Safety and Efficacy of RAD001 (Everolimus) Monotherapy Plus Best Supportive Care in Patients With Advanced Gastric Cancer (AGC) (GRANITE-1)

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Gastric Cancer
• Intervention / Treatment: Drug: Everolimus; Drug: Best Supportive Care (BSC); Drug: Everolimus placebo

• Study Type: Interventional
• Enrollment (Actual): 656
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1264AAA
    • Novartis Investigative Site
  • Cordoba, Argentina, X5000IUG
    • Novartis Investigative Site
  • Viedma
    • Rio Negro, Viedma, Argentina, 8500
      • Novartis Investigative Site
• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • Novartis Investigative Site
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Novartis Investigative Site
  • South Australia
    • Kurralta Park, South Australia, Australia, 5037
      • Novartis Investigative Site
    • North Adelaide, South Australia, Australia, 5006
      • Novartis Investigative Site
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Novartis Investigative Site
    • Clayton, Victoria, Australia, 3168
      • Novartis Investigative Site
    • Footscray, Victoria, Australia, 3011
      • Novartis Investigative Site
    • Heidelberg, Victoria, Australia, 3084
      • Novartis Investigative Site
    • Prahran, Victoria, Australia, 3181
      • Novartis Investigative Site
• Belgium
  • Charleroi, Belgium, 6000
    • Novartis Investigative Site
  • Gent, Belgium, 9000
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Liege, Belgium, 4000
    • Novartis Investigative Site
• Canada
  • British Columbia
    • North Vancouver, British Columbia, Canada, V7L 2L7
      • Novartis Investigative Site
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Novartis Investigative Site
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5B 1W8
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
      • Novartis Investigative Site
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Novartis Investigative Site
• China
  • Beijing, China, 100039
    • Novartis Investigative Site
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Guangzhou, China, 510060
    • Novartis Investigative Site
  • Shanghai, China, 200032
    • Novartis Investigative Site
  • Shanghai, China, 200003
    • Novartis Investigative Site
  • Shanghai, China, 200025
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Novartis Investigative Site
  • Hebei
    • Shijiazhuang, Hebei, China, 050011
      • Novartis Investigative Site
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150081
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210002
      • Novartis Investigative Site
    • Suzhou, Jiangsu, China, 215006
      • Novartis Investigative Site
  • Liaoning
    • Shenyang, Liaoning, China
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310016
      • Novartis Investigative Site
• France
  • Avignon Cedex, France, 84082
    • Novartis Investigative Site
  • Clermont Ferrand cedex 1, France, 63003
    • Novartis Investigative Site
  • Clichy, France, 92110
    • Novartis Investigative Site
  • Dijon, France, 21079
    • Novartis Investigative Site
  • Lyon Cedex 08, France, 69373
    • Novartis Investigative Site
  • Marseille cedex 05, France, 13385
    • Novartis Investigative Site
  • Montpellier Cedex 5, France, 34298
    • Novartis Investigative Site
  • Nice Cedex 2, France, 06189
    • Novartis Investigative Site
  • Paris, France, 75015
    • Novartis Investigative Site
  • Pessac Cedex, France, 33604
    • Novartis Investigative Site
  • Poitiers, France, 86000
    • Novartis Investigative Site
  • Reims, France, 51092
    • Novartis Investigative Site
  • Rennes Cedex, France, 35062
    • Novartis Investigative Site
  • Toulouse Cedex 4, France, 31054
    • Novartis Investigative Site
  • Villejuif Cedex, France, 94805
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Bielefeld, Germany, 33604
    • Novartis Investigative Site
  • Frankfurt, Germany, 60488
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • München, Germany, 81675
    • Novartis Investigative Site
  • Offenburg, Germany, 77652
    • Novartis Investigative Site
  • Trier, Germany, 54290
    • Novartis Investigative Site
  • Baden-Württemberg
    • Mannheim, Baden-Württemberg, Germany, 68305
      • Novartis Investigative Site
• Hong Kong
  • Hong Kong SAR, Hong Kong
    • Novartis Investigative Site
• Israel
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
  • Petach Tikva, Israel, 49100
    • Novartis Investigative Site
  • Ramat Gan, Israel, 5266202
    • Novartis Investigative Site
  • Rehovot, Israel, 76100
    • Novartis Investigative Site
• Italy
  • Frattamaggiore, Italy, 80020
    • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • MI
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41100
      • Novartis Investigative Site
  • PN
    • Aviano, PN, Italy, 33081
      • Novartis Investigative Site
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 464-8681
      • Novartis Investigative Site
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • Novartis Investigative Site
  • Ehime
    • Matsuyama, Ehime, Japan, 791-0280
      • Novartis Investigative Site
  • Fukuoka
    • Fukuoka-city, Fukuoka, Japan, 812-8582
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo-city, Hokkaido, Japan, 060-8648
      • Novartis Investigative Site
  • Kanagawa
    • Sagamihara, Kanagawa, Japan, 252-0380
      • Novartis Investigative Site
  • Miyagi
    • Sendai-city, Miyagi, Japan, 980-8574
      • Novartis Investigative Site
  • Osaka
    • OsakaSayama, Osaka, Japan, 589-8511
      • Novartis Investigative Site
    • Takatsuki-city, Osaka, Japan, 569-8686
      • Novartis Investigative Site
  • Saitama
    • Kitaadachi-gun, Saitama, Japan, 362-0806
      • Novartis Investigative Site
  • Tochigi
    • Utsunomiya, Tochigi, Japan, 320-0834
      • Novartis Investigative Site
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • Novartis Investigative Site
    • Koto, Tokyo, Japan, 135-8550
      • Novartis Investigative Site
    • Mitaka-city, Tokyo, Japan, 181-8611
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 136-705
    • Novartis Investigative Site
  • Taegu, Korea, Republic of, 700 - 721
    • Novartis Investigative Site
  • Jeollabuk-do
    • Jeonju-si, Jeollabuk-do, Korea, Republic of, 561-712
      • Novartis Investigative Site
  • Korea
    • Seoul, Korea, Korea, Republic of, 05505
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 06351
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 110 744
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 03722
      • Novartis Investigative Site
• Mexico
  • Distrito Federal
    • México, Distrito Federal, Mexico, 14080
      • Novartis Investigative Site
  • Guanajuato
    • León, Guanajuato, Mexico, 37000
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
• New Zealand
  • Auckland, New Zealand
    • Novartis Investigative Site
• Peru
  • Lima
    • San Borja, Lima, Peru, 41
      • Novartis Investigative Site
    • San Isidro, Lima, Peru, 27
      • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Novartis Investigative Site
  • St. Petersburg, Russian Federation, 197758
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Taiwan
  • Liouying Township, Taiwan
    • Novartis Investigative Site
  • Niaosong Township, Taiwan, 83301
    • Novartis Investigative Site
  • Taipei, Taiwan, 10048
    • Novartis Investigative Site
  • Taipei, Taiwan
    • Novartis Investigative Site
  • Taoyuan/ Taiwan ROC
    • Kuei-Shan Chiang, Taoyuan/ Taiwan ROC, Taiwan, 33305
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Songkla, Thailand, 90110
    • Novartis Investigative Site
• United Kingdom
  • East Yorkshire, United Kingdom, HU16 5JQ
    • Novartis Investigative Site
  • London, United Kingdom, SW3 6JJ
    • Novartis Investigative Site
  • London, United Kingdom, WC1E 6HX
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 4BX
    • Novartis Investigative Site
  • Wolverhampton, United Kingdom, WV10 0QP
    • Novartis Investigative Site
  • Middlesex
    • Northwood, Middlesex, United Kingdom, HA6 2RN
      • Novartis Investigative Site
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Novartis Investigative Site
• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group DeptofHighlandsOncologyGrp(2)
  • California
    • Redlands, California, United States, 92374
      • Loma Linda Oncology Medical Group Loma Linda
  • Michigan
    • Detroit, Michigan, United States, 48202-2689
      • Henry Ford Hospital Dept. of Henry Ford Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390-8527
      • University of Texas Southwestern Medical Center DeptofSimmons Cancer Center(4)
    • Fort Worth, Texas, United States, 76104
      • The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD(2)
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Gastrointestinal Med. Oncology
  • Washington
    • Seattle, Washington, United States, 98109-1023
      • University of Washington Cancer Care Seattle Cancer Alliance

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:

• 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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus + BSC; All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.	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.; Other Names: RAD001; Drug: 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.
Placebo Comparator: Placebo + BSC; All patients were randomized to receive placebo + BSC. All patients orally took two 5 mg tablets of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.	Drug: 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.; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K, Muro K, Kim YH, Ferry D, Tebbutt NC, Al-Batran SE, Smith H, Costantini C, Rizvi S, Lebwohl D, Van Cutsem E. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013 Nov 1;31(31):3935-43. doi: 10.1200/JCO.2012.48.3552. Epub 2013 Sep 16.

Helpful Links

• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: April 8, 2009
• First Submitted That Met QC Criteria: April 9, 2009
• First Posted (Estimate): April 10, 2009

Study Record Updates

• Last Update Posted (Estimate): November 3, 2015
• Last Update Submitted That Met QC Criteria: October 8, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: GI neoplasm; Gastric cancer,; advanced gastric cancer,; stomach neoplasm,; stomach disease,; adenocarcinoma of stomach,
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CRAD001R2301; 2008-006544-20 (EudraCT Number)