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

Carcinoma Clinical Trial

— EVOLVE-1  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01035229
• Other study ID #: CRAD001O2301
• Secondary ID: 2009-010196-25
• Status: Completed
• Phase: Phase 3
• First received: December 17, 2009
• Last updated: October 30, 2014
• Start date: April 2010
• Est. completion date: October 2013

Study information

• Verified date: October 2014
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustria: EthikkommissionBelgium: Institutional Review BoardFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Hungary: Institutional Ethics CommitteeGreece: Ethics CommitteeItaly: Ethics CommitteeGermany: German Institute of Medical Documentation and InformationSpain: Ministry of HealthCanada: Health CanadaJapan: Institutional Review BoardAustralia: Department of Health and Ageing Therapeutic Goods AdministrationChina: Ethics CommitteeHong Kong: Department of HealthKorea: Food and Drug AdministrationIsrael: Ministry of HealthTaiwan: Center for Drug EvaluationThailand: Food and Drug Administration
• Study type: Interventional

Clinical 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 546
• Est. completion date: October 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular

Intervention

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

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Camperdown	New South Wales
Australia	Novartis Investigative Site	Heidelberg	Victoria
Australia	Novartis Investigative Site	Kogarah	New South Wales
Australia	Novartis Investigative Site	Parkville	Victoria
Australia	Novartis Investigative Site	Westmead	New South Wales
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Innsbruck
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Edegem
Belgium	Novartis Investigative Site	Leuven
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Guangzhou
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Xi'an	Shanxi
France	Novartis Investigative Site	Amiens cedex 1
France	Novartis Investigative Site	Avignon Cedex
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Caen Cedex9
France	Novartis Investigative Site	Chambray-lès-Tours
France	Novartis Investigative Site	Clermont Ferrand cedex 1
France	Novartis Investigative Site	Clichy
France	Novartis Investigative Site	Dijon
France	Novartis Investigative Site	LILLE Cedex
France	Novartis Investigative Site	Lyon Cedex 04
France	Novartis Investigative Site	Marseille Cédex 5
France	Novartis Investigative Site	Montpellier Cedex 5
France	Novartis Investigative Site	Nantes Cedex 1
France	Novartis Investigative Site	Nice Cedex 3
France	Novartis Investigative Site	Reims
France	Novartis Investigative Site	Rouen Cedex
France	Novartis Investigative Site	St Priest en Jarez Cedex
France	Novartis Investigative Site	Strasbourg
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Esslingen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Göttingen
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mannheim	Baden-Württemberg
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Würzburg
Greece	Novartis Investigative Site	Athens	GR
Greece	Novartis Investigative Site	Larissa	GR
Greece	Novartis Investigative Site	Thessaloniki
Hong Kong	Novartis Investigative Site	Hong Kong
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Szeged
Hungary	Novartis Investigative Site	Szombathely
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Ramat Gan
Italy	Novartis Investigative Site	Aviano	PN
Italy	Novartis Investigative Site	Benevento	BN
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Foggia	FG
Italy	Novartis Investigative Site	Frattamaggiore
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Padova
Italy	Novartis Investigative Site	Palermo	PA
Italy	Novartis Investigative Site	Pavia	PV
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Rozzano	MI
Japan	Novartis Investigative Site	Chiba-city	Chiba
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka
Japan	Novartis Investigative Site	Fukuoka
Japan	Novartis Investigative Site	Gifu-shi	Gifu
Japan	Novartis Investigative Site	Iizuka	Fukuoka
Japan	Novartis Investigative Site	Kanazawa	Ishikawa
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Kumamoto City	Kumamoto
Japan	Novartis Investigative Site	Matsuyama	Ehime
Japan	Novartis Investigative Site	Mitaka-city	Tokyo
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Ogaki-city	Gifu
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	OsakaSayama	Osaka
Japan	Novartis Investigative Site	Sendai-city	Miyagi
Japan	Novartis Investigative Site	Shinagawa-ku	Tokyo
Japan	Novartis Investigative Site	Yokohama	Kanagawa
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Cordoba	Andalucia
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Pamplona	Navarra
Spain	Novartis Investigative Site	Sabadell	Barcelona
Taiwan	Novartis Investigative Site	Lin-Ko
Taiwan	Novartis Investigative Site	Liouying Township
Taiwan	Novartis Investigative Site	Niaosong Township
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Tainan
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei	Taiwan, ROC
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
United States	Texas Cancer Center - Abilene	Abilene	Texas
United States	The Sidney Kimmel Cancer Center at Johns Hopkins Hospital Dept. of SKCC @ JHU	Baltimore	Maryland
United States	St. Luke's Hospital and Health Network St. Luke's Cancer Network (2)	Bethlehem	Pennsylvania
United States	Massachusetts General Hospital Dept. of Mass General Hospital	Boston	Massachusetts
United States	Methodist Charlton Cancer Center Methodist	Dallas	Texas
United States	University of Texas Southwestern Medical Center DeptofSimmons Cancer Center(3)	Dallas	Texas
United States	Highlands Oncology Group Dept of Highlands Oncology Grp	Fayetteville	Arkansas
United States	Compassionate Cancer Care Medical Group CCCMG	Fountain Valley	California
United States	Rocky Mountain Cancer Centers RMCC - Denver-Midtown (4)	Greenwood Village	Colorado
United States	Queen's Medical Center Queens Cancer Center	Honolulu	Hawaii
United States	Midwest Cancer Care Physicians Research Medical Center	Kansas City	Missouri
United States	University of California San Diego SC - 3	La Jolla	California
United States	Northwest Cancer Specialists Rose Quarter Cancer Center	Portland	Oregon
United States	VA Sierra Nevada Health Care System Dept. of VA Sierra Nevada HCS	Reno	Nevada
United States	Blue Ridge Research Center at Roanoke Neurological Center Blue Ridge Cancer Care	Roanoke	Virginia
United States	University of Rochester Medical Center Rochester	Rochester	New York
United States	Cancer Care Centers of South Texas / HOAST CCC of So. TX- San Antonio	San Antonio	Texas
United States	California Pacific Medical Center California Pacific Med	San Francisco	California
United States	University of Washington Cancer Care SC	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  China,  France,  Germany,  Greece,  Hong Kong,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Spain,  Taiwan,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No

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