Safety and Efficacy of RAD001 (Everolimus) Monotherapy Plus Best Supportive Care in Patients With Advanced Gastric Cancer (AGC)

Advanced Gastric Cancer Clinical Trial

— GRANITE-1  

Official title:

A Randomized, Double-blind, Multi-center Phase III Study Comparing Everolimus (RAD001) Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Patients With Advanced Gastric Cancer After Progression on 1 or 2 Prior Systemic Chemotherapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00879333
• Other study ID #: CRAD001R2301
• Secondary ID: 2008-006544-20
• Status: Completed
• Phase: Phase 3
• First received: April 8, 2009
• Last updated: October 8, 2015
• Start date: July 2009
• Est. completion date: January 2014

Study information

• Verified date: October 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health CanadaIsrael: Ministry of HealthRussia: Pharmacological Committee, Ministry of HealthMexico: Ministry of HealthColombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y AlimentosBrazil: Ministry of HealthVenezuela: Ministry of Health and Social DevelopmentArgentina: Ministry of HealthChina: Ministry of HealthJapan: Pharmaceuticals and Medical Devices AgencyKorea: Food and Drug AdministrationTaiwan: Department of HealthThailand: Food and Drug AdministrationHong Kong: Department of HealthAustralia: Department of Health and Ageing Therapeutic Goods AdministrationNew Zealand: Medsafe
• Study type: Interventional

Clinical Trial Summary

This study is designed to assess the safety and efficacy of RAD001 monotherapy in patients with advanced gastric cancer which has progressed after one or two lines of prior chemotherapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 656
• Est. completion date: January 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female patients > 18 years old

• Histologically or cytologically confirmed and documented gastric adenocarcinoma

• Documented progression after 1 or 2 prior chemotherapy treatments for advanced disease

• ECOG Performance Status of < 2

• Lab parameters within specifically defined intervals

• Able to provide written informed consent

Exclusion Criteria:

• Patients who have received > 2 prior systemic therapies for advanced disease

• Administration of another anticancer therapy within 3 weeks prior to randomization

• Chronic treatment with steroids or another immunosuppressive agent

• Major surgery within 2 weeks prior to randomization

• Patients with CNS metastases

• Any other severe and/or uncontrolled medical condition

Other protocol-defined inclusion/exclusion criteria may apply

Study Design

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

Related Conditions & MeSH terms

• Advanced Gastric Cancer
• Stomach Neoplasms

Intervention

Drug:
• Everolimus
Everolimus was formulated as tablets of 5 mg strength. In both treatment arms, the study drug was given by continuous oral daily dosing of 10 mg (2 tablets x 5 mg) each morning.
• Everolimus placebo
Placebo was formulated to be indistinguishable from the everolimus tablets, also formulated as tablets of 5 mg strength. In both treatment arms, the study drug was given by continuous oral daily dosing of 10 mg (2 tablets x 5 mg) each morning.
• Best Supportive Care (BSC)
Best supportive care is defined as care in accordance with the local practice of an individual institution or center, specifically excluding anti-cancer treatments.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Rio Negro	Viedma
Australia	Novartis Investigative Site	Box Hill	Victoria
Australia	Novartis Investigative Site	Canberra	Australian Capital Territory
Australia	Novartis Investigative Site	Clayton	Victoria
Australia	Novartis Investigative Site	Footscray	Victoria
Australia	Novartis Investigative Site	Heidelberg	Victoria
Australia	Novartis Investigative Site	Herston	Queensland
Australia	Novartis Investigative Site	Kurralta Park	South Australia
Australia	Novartis Investigative Site	North Adelaide	South Australia
Australia	Novartis Investigative Site	Prahran	Victoria
Belgium	Novartis Investigative Site	Charleroi
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	North Vancouver	British Columbia
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Guangzhou
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Harbin	Heilongjiang
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Shenyang	Liaoning
China	Novartis Investigative Site	Shijiazhuang	Hebei
China	Novartis Investigative Site	Suzhou	Jiangsu
France	Novartis Investigative Site	Avignon Cedex
France	Novartis Investigative Site	Clermont Ferrand cedex 1
France	Novartis Investigative Site	Clichy
France	Novartis Investigative Site	Dijon
France	Novartis Investigative Site	Lyon Cedex 08
France	Novartis Investigative Site	Marseille cedex 05
France	Novartis Investigative Site	Montpellier Cedex 5
France	Novartis Investigative Site	Nice Cedex 2
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Pessac Cedex
France	Novartis Investigative Site	Poitiers
France	Novartis Investigative Site	Reims
France	Novartis Investigative Site	Rennes Cedex
France	Novartis Investigative Site	Toulouse Cedex 4
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bielefeld
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Mannheim	Baden-Württemberg
Germany	Novartis Investigative Site	München
Germany	Novartis Investigative Site	Offenburg
Germany	Novartis Investigative Site	Trier
Hong Kong	Novartis Investigative Site	Hong Kong SAR
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Rehovot
Italy	Novartis Investigative Site	Aviano	PN
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Frattamaggiore
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Rozzano	MI
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka-city	Fukuoka
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Kitaadachi-gun	Saitama
Japan	Novartis Investigative Site	Koto	Tokyo
Japan	Novartis Investigative Site	Matsuyama	Ehime
Japan	Novartis Investigative Site	Mitaka-city	Tokyo
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	OsakaSayama	Osaka
Japan	Novartis Investigative Site	Sagamihara	Kanagawa
Japan	Novartis Investigative Site	Sapporo-city	Hokkaido
Japan	Novartis Investigative Site	Sendai-city	Miyagi
Japan	Novartis Investigative Site	Takatsuki-city	Osaka
Japan	Novartis Investigative Site	Utsunomiya	Tochigi
Korea, Republic of	Novartis Investigative Site	Jeonju-si	Jeollabuk-do
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	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Taegu
Mexico	Novartis Investigative Site	León	Guanajuato
Mexico	Novartis Investigative Site	México	Distrito Federal
Netherlands	Novartis Investigative Site	Amsterdam
New Zealand	Novartis Investigative Site	Auckland
Peru	Novartis Investigative Site	San Borja	Lima
Peru	Novartis Investigative Site	San Isidro	Lima
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St. Petersburg
Spain	Novartis Investigative Site	Barcelona	Catalunya
Taiwan	Novartis Investigative Site	Kuei-Shan Chiang	Taoyuan/ Taiwan ROC
Taiwan	Novartis Investigative Site	Liouying Township
Taiwan	Novartis Investigative Site	Niaosong Township
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Songkla
United Kingdom	Novartis Investigative Site	East Yorkshire
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Northwood	Middlesex
United Kingdom	Novartis Investigative Site	Sutton	Surrey
United Kingdom	Novartis Investigative Site	Wolverhampton
United States	University of Texas Southwestern Medical Center DeptofSimmons Cancer Center(4)	Dallas	Texas
United States	Henry Ford Hospital Dept. of Henry Ford Hospital	Detroit	Michigan
United States	Highlands Oncology Group DeptofHighlandsOncologyGrp(2)	Fayetteville	Arkansas
United States	The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD(2)	Fort Worth	Texas
United States	University of Texas/MD Anderson Cancer Center Gastrointestinal Med. Oncology	Houston	Texas
United States	University of Minnesota Cancer Center	Minneapolis	Minnesota
United States	Loma Linda Oncology Medical Group Loma Linda	Redlands	California
United States	University of Washington Cancer Care Seattle Cancer Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  China,  France,  Germany,  Hong Kong,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Peru,  Russian Federation,  Spain,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	The primary objective of this study was to compare OS between everolimus + best supportive care (BSC) and placebo + BSC. OS, was defined as the time from date of randomization to the date of death due to any cause. If at the analysis cut-off date a patient was not known to have died, survival was censored at the date of the last contact. OS was analyzed using the Kaplan Meier estimates method.	2.5 years	No
Secondary	Progression Free Survival (PFS)	Progression free survival was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, where progression was based on Investigator assessment of baseline and post-baseline scans according to RECIST. Progression free survival was censored if no PFS event was observed before the first to occur out of (i) the cut-off date, or (ii) the date when a further anticancer therapy was started. The censoring date was the date of the last adequate tumor assessment before either of these two events occurred. If a PFS event was observed after two or more missing or non-evaluable tumor assessments, then the date of progression was censored at the date of the last adequate tumor assessment; for a PFS event observed after a single missing or non-evaluable tumor assessment, the actual date of disease progression was used. Anslsis was done using Kaplan-Meier estimates method.	2.5 years	No
Secondary	Patient Reported Outcome (PRO): Time to Definitive Deterioration of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) Scores	The EORTC QLQ-C30 global health status/quality of life sub-scale (QL) was pre-specified as the primary domain of interest, followed by physical functioning (PF), social functioning (SF) and emotional functioning (EF).The EORTC QLQ-C30 questionnaire, along with a module specific for gastric cancer patients (EORTC QLQ-STO22), was used to evaluate PRO. The QLQ-C30 has five function scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting) and a global health status/quality of life scale. In addition, there are questions that assess specific symptoms. The QLQ-STO22 consists of 22 questions that make up five multi-item scales (dysphagia, pain, reflux, eating and anxiety) and four single-item scales (dry mouth, tasting, body image and hair loss).	2.5 years	No
Secondary	Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score	The ECOG PS scale was used to classify patients according to their functional impairment, with scores ranging from 0 (fully active) to 5 (dead). An analysis of the time to definitive deterioration of the ECOG PS by one category of the score from baseline was performed. Definitive deterioration was defined as a definitive increase by one category from baseline in ECOG PS, with no later improvements observed during the course of the study. A single measure reporting an increase in ECOG PS is sufficient to consider it as a definitive worsening only if it was the last one available for the patient. Kaplan-Meier method was used to estimate the distribution function of time to definitive worsening.	2.5 years	No
Secondary	Overall Response Rate (ORR)	ORR was defined as the proportion of patients with measurable disease in whom best overall response (OR) was either complete response (CR) or partial response (PR) according to RECIST criteria.	2.5 years	No
Secondary	Everolimus Steady State Concentraions at Predose (Cmin) and Cmax at Week 5	Cmin is the minimum (trough) steady-state drug concentration in the blood during multiple dosing and Cmax is the maximum (peak) blood drug concentration after dose administration. Cmax is estimated as the maximum of C1h and C2H. C1h is 1 hour post-dose blood concentration and C2h is 2 hour post-dose blood concentration. Only valid pre-dose (Cmin), C1h, and C2h everolimus samples were included in the analysis. Valid pre-dose samples were confirmed blood samples collected at steady-state, collected immediately prior to dosing on the same study day, and collected at approximately 24 ± 4 hours after the previous dose and with no vomiting within the first 4 hours following the last dose. Valid C1h and C2h samples were confirmed blood samples collected at steady-state and within ± 1 hour window and with no vomiting within the first 4 hours following the current and previous dose.	Week 5	No
Secondary	Everolimus Steady State Concentraions at Predose (Cmin) and Cmax by Region Asia vs. Rest of the World (ROW) at Week 5	Cmin is the minimum (trough) steady-state drug concentration in the blood during multiple dosing and Cmax is the maximum (peak) blood drug concentration after dose administration. Cmax is estimated as the maximum of C1h and C2H. C1h is 1 hour post-dose blood concentration and C2h is 2 hour post-dose blood concentration. Only valid pre-dose (Cmin), C1h, and C2h everolimus samples were included in the analysis. Valid pre-dose samples were confirmed blood samples collected at steady-state, collected immediately prior to dosing on the same study day, and collected at approximately 24 ± 4 hours after the previous dose and with no vomiting within the first 4 hours following the last dose. Valid C1h and C2h samples were confirmed blood samples collected at steady-state and within ± 1 hour window and with no vomiting within the first 4 hours following the current and previous dose.	Week 5	No