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RAMSETE: RAD001 in Advanced and Metastatic Silent Neuro-endocrine Tumors in Europe (RAMSETE/CDE16)

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: NCT00688623
Recruitment Status : Completed
First Posted : June 3, 2008
Results First Posted : January 25, 2019
Last Update Posted : January 25, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Advanced and Metastatic Silent Neuro-Endocrine Tumors
Carcinoma
Neuroendocrine
Non Functioning Neuroendocrine Tumors (NETs)
Non Syndromic Neuroendocrine Tumors
Carcinoids
Non Functioning
Intervention Drug: Everolimus
Enrollment 73
Recruitment Details  
Pre-assignment Details Eighty-two patients were screened and 73 were treated with study drug.
Arm/Group Title Everolimus
Hide Arm/Group Description 10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Period Title: Overall Study
Started 73 [1]
Safety Analysis Set 73 [2]
Per Protocol (PP) 60 [3]
Completed 18
Not Completed 55
Reason Not Completed
Adverse Event             22
abnormal lab value             1
Withdrawal by Subject             4
Death             3
disease progression             23
Protocol Violation             2
[1]
Intent to treat (ITT)
[2]
received at least one dose of study drug and had at least one post-baseline safety assessment
[3]
no major protocol deviation and 50% of planned dose of 8 weeks or d/c due to disease progression
Arm/Group Title Everolimus
Hide Arm/Group Description 10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Number of Baseline Participants 73
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 73 participants
59.9  (13.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 73 participants
Female
33
  45.2%
Male
40
  54.8%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 73 participants
Caucasian
71
  97.3%
Other
2
   2.7%
Tumor histology/cytology  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 73 participants
Bronchial (thymic) carcinoid -typical
9
  12.3%
Bronchial (thymic) carcinoid -atypical
12
  16.4%
Neuroendocrine tumor
16
  21.9%
Neuroendocrine carcinoma
36
  49.3%
Time since first diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 73 participants
< 1 year
19
  26.0%
1 year to < 3 years
26
  35.6%
3 years to < 6 years
17
  23.3%
6 years to < 10 years
3
   4.1%
≥ 10 years
6
   8.2%
Missing
2
   2.7%
1.Primary Outcome
Title Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP)
Hide Description Overall response rate (ORR) was based on RECIST central assessment and defined as the percentage of patients with best overall response (BOR) of a confirmed complete response (CR) or partial response (PR). The BOR was calculated on basis of the tumor of overall lesion response evaluated at each visit. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments obtained within 4 weeks after the criteria for response were first met. Assessments was based on RECIST criteria 1.0. Measurable disease lesions had to be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). PR required at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. CR required disappearance of all target and non-target lesions.
Time Frame baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Everolimus
Hide Arm/Group Description:
10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Number of Participants Analyzed 60
Measure Type: Number
Unit of Measure: percentage of participants
Complete response (CR) 0.0
Partial response 0.0
Stable disease (SD) 56.7
Progressive disease (PD) 43.3
Unknown 0.0
2.Primary Outcome
Title Percentage of Participants With Objective Response Rate at 12 Months - Per Protocol Set (PP)
Hide Description Overall Response Rate (ORR) was calculated for total PP population based on central review as confirmatory, primary analysis as well as for ITT population as sensitivity analysis. It was presented with relative frequencies and the exact 2-sided 80% confidence limit (CI) computed using the Clopper-Pearson method). If the lower limit of the CI did not include p0=5%, the hypothesis that p ≤ 5% was rejected. The primary analysis was based on the PP Set
Time Frame baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Everolimus
Hide Arm/Group Description:
10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Number of Participants Analyzed 60
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of participants
0.0
(0.0 to 3.8)
3.Primary Outcome
Title Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set
Hide Description

The best overall response (BOR) was calculated on basis of the tumor of overall lesion response evaluated at each visit. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed not less than 4 weeks after the criteria for response were first met. Assessments was based on RECIST criteria 1.0. Measurable disease lesions had to be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). PR required at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.

CR required disappearance of all target and non-target lesions.

Time Frame baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Everolimus
Hide Arm/Group Description:
10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Number of Participants Analyzed 73
Measure Type: Number
Unit of Measure: percentage of participants
Complete response (CR) 0.0
Partial response 0.0
Stable disease (SD) 74.0
Progressive disease (PD) 16.4
Unknown 9.6
4.Primary Outcome
Title Percentage of Participants With Objective Response Rate at 12 Months ITT Set
Hide Description Overall Response Rate (ORR) was presented for ITT population as sensitivity analysis. It was presented with relative frequencies and the exact 2-sided 80% confidence limit (CL; computed using the Clopper-Pearson method). If the lower limit of the CI did not include p0=5%, the hypothesis that p ≤ 5% was rejected.
Time Frame baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Everolimus
Hide Arm/Group Description:
10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Number of Participants Analyzed 73
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of participants
0.0
(0.0 to 3.1)
5.Secondary Outcome
Title Percentage of Participants With Disease Control Rate (DCR) at 12 Months for Per Protocol (PP) and ITT Sets
Hide Description DCR was based on central radiologic review and is defined as the percentage of patients with a best overall response of ‘Complete response’ (CR), ‘Partial response’ (PR) or ‘Stable disease’ (SD). Relative frequencies together with their exact 2-sided 80% confidence intervals were presented
Time Frame baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
subjects who met required criteria
Arm/Group Title Everolimus
Hide Arm/Group Description:
10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Number of Participants Analyzed 73
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: percentage of participants
DCR for Per protocol set Number Analyzed 60 participants
56.7
(47.6 to 65.4)
DCR for Intent to treat set Number Analyzed 73 participants
50.7
(42.6 to 58.8)
6.Secondary Outcome
Title Percentage of Participants' Biochemical Response Rate Based on the Tumor Marker Chromogranin A (CgA)
Hide Description Biochemical response was defined as level and change from baseline in CgA during the course of the trial. The resulting values showed a high variation and were not interpretable, as different methodology was used for the assessment of CgA at the individual centers.
Time Frame baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
The resulting values showed a high variation and were not interpretable, as different methodology was used for the assessment of CgA at the individual centers.
Arm/Group Title Everolimus
Hide Arm/Group Description:
10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
7.Secondary Outcome
Title Duration of Progression Free Survival (PFS) for Per Protocol (PP) and ITT Sets
Hide Description Duration of PFS was defined as the time from first study drug administration to objective tumor progression or death from any cause. Observations from patients not experiencing tumor progression or death at date of database closure were censored with the date of their last adequate tumor assessment. Progression was either 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline or 2) the appearance of a new lesion or 3) the unequivocal progression of non-target lesions.
Time Frame baseline up to approximately 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
subjects who met required criteria
Arm/Group Title Everolimus
Hide Arm/Group Description:
10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Number of Participants Analyzed 73
Median (95% Confidence Interval)
Unit of Measure: days
PFS days for Per protocol set Number Analyzed 60 participants
185
(160 to 262)
PFS days for Intent to treat set Number Analyzed 73 participants
190
(161 to 262)
8.Secondary Outcome
Title Overall Survival (OS) for Per Protocol (PP) and ITT Sets
Hide Description OS was defined as the time from first study drug administration to death from any cause. If a patient was not known to have died at date of database closure, overall survival was censored at the date of last contact.
Time Frame baseline up to approximately 15 months
Hide Outcome Measure Data
Hide Analysis Population Description
subjects who met required criteria
Arm/Group Title Everolimus
Hide Arm/Group Description:
10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Number of Participants Analyzed 73
Mean (Standard Error)
Unit of Measure: days
OS for Per protocol set Number Analyzed 60 participants
451.8  (19.8)
OS for Intent to treat set Number Analyzed 73 participants
437.1  (18.6)
Time Frame Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit up to approximately 15 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Everolimus
Hide Arm/Group Description Everolimus
All-Cause Mortality
Everolimus
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Everolimus
Affected / at Risk (%)
Total   48/73 (65.75%) 
Blood and lymphatic system disorders   
Anaemia  1  1/73 (1.37%) 
Lymphatic obstruction  1  1/73 (1.37%) 
Cardiac disorders   
Arrhythmia  1  1/73 (1.37%) 
Atrioventricular block  1  1/73 (1.37%) 
Myocardial infarction  1  1/73 (1.37%) 
Palpitations  1  1/73 (1.37%) 
Tachycardia  1  1/73 (1.37%) 
Ear and labyrinth disorders   
Vertigo  1  1/73 (1.37%) 
Endocrine disorders   
Adrenocortical insufficiency acute  1  1/73 (1.37%) 
Eye disorders   
Retinal detachment  1  1/73 (1.37%) 
Gastrointestinal disorders   
Abdominal pain  1  2/73 (2.74%) 
Ascites  1  2/73 (2.74%) 
Constipation  1  2/73 (2.74%) 
Diarrhoea  1  5/73 (6.85%) 
Enteritis  1  1/73 (1.37%) 
Flatulence  1  1/73 (1.37%) 
Gastrointestinal obstruction  1  1/73 (1.37%) 
Intestinal obstruction  1  3/73 (4.11%) 
Intestinal perforation  1  1/73 (1.37%) 
Melaena  1  1/73 (1.37%) 
Nausea  1  1/73 (1.37%) 
Subileus  1  2/73 (2.74%) 
Vomiting  1  2/73 (2.74%) 
General disorders   
Asthenia  1  1/73 (1.37%) 
Fatigue  1  2/73 (2.74%) 
General physical health deterioration  1  1/73 (1.37%) 
Oedema  1  3/73 (4.11%) 
Oedema peripheral  1  1/73 (1.37%) 
Pyrexia  1  1/73 (1.37%) 
Sudden death  1  1/73 (1.37%) 
Hepatobiliary disorders   
Acute hepatic failure  1  1/73 (1.37%) 
Cholangitis  1  1/73 (1.37%) 
Infections and infestations   
Febrile infection  1  1/73 (1.37%) 
Gastroenteritis  1  1/73 (1.37%) 
Gastroenteritis viral  1  1/73 (1.37%) 
Gastrointestinal infection  1  2/73 (2.74%) 
H1N1 influenza  1  1/73 (1.37%) 
Herpes zoster  1  1/73 (1.37%) 
Liver abscess  1  1/73 (1.37%) 
Lung abscess  1  1/73 (1.37%) 
Lymphangitis  1  1/73 (1.37%) 
Pneumonia  1  5/73 (6.85%) 
Pseudomonas infection  1  1/73 (1.37%) 
Pyelonephritis acute  1  1/73 (1.37%) 
Respiratory tract infection  1  1/73 (1.37%) 
Subdiaphragmatic abscess  1  1/73 (1.37%) 
Injury, poisoning and procedural complications   
Expired product administered  1  1/73 (1.37%) 
Toxicity to various agents  1  1/73 (1.37%) 
Investigations   
Alanine aminotransferase increased  1  3/73 (4.11%) 
Aspartate aminotransferase increased  1  3/73 (4.11%) 
Blood alkaline phosphatase increased  1  1/73 (1.37%) 
Blood lactate dehydrogenase increased  1  1/73 (1.37%) 
Blood potassium decreased  1  1/73 (1.37%) 
Gamma-glutamyltransferase increased  1  1/73 (1.37%) 
Haemoglobin decreased  1  2/73 (2.74%) 
Metabolism and nutrition disorders   
Dehydration  1  2/73 (2.74%) 
Diabetes mellitus  1  1/73 (1.37%) 
Hypokalaemia  1  2/73 (2.74%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  1/73 (1.37%) 
Back pain  1  3/73 (4.11%) 
Bone pain  1  1/73 (1.37%) 
Musculoskeletal pain  1  1/73 (1.37%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Metastases to central nervous system  1  1/73 (1.37%) 
Nervous system disorders   
Presyncope  1  1/73 (1.37%) 
Psychiatric disorders   
Completed suicide  1  1/73 (1.37%) 
Restlessness  1  1/73 (1.37%) 
Renal and urinary disorders   
Acute kidney injury  1  1/73 (1.37%) 
Incontinence  1  1/73 (1.37%) 
Renal failure  1  1/73 (1.37%) 
Reproductive system and breast disorders   
Vaginal haemorrhage  1  1/73 (1.37%) 
Respiratory, thoracic and mediastinal disorders   
Chronic obstructive pulmonary disease  1  1/73 (1.37%) 
Dyspnoea  1  4/73 (5.48%) 
Lung infiltration  1  1/73 (1.37%) 
Pleural effusion  1  1/73 (1.37%) 
Pneumonitis  1  2/73 (2.74%) 
Pulmonary embolism  1  2/73 (2.74%) 
Surgical and medical procedures   
Astringent therapy  1  1/73 (1.37%) 
Vascular disorders   
Aortic rupture  1  1/73 (1.37%) 
Circulatory collapse  1  1/73 (1.37%) 
Hypotension  1  1/73 (1.37%) 
Lymphoedema  1  1/73 (1.37%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (18.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Everolimus
Affected / at Risk (%)
Total   72/73 (98.63%) 
Blood and lymphatic system disorders   
Anaemia  1  11/73 (15.07%) 
Cardiac disorders   
Tachycardia  1  7/73 (9.59%) 
Gastrointestinal disorders   
Abdominal pain  1  18/73 (24.66%) 
Abdominal pain upper  1  9/73 (12.33%) 
Aphthous ulcer  1  4/73 (5.48%) 
Constipation  1  9/73 (12.33%) 
Diarrhoea  1  30/73 (41.10%) 
Dry mouth  1  4/73 (5.48%) 
Flatulence  1  4/73 (5.48%) 
Mouth ulceration  1  12/73 (16.44%) 
Nausea  1  22/73 (30.14%) 
Stomatitis  1  15/73 (20.55%) 
Vomiting  1  18/73 (24.66%) 
General disorders   
Asthenia  1  19/73 (26.03%) 
Chest pain  1  8/73 (10.96%) 
Chills  1  5/73 (6.85%) 
Fatigue  1  19/73 (26.03%) 
Mucosal inflammation  1  18/73 (24.66%) 
Oedema  1  5/73 (6.85%) 
Oedema peripheral  1  15/73 (20.55%) 
Pain  1  5/73 (6.85%) 
Pyrexia  1  11/73 (15.07%) 
Infections and infestations   
Conjunctivitis  1  4/73 (5.48%) 
Cystitis  1  5/73 (6.85%) 
Nasopharyngitis  1  8/73 (10.96%) 
Pneumonia  1  5/73 (6.85%) 
Respiratory tract infection  1  4/73 (5.48%) 
Urinary tract infection  1  11/73 (15.07%) 
Investigations   
Alanine aminotransferase increased  1  5/73 (6.85%) 
Aspartate aminotransferase increased  1  5/73 (6.85%) 
Blood alkaline phosphatase increased  1  7/73 (9.59%) 
Blood glucose increased  1  5/73 (6.85%) 
Blood lactate dehydrogenase increased  1  5/73 (6.85%) 
Blood potassium decreased  1  5/73 (6.85%) 
Blood thyroid stimulating hormone decreased  1  5/73 (6.85%) 
Blood triglycerides increased  1  4/73 (5.48%) 
Gamma-glutamyltransferase increased  1  8/73 (10.96%) 
Haemoglobin decreased  1  5/73 (6.85%) 
Neutrophil count decreased  1  4/73 (5.48%) 
Platelet count decreased  1  6/73 (8.22%) 
Weight decreased  1  17/73 (23.29%) 
White blood cell count decreased  1  4/73 (5.48%) 
Metabolism and nutrition disorders   
Decreased appetite  1  23/73 (31.51%) 
Hypercholesterolaemia  1  12/73 (16.44%) 
Hyperglycaemia  1  6/73 (8.22%) 
Hypertriglyceridaemia  1  8/73 (10.96%) 
Hypokalaemia  1  9/73 (12.33%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  7/73 (9.59%) 
Back pain  1  12/73 (16.44%) 
Flank pain  1  4/73 (5.48%) 
Musculoskeletal pain  1  4/73 (5.48%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Cancer pain  1  4/73 (5.48%) 
Nervous system disorders   
Dizziness  1  5/73 (6.85%) 
Dysgeusia  1  7/73 (9.59%) 
Headache  1  10/73 (13.70%) 
Lethargy  1  8/73 (10.96%) 
Psychiatric disorders   
Depression  1  4/73 (5.48%) 
Insomnia  1  7/73 (9.59%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  23/73 (31.51%) 
Dyspnoea  1  18/73 (24.66%) 
Epistaxis  1  10/73 (13.70%) 
Oropharyngeal pain  1  7/73 (9.59%) 
Pneumonitis  1  7/73 (9.59%) 
Skin and subcutaneous tissue disorders   
Dry skin  1  7/73 (9.59%) 
Onychoclasis  1  7/73 (9.59%) 
Pruritus  1  8/73 (10.96%) 
Rash  1  32/73 (43.84%) 
Vascular disorders   
Flushing  1  4/73 (5.48%) 
Hypertension  1  5/73 (6.85%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (18.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
EMail: Novartis.email@novartis.com
Layout table for additonal information
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00688623     History of Changes
Other Study ID Numbers: CRAD001CDE16
First Submitted: May 30, 2008
First Posted: June 3, 2008
Results First Submitted: November 7, 2017
Results First Posted: January 25, 2019
Last Update Posted: January 25, 2019