Everolimus and Octreotide in Patients With Advanced Carcinoid Tumor (RADIANT-2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00412061
First received: December 13, 2006
Last updated: August 21, 2014
Last verified: August 2014
Results First Received: October 25, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Conditions: Carcinoid Tumor
Malignant Carcinoid Syndrome
Interventions: Drug: Octreotide
Drug: Placebo
Drug: Everolimus

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Total 429 patients were randomized to double blind phase of treatment. 170 patients moved to the Open Label Phase.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Followed by Open Label Arm Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. Open Label - Patients who had progressive disease in this arm, can move to the open label Everolimus + depot octreotide by choice.

Participant Flow for 2 periods

Period 1:   Double Blind Phase
    Octreotide+ Everolimus     Octreotide+ Placebo Followed by Open Label Arm  
STARTED     216     213  
Safety Set     215 [1]   211 [2]
COMPLETED     0     0  
NOT COMPLETED     216     213  
Disease Progression                 101                 154  
Adverse Event                 61                 16  
Final Primary Analysis                 26                 14  
Withdrawal by Subject                 18                 20  
Death                 6                 3  
Protocol Violation                 3                 4  
New Cander Therapy                 1                 1  
Lost to Follow-up                 0                 1  
[1] 1 patient did not provide at laest one valid post baseline safety assessment.
[2] 1 pt randomized never took drug Another randomized did not have valid post BL safety assessment

Period 2:   Open Label Phase
    Octreotide+ Everolimus     Octreotide+ Placebo Followed by Open Label Arm  
STARTED     0     170  
COMPLETED     0     0  
NOT COMPLETED     0     170  
Disease Progression                 0                 86  
Adverse Event                 0                 46  
Withdrawal by Subject                 0                 15  
Administrative Problems                 0                 13  
Death                 0                 7  
Lost to Follow-up                 0                 2  
New Cancer Therapy                 0                 1  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
Total Total of all reporting groups

Baseline Measures
    Octreotide+ Everolimus     Octreotide+ Placebo     Total  
Number of Participants  
[units: participants]
  216     213     429  
Age  
[units: years]
Mean ± Standard Deviation
  60.1  ± 10.72     59.4  ± 11.13     59.8  ± 10.92  
Gender  
[units: Participants]
     
Female     119     89     208  
Male     97     124     221  



  Outcome Measures
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1.  Primary:   Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review   [ Time Frame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 ]

Measure Type Primary
Measure Title Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review
Measure Description Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary analysis of PFS was based on the independent central adjudicated assessment using Kaplan-Meier method.
Time Frame Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS) consisted of all randomized patients.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.

Measured Values
    Octreotide+ Everolimus     Octreotide+ Placebo  
Number of Participants Analyzed  
[units: participants]
  216     213  
Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review  
[units: Months]
Median ( 95% Confidence Interval )
  16.43  
  ( 13.67 to 21.19 )  
  11.33  
  ( 8.44 to 14.59 )  

No statistical analysis provided for Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review



2.  Secondary:   Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST)   [ Time Frame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 ]

Measure Type Secondary
Measure Title Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST)
Measure Description The best overall response rate is defined as the percentage of patients having achieved confirmed Complete Response + Partial Response. Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression. • Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression.
Time Frame Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.

Measured Values
    Octreotide+ Everolimus     Octreotide+ Placebo  
Number of Participants Analyzed  
[units: participants]
  216     213  
Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST)  
[units: Percentage of patients]
Number ( 95% Confidence Interval )
  2.3  
  ( 0.8 to 5.30 )  
  1.9  
  ( 0.5 to 4.7 )  

No statistical analysis provided for Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST)



3.  Secondary:   Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level   [ Time Frame: If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 ]

Measure Type Secondary
Measure Title Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level
Measure Description 5-HIAA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of 5-HIAA in urine were defined as ‘High’ if they exceeded the median value, and ‘Low’ if they were lower than or equal to the median.
Time Frame If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients. This analysis includes PFS patients with non missing baseline 5-HIAA data.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.

Measured Values
    Octreotide+ Everolimus     Octreotide+ Placebo  
Number of Participants Analyzed  
[units: participants]
  187     191  
Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level  
[units: Months]
Median ( 95% Confidence Interval )
   
5-HIAA <=median (n=93,96)     21.75  
  ( 13.93 to NA ) [1]
  13.90  
  ( 8.71 to 22.44 )  
5-HIAA >= median (n=94,95)     13.83  
  ( 10.61 to 18.63 )  
  8.41  
  ( 8.08 to 11.33 )  
[1] Upper Limit was not applicable or computable as median was just reached.

No statistical analysis provided for Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level



4.  Secondary:   Overall Survival Using Kaplan-Meier Methodology   [ Time Frame: Months 12, 24, 36, 48 ]

Measure Type Secondary
Measure Title Overall Survival Using Kaplan-Meier Methodology
Measure Description Overall survival was defined as the time from the date of randomization to the date of death from any cause. If a patient was not known to have died, survival was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group.
Time Frame Months 12, 24, 36, 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Followed by Open Label Arm Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. Open Label - Patients who had progressive disease in this arm, can move to the open label Everolimus + depot octreotide by choice.

Measured Values
    Octreotide+ Everolimus     Octreotide+ Placebo Followed by Open Label Arm  
Number of Participants Analyzed  
[units: participants]
  216     213  
Overall Survival Using Kaplan-Meier Methodology  
[units: Percentage of Participants]
Number ( 95% Confidence Interval )
   
12 Months     80.5  
  ( 74.5 to 85.3 )  
  81.8  
  ( 75.8 to 86.4 )  
24 Months     57.0  
  ( 49.9 to 63.4 )  
  63.6  
  ( 56.6 to 69.8 )  
36 Months     42.9  
  ( 36.0 to 49.6 )  
  48.5  
  ( 41.4 to 55.3 )  
48 Months     38.0  
  ( 31.2 to 44.7 )  
  41.6  
  ( 34.6 to 48.5 )  

No statistical analysis provided for Overall Survival Using Kaplan-Meier Methodology



5.  Secondary:   Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase)   [ Time Frame: From first day of treatment up to 28 days after last day of treatment in double blind ]

Measure Type Secondary
Measure Title Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase)
Measure Description AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
Time Frame From first day of treatment up to 28 days after last day of treatment in double blind  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Safety Set consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.

Measured Values
    Octreotide+ Everolimus     Octreotide+ Placebo  
Number of Participants Analyzed  
[units: participants]
  215     211  
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase)  
[units: Patients]
   
Clinically notable AE     208     146  
Grade 3-4 Adverse Events     162     109  
On treatment death     19     11  
Serious adverse events     126     74  

No statistical analysis provided for Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase)



6.  Secondary:   Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase)   [ Time Frame: From first day of treatment up to 28 days after last day of treatment in double blind ]

Measure Type Secondary
Measure Title Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase)
Measure Description AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
Time Frame From first day of treatment up to 28 days after last day of treatment in double blind  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Safety Set consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment.

Reporting Groups
  Description
Everolimus Open Label Arm Patients who had progressive disease in this arm, can move to the open label Everolimus + depot octreotide by choice.

Measured Values
    Everolimus Open Label Arm  
Number of Participants Analyzed  
[units: participants]
  170  
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase)  
[units: Patients]
 
Clinically notable AE     154  
Grade 3-4 Adverse Events     115  
On treatment death     22  
Serious adverse events     93  

No statistical analysis provided for Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase)



7.  Secondary:   Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA)   [ Time Frame: If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 ]

Measure Type Secondary
Measure Title Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA)
Measure Description Serum CgA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of serum CgA were characterized relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be ‘Elevated’; otherwise considered as "Non-elevated".
Time Frame If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients. This analysis includes PFS patients with non missing baseline CgA data.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.

Measured Values
    Octreotide+ Everolimus     Octreotide+ Placebo  
Number of Participants Analyzed  
[units: participants]
  212     208  
Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA)  
[units: Months]
Median ( 95% Confidence Interval )
   
CgA<=2x ULN (n=60,78)     31.31  
  ( 19.32 to NA ) [1]
  20.07  
  ( 13.04 to NA ) [1]
CgA>=2x ULN (n=152,130)     13.93  
  ( 11.30 to 17.08 )  
  8.41  
  ( 7.72 to 11.14 )  
[1] Upper Limit was not applicable or computable as median was just reached.

No statistical analysis provided for Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA)




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


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