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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00688623
• Collaborator: (none)
• Enrollment: 73
• Locations: 40
• Arm: 1
• Actual Duration (Months): 88.5
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To evaluate the preliminary efficacy and safety of RAD001 as monotherapy for first-line treatment of patients with metastatic papillary carcinoma of the kidney.

Condition or Disease	Intervention/Treatment	Phase
Advanced and Metastatic Silent Neuro-Endocrine Tumors; Carcinoma; Neuroendocrine; Non Functioning Neuroendocrine Tumors (NETs); Non Syndromic Neuroendocrine Tumors; Carcinoids; Non Functioning	Drug: Everolimus	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 73 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm, Multicenter Single Stage Phase II Trial of RAD001 as Monotherapy in the Treatment of Metastatic Non Syndromic Neuro-endocrine Tumors
• Actual Study Start Date: Jun 24, 2009
• Actual Primary Completion Date: Nov 7, 2016
• Actual Study Completion Date: Nov 7, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Everolimus Everolimus	Drug: Everolimus; Everolimus 5 mg tablets were supplied in blister packs

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP) [baseline up to approximately 12 months]

   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.

2. Percentage of Participants With Objective Response Rate at 12 Months - Per Protocol Set (PP) [baseline up to approximately 12 months]

   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

3. Percentage of Participants With a Overall Response Rate With a Complete Response (CR) or Partial Response (PR) at 12 Months ITT Set [baseline up to approximately 12 months]

   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.

4. Percentage of Participants With Objective Response Rate at 12 Months ITT Set [baseline up to approximately 12 months]

   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.

Secondary Outcome Measures

1. Percentage of Participants With Disease Control Rate (DCR) at 12 Months for Per Protocol (PP) and ITT Sets [baseline up to approximately 12 months]

   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

2. Percentage of Participants' Biochemical Response Rate Based on the Tumor Marker Chromogranin A (CgA) [baseline up to approximately 12 months]

   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.

3. Duration of Progression Free Survival (PFS) for Per Protocol (PP) and ITT Sets [baseline up to approximately 12 months]

   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.

4. Overall Survival (OS) for Per Protocol (PP) and ITT Sets [baseline up to approximately 15 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. ≥ 18 years old

2. Patients with advanced (unresectable or metastatic) biopsy proven non-syndromic neuro-endocrine carcinoma, low or intermediate grade

3. Radiological documentation of disease progression within 12 months prior to study entry. If patients received anti-tumor therapy during the past 12 months, they must have radiological documentation of progressive disease (PD) while on or after receiving the therapy

4. Patients may have received previous treatments (chemotherapy, biotherapy, peptide-receptor radionuclide therapy); an overall maximum of 3 systemic treatment is allowed

5. Patients with at least one measurable lesion

6. Patients with an ECOG (Eastern Cooperative Oncology Group) Performance Status 0-2

7. Adequate bone marrow function

8. Adequate liver function

9. Adequate renal function

10. Adequate lipid profile

Exclusion criteria:

1. Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma

2. Patients with carcinoid with hormone related symptoms (diarrhea ≥ 4 stools per day and/or flushes)

3. Patients with Islet cell carcinomas or pancreatic NET

4. Patients who received prior therapy with Vascular Endothelial Growth Factor (VEGF) pathway inhibitor within 4 weeks prior to study entry

5. Patients who entered peptide receptor radionuclide therapy (PRRT) within 3 months prior to study entry

6. Patients who received CT, biotherapy or radiotherapy within 4 weeks prior to study entry

7. Patients who have previously received systemic (mammalian target of rapamycin) mTOR inhibitors

8. Patients with a known hypersensitivity to everolimus or other rapamycins or to its excipients

9. Patients with uncontrolled central nervous system (CNS) metastases

10. Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent

11. Patients with a known history of HIV seropositivity

12. Patients with autoimmune hepatitis

13. Patients with an active, bleeding diathesis

14. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study

15. Patients who have a history of another primary malignancy and off treatment ≤ 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix

16. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods

17. Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study treatment start

18. Patients unwilling to or unable to comply with the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Bordeaux		France
2	Novartis Investigative Site	Lyon		France
3	Novartis Investigative Site	Marseille		France
4	Novartis Investigative Site	Paris		France
5	Novartis Investigative Site	Bad Berka		Germany	99438
6	Novartis Investigative Site	Bad Berka		Germany
7	Novartis Investigative Site	Berlin		Germany	13353
8	Novartis Investigative Site	Berlin		Germany
9	Novartis Investigative Site	Bonn		Germany
10	Novartis Investigative Site	Frankfurt		Germany
11	Novartis Investigative Site	Heidelberg		Germany	69120
12	Novartis Investigative Site	Heidelberg		Germany
13	Novartis Investigative Site	Mainz		Germany	55131
14	Novartis Investigative Site	Mainz		Germany
15	Novartis Investigative Site	Munich		Germany
16	Novartis Investigative Site	Bologna	BO	Italy	40138
17	Novartis Investigative Site	Viagrande	CT	Italy	95029
18	Novartis Investigative Site	Milano	MI	Italy	20141
19	Novartis Investigative Site	Perugia	PG	Italy	06129
20	Novartis Investigative Site	Roma	RM	Italy	00189
21	Novartis Investigative Site	Bologna		Italy
22	Novartis Investigative Site	Milano		Italy
23	Novartis Investigative Site	Perugia		Italy
24	Novartis Investigative Site	Roma		Italy
25	Novartis Investigative Site	Viagrande		Italy
26	Novartis Investigative Site	Rotterdam		Netherlands
27	Novartis Investigative Site	Gdansk		Poland	80-952
28	Novartis Investigative Site	Gdansk		Poland
29	Novartis Investigative Site	Warszawa		Poland
30	Novartis Investigative Site	Barcelona	Cataluña	Spain	08907
31	Novartis Investigative Site	Barcelona	Cataluña	Spain
32	Novartis Investigative Site	Barcelona		Spain
33	Novartis Investigative Site	Madrid		Spain
34	Novartis Investigative Site	Uppsala		Spain
35	Novartis Investigative Site	Stockholm		Sweden
36	Novartis Investigative Site	Uppsala		Sweden	SE-751 85
37	Novartis Investigative Site	Glasgow - Scotland		United Kingdom	G12 OYN
38	Novartis Investigative Site	Glasgow		United Kingdom
39	Novartis Investigative Site	Manchester		United Kingdom	M20 9BX
40	Novartis Investigative Site	Manchester		United Kingdom

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00688623
• Other Study ID Numbers: CRAD001CDE16
• First Posted: Jun 3, 2008
• Last Update Posted: Jan 25, 2019
• Last Verified: Aug 1, 2018

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Neuroendocrine tumors; non functioning neuroendocrine tumors; Non syndromic neuroendocrine tumors; carcinoids; non-functioning carcinoids; adults; everolimus; NET; RAMSETE; CRAD001; non-functioning neuroendocrine tumors carcinoids
• Additional relevant MeSH terms: Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor; Endocrine Gland Neoplasms; Everolimus

Study Results

Participant Flow

Pre-assignment Detail	Eighty-two patients were screened and 73 were treated with study drug.

Arm/Group Title	Everolimus
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
Safety Analysis Set	73
Per Protocol (PP)	60
COMPLETED	18
NOT COMPLETED	55

Baseline Characteristics

Arm/Group Title	Everolimus
Arm/Group Description	10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Overall Participants	73
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.9 (13.0)
Sex: Female, Male (Count of Participants)
Female	33 45.2%
Male	40 54.8%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	71 97.3%
Other	2 2.7%
Tumor histology/cytology (Count of 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 (Count of Participants)
< 1 year	19 26%
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%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants' Best Overall Response Rate at 12 Months - Per Protocol Set (PP)
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus
Arm/Group Description	10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Measure Participants	60
Complete response (CR)	0.0 0%
Partial response	0.0 0%
Stable disease (SD)	56.7 77.7%
Progressive disease (PD)	43.3 59.3%
Unknown	0.0 0%

2. Primary Outcome

Title	Percentage of Participants With Objective Response Rate at 12 Months - Per Protocol Set (PP)
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus
Arm/Group Description	10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Measure Participants	60
Number (80% Confidence Interval) [percentage of participants]	0.0 0%

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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus
Arm/Group Description	10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Measure Participants	73
Complete response (CR)	0.0 0%
Partial response	0.0 0%
Stable disease (SD)	74.0 101.4%
Progressive disease (PD)	16.4 22.5%
Unknown	9.6 13.2%

4. Primary Outcome

Title	Percentage of Participants With Objective Response Rate at 12 Months ITT Set
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus
Arm/Group Description	10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Measure Participants	73
Number (80% Confidence Interval) [percentage of participants]	0.0 0%

5. Secondary Outcome

Title	Percentage of Participants With Disease Control Rate (DCR) at 12 Months for Per Protocol (PP) and ITT Sets
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

Outcome Measure Data

Analysis Population Description

subjects who met required criteria

Arm/Group Title	Everolimus
Arm/Group Description	10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Measure Participants	73
DCR for Per protocol set	56.7 77.7%
DCR for Intent to treat set	50.7 69.5%

6. Secondary Outcome

Title	Percentage of Participants' Biochemical Response Rate Based on the Tumor Marker Chromogranin A (CgA)
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

Outcome Measure Data

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
Arm/Group Description	10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Measure Participants	0

7. Secondary Outcome

Title	Duration of Progression Free Survival (PFS) for Per Protocol (PP) and ITT Sets
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

Outcome Measure Data

Analysis Population Description

subjects who met required criteria

Arm/Group Title	Everolimus
Arm/Group Description	10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Measure Participants	73
PFS days for Per protocol set	185
PFS days for Intent to treat set	190

8. Secondary Outcome

Title	Overall Survival (OS) for Per Protocol (PP) and ITT Sets
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

Outcome Measure Data

Analysis Population Description

subjects who met required criteria

Arm/Group Title	Everolimus
Arm/Group Description	10 mg/day dose of everolimus was given by continuous oral daily dosing of two 5 mg tablets
Measure Participants	73
OS for Per protocol set	451.8 (19.8)
OS for Intent to treat set	437.1 (18.6)

Adverse Events

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
Arm/Group Title	Everolimus
Arm/Group Description	Everolimus
All Cause Mortality
	Everolimus
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	48/73 (65.8%)
Blood and lymphatic system disorders
Anaemia	1/73 (1.4%)
Lymphatic obstruction	1/73 (1.4%)
Cardiac disorders
Arrhythmia	1/73 (1.4%)
Atrioventricular block	1/73 (1.4%)
Myocardial infarction	1/73 (1.4%)
Palpitations	1/73 (1.4%)
Tachycardia	1/73 (1.4%)
Ear and labyrinth disorders
Vertigo	1/73 (1.4%)
Endocrine disorders
Adrenocortical insufficiency acute	1/73 (1.4%)
Eye disorders
Retinal detachment	1/73 (1.4%)
Gastrointestinal disorders
Abdominal pain	2/73 (2.7%)
Ascites	2/73 (2.7%)
Constipation	2/73 (2.7%)
Diarrhoea	5/73 (6.8%)
Enteritis	1/73 (1.4%)
Flatulence	1/73 (1.4%)
Gastrointestinal obstruction	1/73 (1.4%)
Intestinal obstruction	3/73 (4.1%)
Intestinal perforation	1/73 (1.4%)
Melaena	1/73 (1.4%)
Nausea	1/73 (1.4%)
Subileus	2/73 (2.7%)
Vomiting	2/73 (2.7%)
General disorders
Asthenia	1/73 (1.4%)
Fatigue	2/73 (2.7%)
General physical health deterioration	1/73 (1.4%)
Oedema	3/73 (4.1%)
Oedema peripheral	1/73 (1.4%)
Pyrexia	1/73 (1.4%)
Sudden death	1/73 (1.4%)
Hepatobiliary disorders
Acute hepatic failure	1/73 (1.4%)
Cholangitis	1/73 (1.4%)
Infections and infestations
Febrile infection	1/73 (1.4%)
Gastroenteritis	1/73 (1.4%)
Gastroenteritis viral	1/73 (1.4%)
Gastrointestinal infection	2/73 (2.7%)
H1N1 influenza	1/73 (1.4%)
Herpes zoster	1/73 (1.4%)
Liver abscess	1/73 (1.4%)
Lung abscess	1/73 (1.4%)
Lymphangitis	1/73 (1.4%)
Pneumonia	5/73 (6.8%)
Pseudomonas infection	1/73 (1.4%)
Pyelonephritis acute	1/73 (1.4%)
Respiratory tract infection	1/73 (1.4%)
Subdiaphragmatic abscess	1/73 (1.4%)
Injury, poisoning and procedural complications
Expired product administered	1/73 (1.4%)
Toxicity to various agents	1/73 (1.4%)
Investigations
Alanine aminotransferase increased	3/73 (4.1%)
Aspartate aminotransferase increased	3/73 (4.1%)
Blood alkaline phosphatase increased	1/73 (1.4%)
Blood lactate dehydrogenase increased	1/73 (1.4%)
Blood potassium decreased	1/73 (1.4%)
Gamma-glutamyltransferase increased	1/73 (1.4%)
Haemoglobin decreased	2/73 (2.7%)
Metabolism and nutrition disorders
Dehydration	2/73 (2.7%)
Diabetes mellitus	1/73 (1.4%)
Hypokalaemia	2/73 (2.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/73 (1.4%)
Back pain	3/73 (4.1%)
Bone pain	1/73 (1.4%)
Musculoskeletal pain	1/73 (1.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system	1/73 (1.4%)
Nervous system disorders
Presyncope	1/73 (1.4%)
Psychiatric disorders
Completed suicide	1/73 (1.4%)
Restlessness	1/73 (1.4%)
Renal and urinary disorders
Acute kidney injury	1/73 (1.4%)
Incontinence	1/73 (1.4%)
Renal failure	1/73 (1.4%)
Reproductive system and breast disorders
Vaginal haemorrhage	1/73 (1.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/73 (1.4%)
Dyspnoea	4/73 (5.5%)
Lung infiltration	1/73 (1.4%)
Pleural effusion	1/73 (1.4%)
Pneumonitis	2/73 (2.7%)
Pulmonary embolism	2/73 (2.7%)
Surgical and medical procedures
Astringent therapy	1/73 (1.4%)
Vascular disorders
Aortic rupture	1/73 (1.4%)
Circulatory collapse	1/73 (1.4%)
Hypotension	1/73 (1.4%)
Lymphoedema	1/73 (1.4%)
Other (Not Including Serious) Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	72/73 (98.6%)
Blood and lymphatic system disorders
Anaemia	11/73 (15.1%)
Cardiac disorders
Tachycardia	7/73 (9.6%)
Gastrointestinal disorders
Abdominal pain	18/73 (24.7%)
Abdominal pain upper	9/73 (12.3%)
Aphthous ulcer	4/73 (5.5%)
Constipation	9/73 (12.3%)
Diarrhoea	30/73 (41.1%)
Dry mouth	4/73 (5.5%)
Flatulence	4/73 (5.5%)
Mouth ulceration	12/73 (16.4%)
Nausea	22/73 (30.1%)
Stomatitis	15/73 (20.5%)
Vomiting	18/73 (24.7%)
General disorders
Asthenia	19/73 (26%)
Chest pain	8/73 (11%)
Chills	5/73 (6.8%)
Fatigue	19/73 (26%)
Mucosal inflammation	18/73 (24.7%)
Oedema	5/73 (6.8%)
Oedema peripheral	15/73 (20.5%)
Pain	5/73 (6.8%)
Pyrexia	11/73 (15.1%)
Infections and infestations
Conjunctivitis	4/73 (5.5%)
Cystitis	5/73 (6.8%)
Nasopharyngitis	8/73 (11%)
Pneumonia	5/73 (6.8%)
Respiratory tract infection	4/73 (5.5%)
Urinary tract infection	11/73 (15.1%)
Investigations
Alanine aminotransferase increased	5/73 (6.8%)
Aspartate aminotransferase increased	5/73 (6.8%)
Blood alkaline phosphatase increased	7/73 (9.6%)
Blood glucose increased	5/73 (6.8%)
Blood lactate dehydrogenase increased	5/73 (6.8%)
Blood potassium decreased	5/73 (6.8%)
Blood thyroid stimulating hormone decreased	5/73 (6.8%)
Blood triglycerides increased	4/73 (5.5%)
Gamma-glutamyltransferase increased	8/73 (11%)
Haemoglobin decreased	5/73 (6.8%)
Neutrophil count decreased	4/73 (5.5%)
Platelet count decreased	6/73 (8.2%)
Weight decreased	17/73 (23.3%)
White blood cell count decreased	4/73 (5.5%)
Metabolism and nutrition disorders
Decreased appetite	23/73 (31.5%)
Hypercholesterolaemia	12/73 (16.4%)
Hyperglycaemia	6/73 (8.2%)
Hypertriglyceridaemia	8/73 (11%)
Hypokalaemia	9/73 (12.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/73 (9.6%)
Back pain	12/73 (16.4%)
Flank pain	4/73 (5.5%)
Musculoskeletal pain	4/73 (5.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	4/73 (5.5%)
Nervous system disorders
Dizziness	5/73 (6.8%)
Dysgeusia	7/73 (9.6%)
Headache	10/73 (13.7%)
Lethargy	8/73 (11%)
Psychiatric disorders
Depression	4/73 (5.5%)
Insomnia	7/73 (9.6%)
Respiratory, thoracic and mediastinal disorders
Cough	23/73 (31.5%)
Dyspnoea	18/73 (24.7%)
Epistaxis	10/73 (13.7%)
Oropharyngeal pain	7/73 (9.6%)
Pneumonitis	7/73 (9.6%)
Skin and subcutaneous tissue disorders
Dry skin	7/73 (9.6%)
Onychoclasis	7/73 (9.6%)
Pruritus	8/73 (11%)
Rash	32/73 (43.8%)
Vascular disorders
Flushing	4/73 (5.5%)
Hypertension	5/73 (6.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.