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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00879333
Recruitment Status : Completed
First Posted : April 10, 2009
Results First Posted : April 6, 2015
Last Update Posted : November 3, 2015
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE April 8, 2009
First Posted Date  ICMJE April 10, 2009
Results First Submitted Date  ICMJE January 28, 2015
Results First Posted Date  ICMJE April 6, 2015
Last Update Posted Date November 3, 2015
Study Start Date  ICMJE July 2009
Actual Primary Completion Date January 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 2, 2015)
Overall Survival (OS) [ Time Frame: 2.5 years ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 9, 2009)
Compare Overall Survival in RAD vs. Placebo group [ Time Frame: 2.5 years ]
Change History Complete list of historical versions of study NCT00879333 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 2, 2015)
  • Progression Free Survival (PFS) [ Time Frame: 2.5 years ]
    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.
  • 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 [ Time Frame: 2.5 years ]
    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).
  • Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score [ Time Frame: 2.5 years ]
    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.
  • Overall Response Rate (ORR) [ Time Frame: 2.5 years ]
    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.
  • Everolimus Steady State Concentraions at Predose (Cmin) and Cmax at Week 5 [ Time Frame: 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.
  • Everolimus Steady State Concentraions at Predose (Cmin) and Cmax by Region Asia vs. Rest of the World (ROW) at Week 5 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2009)
  • Compare PFS in RAD vs. Placebo group [ Time Frame: 2.5 years ]
  • Compare QOL in RAD vs. Placebo group [ Time Frame: 2.5 years ]
  • Compare time to deterioration of ECOG PS in RAD vs. Placebo group [ Time Frame: 2.5 years ]
  • Compare Cmin and Cmax between patients with and without gastrectomy [ Time Frame: 2.5 years ]
  • Compare exposure levels (Cmin and Cmax) of Asia vs. ROW gastric cancer patients [ Time Frame: 2.5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of RAD001 (Everolimus) Monotherapy Plus Best Supportive Care in Patients With Advanced Gastric Cancer (AGC)
Official Title  ICMJE 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
Brief 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Advanced Gastric Cancer
Intervention  ICMJE
  • 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 Name: RAD001
  • 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.
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Everolimus
    • Drug: Best Supportive Care (BSC)
  • 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.
    Interventions:
    • Drug: Everolimus placebo
    • Drug: Best Supportive Care (BSC)
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 2, 2015)
656
Original Estimated Enrollment  ICMJE
 (submitted: April 9, 2009)
633
Actual Study Completion Date  ICMJE January 2014
Actual Primary Completion Date January 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Mexico,   Argentina,   Australia,   Belgium,   Canada,   China,   France,   Germany,   Hong Kong,   Israel,   Italy,   Japan,   Korea, Republic of,   Netherlands,   New Zealand,   Peru,   Russian Federation,   Spain,   Taiwan,   Thailand,   United Kingdom,   United States
Removed Location Countries Brazil,   Colombia,   Venezuela
 
Administrative Information
NCT Number  ICMJE NCT00879333
Other Study ID Numbers  ICMJE CRAD001R2301
2008-006544-20 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date October 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP