
131 sitesin 18 countries
Study dates
Apr 2010to Oct 2013
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 10Show fewer
  • 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

Who cannot join

  • 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

Trial locations and contacts

131 sites in 18 countries.

131 sites in 18 countries

United States19 sites

  • Texas Cancer Center - Abilene

    Abilene, Texas, 79606

  • The Sidney Kimmel Cancer Center at Johns Hopkins Hospital Dept. of SKCC @ JHU

    Baltimore, Maryland, 21287-0013

  • St. Luke's Hospital and Health Network St. Luke's Cancer Network (2)

    Bethlehem, Pennsylvania

  • Massachusetts General Hospital Dept. of Mass General Hospital

    Boston, Massachusetts, 02114

  • Methodist Charlton Cancer Center Methodist

    Dallas, Texas, 75237

  • University of Texas Southwestern Medical Center DeptofSimmons Cancer Center(3)

    Dallas, Texas, 75390-8527

  • Highlands Oncology Group Dept of Highlands Oncology Grp

    Fayetteville, Arkansas, 72703

  • Compassionate Cancer Care Medical Group CCCMG

    Fountain Valley, California, 92708

  • Rocky Mountain Cancer Centers RMCC - Denver-Midtown (4)

    Greenwood Village, Colorado

  • Queen's Medical Center Queens Cancer Center

    Honolulu, Hawaii, 96817

  • Midwest Cancer Care Physicians Research Medical Center

    Kansas City, Missouri, 64131

  • University of California San Diego - Moores Cancer Center SC - 3

    La Jolla, California, 92093-0658

  • Northwest Cancer Specialists Rose Quarter Cancer Center

    Portland, Oregon, 97210

  • VA Sierra Nevada Health Care System Dept. of VA Sierra Nevada HCS

    Reno, Nevada, 89502

  • Blue Ridge Research Center at Roanoke Neurological Center Blue Ridge Cancer Care

    Roanoke, Virginia, 24018

  • University of Rochester Medical Center Rochester

    Rochester, New York, 14642

  • Cancer Care Centers of South Texas / HOAST CCC of So. TX- San Antonio

    San Antonio, Texas, 78229

  • California Pacific Medical Center California Pacific Med

    San Francisco, California, 94120-7999

  • University of Washington Cancer Care SC

    Seattle, Washington, 98109-1023

Other trials in United States

France18 sites

  • Novartis Investigative Site

    Amiens, 80054

  • Novartis Investigative Site

    Avignon, 84082

  • Novartis Investigative Site

    Bordeaux, 33075

  • Novartis Investigative Site

    Caen Cedex9, 14033

  • Novartis Investigative Site

    Chambray-lès-Tours, 37170

  • Novartis Investigative Site

    Clermont-Ferrand, 63003

  • Novartis Investigative Site

    Clichy, 92110

  • Novartis Investigative Site

    Dijon, 21079

  • Novartis Investigative Site

    Lille, 59037

  • Novartis Investigative Site

    Lyon, 69317

  • Novartis Investigative Site

    Marseille Cédex 5, 13385

  • Novartis Investigative Site

    Montpellier, 34298

  • Novartis Investigative Site

    Nantes, 44093

  • Novartis Investigative Site

    Nice, 06202

  • Novartis Investigative Site

    Reims, 51092

  • Novartis Investigative Site

    Rouen, 76031

  • Novartis Investigative Site

    Saint-Priest-en-Jarez, 42277

  • Novartis Investigative Site

    Strasbourg, 67091

Other trials in France

Japan18 sites

  • Novartis Investigative Site

    Chiba, Chiba, 260-8677

  • Novartis Investigative Site

    Chuo-ku, Tokyo, 104-0045

  • Novartis Investigative Site

    Fukuoka, Fukuoka, 810-8563

  • Novartis Investigative Site

    Fukuoka, Fukuoka, 811-1395

  • Novartis Investigative Site

    Gifu, Gifu, 500-8513

  • Novartis Investigative Site

    Iizuka, Fukuoka, 820-8505

  • Novartis Investigative Site

    Kanazawa, Ishikawa-ken, 920-8641

  • Novartis Investigative Site

    Kashiwa, Chiba, 277-8577

  • Novartis Investigative Site

    Kumamoto, Kumamoto, 860-8556

  • Novartis Investigative Site

    Matsuyama, Ehime, 791-0280

  • Novartis Investigative Site

    Mitaka, Tokyo, 181-8611

  • Novartis Investigative Site

    Nagoya, Aichi-ken, 464-8681

  • Novartis Investigative Site

    Ōgaki, Gifu, 503-8502

  • Novartis Investigative Site

    Osaka, Osaka, 537-8511

  • Novartis Investigative Site

    Sayama, Osaka, 589-8511

  • Novartis Investigative Site

    Sendai, Miyagi, 980-8574

  • Novartis Investigative Site

    Shinagawa-ku, Tokyo, 141-8625

  • Novartis Investigative Site

    Yokohama, Kanagawa, 232-0024

Other trials in Japan

Italy14 sites

  • Novartis Investigative Site

    Aviano, PN, 33081

  • Novartis Investigative Site

    Benevento, BN, 82100

  • Novartis Investigative Site

    Bologna, BO, 40138

  • Novartis Investigative Site

    Foggia, FG, 71100

  • Novartis Investigative Site

    Frattamaggiore, 80020

  • Novartis Investigative Site

    Milan, MI, 20122

  • Novartis Investigative Site

    Modena, MO, 41100

  • Novartis Investigative Site

    Naples, 80131

  • Novartis Investigative Site

    Padova, PD, 35128

  • Novartis Investigative Site

    Palermo, PA, 90127

  • Novartis Investigative Site

    Pavia, PV, 27100

  • Novartis Investigative Site

    Roma, RM, 00128

  • Novartis Investigative Site

    Roma, RM, 00168

  • Novartis Investigative Site

    Rozzano, MI, 20089

Other trials in Italy

Germany11 sites

  • Novartis Investigative Site

    Berlin, 13353

  • Novartis Investigative Site

    Essen, 45147

  • Novartis Investigative Site

    Esslingen am Neckar, 73730

  • Novartis Investigative Site

    Frankfurt, 60590

  • Novartis Investigative Site

    Göttingen, D-37075

  • Novartis Investigative Site

    Hamburg, 20246

  • Novartis Investigative Site

    Hanover, 30625

  • Novartis Investigative Site

    Leipzig, 04103

  • Novartis Investigative Site

    Mannheim, Baden-Wurttemberg, 68305

  • Novartis Investigative Site

    München, 81377

  • Novartis Investigative Site

    Würzburg, 97080

Other trials in Germany

Taiwan7 sites

  • Novartis Investigative Site

    Linkou District, 33305

  • Novartis Investigative Site

    Liouying Township

  • 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

    Taipei, Taiwan, ROC, 112

Other trials in Taiwan

China6 sites

  • Novartis Investigative Site

    Beijing, 100039

  • Novartis Investigative Site

    Chengdu, Sichuan, 610041

  • Novartis Investigative Site

    Guangzhou, 510060

  • Novartis Investigative Site

    Hangzhou, Zhejiang, 310016

  • Novartis Investigative Site

    Nanjing, Jiangsu, 210002

  • Novartis Investigative Site

    Xi’an, Shanxi, 710032

Other trials in China

Spain6 sites

  • Novartis Investigative Site

    Barcelona, Catalonia, 08035

  • Novartis Investigative Site

    Barcelona, Catalonia, 08036

  • Novartis Investigative Site

    Córdoba, Andalusia, 14004

  • Novartis Investigative Site

    Madrid, Madrid, 28034

  • Novartis Investigative Site

    Pamplona, Navarre, 31008

  • Novartis Investigative Site

    Sabadell, Barcelona, 08208

Other trials in Spain

Australia5 sites

  • Novartis Investigative Site

    Camperdown, New South Wales, 2050

  • Novartis Investigative Site

    Heidelberg, Victoria, 3084

  • Novartis Investigative Site

    Kogarah, New South Wales, 2217

  • Novartis Investigative Site

    Parkville, Victoria, 3050

  • Novartis Investigative Site

    Westmead, New South Wales, 2145

Other trials in Australia

Belgium4 sites

  • Novartis Investigative Site

    Brussels, 1070

  • Novartis Investigative Site

    Brussels, 1200

  • Novartis Investigative Site

    Edegem, 2650

  • Novartis Investigative Site

    Leuven, 3000

Other trials in Belgium

Canada4 sites

  • Novartis Investigative Site

    London, Ontario, N6A 4L6

  • Novartis Investigative Site

    Montreal, Quebec, H2X 1P1

  • Novartis Investigative Site

    Montreal, Quebec, H3A 1A1

  • Novartis Investigative Site

    Toronto, Ontario, M4N 3M5

Other trials in Canada

Hungary4 sites

  • Novartis Investigative Site

    Budapest, H-1122

  • Novartis Investigative Site

    Debrecen, 4032

  • Novartis Investigative Site

    Szeged, H-6720

  • Novartis Investigative Site

    Szombathely, 9700

Other trials in Hungary

South Korea4 sites

  • Novartis Investigative Site

    Seoul, Korea, 03080

  • Novartis Investigative Site

    Seoul, Korea, 03722

  • Novartis Investigative Site

    Seoul, Korea, 05505

  • Novartis Investigative Site

    Seoul, Korea, 06351

Other trials in South Korea

Austria3 sites

  • Novartis Investigative Site

    Graz, 8036

  • Novartis Investigative Site

    Innsbruck, A-6020

  • Novartis Investigative Site

    Vienna, 1090

Other trials in Austria

Greece3 sites

  • Novartis Investigative Site

    Athens, GR, 124 62

  • Novartis Investigative Site

    Larissa, GR, 411 10

  • Novartis Investigative Site

    Thessaloniki, Greece, 57001

Other trials in Greece

Israel2 sites

  • Novartis Investigative Site

    Petah Tikva, 49100

  • Novartis Investigative Site

    Ramat Gan, 5266202

Other trials in Israel

Thailand2 sites

  • Novartis Investigative Site

    Bangkok, 10400

  • Novartis Investigative Site

    Bangkok, 10700

Other trials in Thailand

Hong Kong1 site

  • Novartis Investigative Site

    Hong Kong

Other trials in Hong Kong

About this study

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

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.

Conditions
Carcinoma
Being tested
Everolimus, Everolimus Placebo, Best Supportive Care (BSC)
Keywords
Hepatocellular carcinoma, randomized trial, medical treatment, RAD001, placebo, Advanced Hepatocellular Carcinoma (HCC)
Medical subject headings
Carcinoma, Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EverolimusDrug

    Also called RAD001

    Everolimus (labeled as RAD001) was formulated as tablets of 2.5 mg strength and blisterpacked in units of 10 tablets.

  • Everolimus PlaceboDrug

    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.

  • Best Supportive Care (BSC)Other

    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

Study groups in NCT01035229
Study groupRoleWhat they receive
Everolimus + Best Supportice Care (BSC)ExperimentalPatients 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.
Receives: Drug: Everolimus; Other: Best Supportive Care (BSC)
Placebo + Best Supportive CarePlacebo comparatorPlacebo 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.
Receives: Drug: Everolimus Placebo; Other: Best Supportive Care (BSC)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: When 454 OS events were observed

Secondary outcomes (6)

  1. 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.

    Measured: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient

  2. 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.

    Measured: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient

  3. 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

    Measured: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.

  4. 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.

    Measured: Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.

  5. 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.

    Measured: Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.

  6. 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.

    Measured: Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Dec 2009 (estimated)
  2. Study startApr 2010
  3. Primary completionOct 2013
  4. Study completionOct 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
546 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01035229
Sponsor's protocol ID
CRAD001O2301
Other IDs
2009-010196-25, 2009
Acronym
EVOLVE-1
Status last verified
Aug 2016
First submitted
17 Dec 2009
Last updated
22 Sep 2016
Data monitoring committee
Yes

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.

    PubMed 27130844

  • 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.

    PubMed 25058218

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Everolimus in people with Carcinoma, run by Novartis Pharmaceuticals at 131 sites in 18 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 131 sites in United States, France, Japan, Italy, Germany and 13 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Oct 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Survival (OS) (time frame: When 454 OS events were observed). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01035229, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2016.

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