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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: November 11, 2014
Last verified: November 2014
Results First Received: October 25, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Participant, 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 
Overall Participants Analyzed 
[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 ]

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 ]

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 ]

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

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 ]

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 ]

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 ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame No text entered.
Additional Description Double blind period, Safety Set consists all patients received at least one dose of study drug and who had at least one valid post-baseline safety assessment. The Open-label Set consists all patients received at least one dose of open-label everolimus and who had at least one valid safety assessment after initiation of open-label treatment

Frequency Threshold
Threshold above which other adverse events are reported   5%  

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

Other Adverse Events
    Everolimus + Octreotide   Placebo + Octreotide   Everolimus Open Label
Total, Other (not including serious) Adverse Events       
# participants affected / at risk   214/215 (99.53%)   194/211 (91.94%)   162/170 (95.29%) 
Blood and lymphatic system disorders       
Anaemia † 1       
# participants affected / at risk   58/215 (26.98%)   21/211 (9.95%)   34/170 (20.00%) 
Leukopenia † 1       
# participants affected / at risk   16/215 (7.44%)   2/211 (0.95%)   2/170 (1.18%) 
Neutropenia † 1       
# participants affected / at risk   18/215 (8.37%)   3/211 (1.42%)   13/170 (7.65%) 
Thrombocytopenia † 1       
# participants affected / at risk   34/215 (15.81%)   1/211 (0.47%)   15/170 (8.82%) 
Gastrointestinal disorders       
Abdominal distension † 1       
# participants affected / at risk   12/215 (5.58%)   12/211 (5.69%)   10/170 (5.88%) 
Abdominal pain † 1       
# participants affected / at risk   65/215 (30.23%)   68/211 (32.23%)   43/170 (25.29%) 
Abdominal pain upper † 1       
# participants affected / at risk   22/215 (10.23%)   26/211 (12.32%)   16/170 (9.41%) 
Aphthous stomatitis † 1       
# participants affected / at risk   28/215 (13.02%)   3/211 (1.42%)   15/170 (8.82%) 
Ascites † 1       
# participants affected / at risk   17/215 (7.91%)   9/211 (4.27%)   8/170 (4.71%) 
Constipation † 1       
# participants affected / at risk   31/215 (14.42%)   22/211 (10.43%)   17/170 (10.00%) 
Diarrhoea † 1       
# participants affected / at risk   114/215 (53.02%)   77/211 (36.49%)   77/170 (45.29%) 
Dry mouth † 1       
# participants affected / at risk   22/215 (10.23%)   6/211 (2.84%)   7/170 (4.12%) 
Dysphagia † 1       
# participants affected / at risk   15/215 (6.98%)   5/211 (2.37%)   4/170 (2.35%) 
Flatulence † 1       
# participants affected / at risk   27/215 (12.56%)   28/211 (13.27%)   12/170 (7.06%) 
Haemorrhoids † 1       
# participants affected / at risk   17/215 (7.91%)   9/211 (4.27%)   9/170 (5.29%) 
Mouth ulceration † 1       
# participants affected / at risk   17/215 (7.91%)   5/211 (2.37%)   11/170 (6.47%) 
Nausea † 1       
# participants affected / at risk   92/215 (42.79%)   63/211 (29.86%)   60/170 (35.29%) 
Stomatitis † 1       
# participants affected / at risk   109/215 (50.70%)   25/211 (11.85%)   63/170 (37.06%) 
Vomiting † 1       
# participants affected / at risk   69/215 (32.09%)   40/211 (18.96%)   30/170 (17.65%) 
General disorders       
Asthenia † 1       
# participants affected / at risk   51/215 (23.72%)   30/211 (14.22%)   30/170 (17.65%) 
Chills † 1       
# participants affected / at risk   15/215 (6.98%)   10/211 (4.74%)   5/170 (2.94%) 
Fatigue † 1       
# participants affected / at risk   103/215 (47.91%)   91/211 (43.13%)   63/170 (37.06%) 
Oedema peripheral † 1       
# participants affected / at risk   92/215 (42.79%)   47/211 (22.27%)   62/170 (36.47%) 
Pyrexia † 1       
# participants affected / at risk   42/215 (19.53%)   21/211 (9.95%)   32/170 (18.82%) 
Infections and infestations       
Bronchitis † 1       
# participants affected / at risk   11/215 (5.12%)   7/211 (3.32%)   8/170 (4.71%) 
Nasopharyngitis † 1       
# participants affected / at risk   19/215 (8.84%)   26/211 (12.32%)   19/170 (11.18%) 
Sinusitis † 1       
# participants affected / at risk   12/215 (5.58%)   9/211 (4.27%)   17/170 (10.00%) 
Upper respiratory tract infection † 1       
# participants affected / at risk   27/215 (12.56%)   12/211 (5.69%)   11/170 (6.47%) 
Urinary tract infection † 1       
# participants affected / at risk   27/215 (12.56%)   16/211 (7.58%)   19/170 (11.18%) 
Investigations       
Alanine aminotransferase increased † 1       
# participants affected / at risk   9/215 (4.19%)   6/211 (2.84%)   10/170 (5.88%) 
Aspartate aminotransferase increased † 1       
# participants affected / at risk   11/215 (5.12%)   8/211 (3.79%)   8/170 (4.71%) 
Blood creatinine increased † 1       
# participants affected / at risk   15/215 (6.98%)   5/211 (2.37%)   8/170 (4.71%) 
Weight decreased † 1       
# participants affected / at risk   59/215 (27.44%)   31/211 (14.69%)   33/170 (19.41%) 
Metabolism and nutrition disorders       
Decreased appetite † 1       
# participants affected / at risk   64/215 (29.77%)   36/211 (17.06%)   33/170 (19.41%) 
Dehydration † 1       
# participants affected / at risk   17/215 (7.91%)   12/211 (5.69%)   9/170 (5.29%) 
Hypercholesterolaemia † 1       
# participants affected / at risk   17/215 (7.91%)   6/211 (2.84%)   7/170 (4.12%) 
Hyperglycaemia † 1       
# participants affected / at risk   42/215 (19.53%)   9/211 (4.27%)   24/170 (14.12%) 
Hyperlipidaemia † 1       
# participants affected / at risk   15/215 (6.98%)   3/211 (1.42%)   4/170 (2.35%) 
Hypocalcaemia † 1       
# participants affected / at risk   17/215 (7.91%)   4/211 (1.90%)   11/170 (6.47%) 
Hypokalaemia † 1       
# participants affected / at risk   50/215 (23.26%)   8/211 (3.79%)   27/170 (15.88%) 
Hypomagnesaemia † 1       
# participants affected / at risk   15/215 (6.98%)   5/211 (2.37%)   6/170 (3.53%) 
Hypophosphataemia † 1       
# participants affected / at risk   11/215 (5.12%)   6/211 (2.84%)   8/170 (4.71%) 
Musculoskeletal and connective tissue disorders       
Arthralgia † 1       
# participants affected / at risk   38/215 (17.67%)   28/211 (13.27%)   19/170 (11.18%) 
Back pain † 1       
# participants affected / at risk   33/215 (15.35%)   41/211 (19.43%)   18/170 (10.59%) 
Muscle spasms † 1       
# participants affected / at risk   17/215 (7.91%)   13/211 (6.16%)   10/170 (5.88%) 
Musculoskeletal chest pain † 1       
# participants affected / at risk   18/215 (8.37%)   7/211 (3.32%)   11/170 (6.47%) 
Musculoskeletal pain † 1       
# participants affected / at risk   21/215 (9.77%)   21/211 (9.95%)   8/170 (4.71%) 
Myalgia † 1       
# participants affected / at risk   16/215 (7.44%)   14/211 (6.64%)   8/170 (4.71%) 
Pain in extremity † 1       
# participants affected / at risk   32/215 (14.88%)   24/211 (11.37%)   19/170 (11.18%) 
Nervous system disorders       
Dizziness † 1       
# participants affected / at risk   29/215 (13.49%)   24/211 (11.37%)   12/170 (7.06%) 
Dysgeusia † 1       
# participants affected / at risk   42/215 (19.53%)   12/211 (5.69%)   30/170 (17.65%) 
Headache † 1       
# participants affected / at risk   65/215 (30.23%)   49/211 (23.22%)   32/170 (18.82%) 
Psychiatric disorders       
Anxiety † 1       
# participants affected / at risk   14/215 (6.51%)   14/211 (6.64%)   12/170 (7.06%) 
Depression † 1       
# participants affected / at risk   16/215 (7.44%)   11/211 (5.21%)   12/170 (7.06%) 
Insomnia † 1       
# participants affected / at risk   20/215 (9.30%)   15/211 (7.11%)   12/170 (7.06%) 
Renal and urinary disorders       
Dysuria † 1       
# participants affected / at risk   12/215 (5.58%)   5/211 (2.37%)   7/170 (4.12%) 
Pollakiuria † 1       
# participants affected / at risk   10/215 (4.65%)   6/211 (2.84%)   11/170 (6.47%) 
Respiratory, thoracic and mediastinal disorders       
Cough † 1       
# participants affected / at risk   59/215 (27.44%)   32/211 (15.17%)   38/170 (22.35%) 
Dyspnoea † 1       
# participants affected / at risk   59/215 (27.44%)   19/211 (9.00%)   27/170 (15.88%) 
Dyspnoea exertional † 1       
# participants affected / at risk   9/215 (4.19%)   11/211 (5.21%)   7/170 (4.12%) 
Epistaxis † 1       
# participants affected / at risk   33/215 (15.35%)   5/211 (2.37%)   24/170 (14.12%) 
Oropharyngeal pain † 1       
# participants affected / at risk   20/215 (9.30%)   6/211 (2.84%)   13/170 (7.65%) 
Pleural effusion † 1       
# participants affected / at risk   12/215 (5.58%)   6/211 (2.84%)   7/170 (4.12%) 
Pneumonitis † 1       
# participants affected / at risk   20/215 (9.30%)   2/211 (0.95%)   6/170 (3.53%) 
Skin and subcutaneous tissue disorders       
Alopecia † 1       
# participants affected / at risk   13/215 (6.05%)   4/211 (1.90%)   7/170 (4.12%) 
Dry skin † 1       
# participants affected / at risk   23/215 (10.70%)   5/211 (2.37%)   9/170 (5.29%) 
Erythema † 1       
# participants affected / at risk   17/215 (7.91%)   4/211 (1.90%)   7/170 (4.12%) 
Hyperhidrosis † 1       
# participants affected / at risk   9/215 (4.19%)   13/211 (6.16%)   5/170 (2.94%) 
Onychoclasis † 1       
# participants affected / at risk   11/215 (5.12%)   1/211 (0.47%)   10/170 (5.88%) 
Pruritus † 1       
# participants affected / at risk   42/215 (19.53%)   12/211 (5.69%)   18/170 (10.59%) 
Rash † 1       
# participants affected / at risk   88/215 (40.93%)   37/211 (17.54%)   59/170 (34.71%) 
Vascular disorders       
Flushing † 1       
# participants affected / at risk   20/215 (9.30%)   20/211 (9.48%)   6/170 (3.53%) 
Hypertension † 1       
# participants affected / at risk   24/215 (11.16%)   21/211 (9.95%)   16/170 (9.41%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA



  Limitations and Caveats
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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
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