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Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib (CELESTIAL)

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ClinicalTrials.gov Identifier: NCT01908426
Recruitment Status : Active, not recruiting
First Posted : July 25, 2013
Results First Posted : March 1, 2019
Last Update Posted : March 1, 2019
Sponsor:
Information provided by (Responsible Party):
Exelixis

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hepatocellular Carcinoma
Interventions Drug: Cabozantinib tablets
Drug: Placebo tablets
Enrollment 707
Recruitment Details First patient enrolled: 26 September 2013, Data cut-off date: 01 June 2017
Pre-assignment Details  
Arm/Group Title Cabozantinib (XL184) Placebo
Hide Arm/Group Description

Cabozantinib (XL184) 60 mg tablet once daily

Cabozantinib tablets

Oral cabozantinib-matched placebo tablet once daily

Placebo tablets

Period Title: Overall Study
Started 470 237
Completed 73 26
Not Completed 397 211
Reason Not Completed
Adverse Event             98             11
Clinical Deterioration             72             38
Lack of Efficacy             3             0
Lost to Follow-up             0             1
Physician Decision             3             3
Withdrawal by Subject             11             6
Progressive Disease             206             152
Protocol Violation             1             0
No Study Treatment Given             3             0
Arm/Group Title Cabozantinib (XL184) Placebo Total
Hide Arm/Group Description

Cabozantinib (XL184) 60 mg tablet once daily

Cabozantinib tablets

Oral cabozantinib-matched placebo tablet once daily

Placebo tablets

Total of all reporting groups
Overall Number of Baseline Participants 470 237 707
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 470 participants 237 participants 707 participants
64.0
(22 to 86)
64.0
(24 to 86)
64.0
(22 to 86)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Age, Customized Number Analyzed 470 participants 237 participants 707 participants
< 65 years old
240
  51.1%
124
  52.3%
364
  51.5%
65 to < 75 years old
158
  33.6%
75
  31.6%
233
  33.0%
75 to < 85 years old
67
  14.3%
35
  14.8%
102
  14.4%
≥ 85 years old
5
   1.1%
3
   1.3%
8
   1.1%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
Female
91
  19.4%
35
  14.8%
126
  17.8%
Male
379
  80.6%
202
  85.2%
581
  82.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
Hispanic or Latino
18
   3.8%
12
   5.1%
30
   4.2%
Not Hispanic or Latino
417
  88.7%
215
  90.7%
632
  89.4%
Unknown or Not Reported
35
   7.4%
10
   4.2%
45
   6.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
159
  33.8%
82
  34.6%
241
  34.1%
Native Hawaiian or Other Pacific Islander
3
   0.6%
0
   0.0%
3
   0.4%
Black or African American
8
   1.7%
11
   4.6%
19
   2.7%
White
264
  56.2%
130
  54.9%
394
  55.7%
More than one race
0
   0.0%
1
   0.4%
1
   0.1%
Unknown or Not Reported
36
   7.7%
13
   5.5%
49
   6.9%
Geographic Region  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
Australia / New Zealand
15
   3.2%
11
   4.6%
26
   3.7%
Asia
116
  24.7%
59
  24.9%
175
  24.8%
Europe
231
  49.1%
108
  45.6%
339
  47.9%
North America (USA / Canada)
108
  23.0%
59
  24.9%
167
  23.6%
Presence of extrahepatic spread of disease and/or macrovascular invasion (stratification per IxRS)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
Yes
368
  78.3%
186
  78.5%
554
  78.4%
No
102
  21.7%
51
  21.5%
153
  21.6%
[1]
Measure Description: Interactive voice/web response system (IxRS)
Etiology of disease (stratification factor per IxRS),  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
HBV (with or without known HCV)
182
  38.7%
90
  38.0%
272
  38.5%
HCV (without known HBV)
100
  21.3%
51
  21.5%
151
  21.4%
Other (neither HBV nor HCV)
188
  40.0%
96
  40.5%
284
  40.2%
Geographic region (stratification factor per IxRS)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
Asia
116
  24.7%
59
  24.9%
175
  24.8%
Other Regions
354
  75.3%
178
  75.1%
532
  75.2%
Eastern Cooperative Oncology Group Performance Status (ECOG PS)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
0
245
  52.1%
131
  55.3%
376
  53.2%
1
224
  47.7%
106
  44.7%
330
  46.7%
2
1
   0.2%
0
   0.0%
1
   0.1%
[1]
Measure Description:

The ECOG performance scale is:

0 = Normal activity. Fully active, able to carry on all predisease performance without restriction, 1 = Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (eg, light housework, office work), 2 = In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours.

Smoking history  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
Current
78
  16.6%
42
  17.7%
120
  17.0%
Former
229
  48.7%
122
  51.5%
351
  49.6%
Never
160
  34.0%
71
  30.0%
231
  32.7%
Missing
3
   0.6%
2
   0.8%
5
   0.7%
Alcohol use  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 470 participants 237 participants 707 participants
Current
65
  13.8%
30
  12.7%
95
  13.4%
Former
223
  47.4%
124
  52.3%
347
  49.1%
Never
176
  37.4%
81
  34.2%
257
  36.4%
Missing
6
   1.3%
2
   0.8%
8
   1.1%
Weight  
Median (Full Range)
Unit of measure:  Kg
Number Analyzed 470 participants 237 participants 707 participants
69
(35 to 130)
71.5
(41 to 125)
70.25
(35 to 130)
Body Mass Index (BMI)  
Median (Full Range)
Unit of measure:  Kg / m^2
Number Analyzed 470 participants 237 participants 707 participants
24.1
(15 to 47)
24.9
(17 to 42)
24.5
(15 to 47)
1.Primary Outcome
Title Overall Survival (OS)
Hide Description The primary analysis of OS is defined as the time from randomization to death from any cause. The analysis was based on a second planned interim analysis prespecified to be performed at approximately the 75% information fraction (ie, at approximately 466 deaths). The data cutoff date for this event-driven analysis in the Intent to Treat (ITT) population was 01 June 2017. Median OS was calculated using the Kaplan-Meier estimates.
Time Frame Up to 45 months
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population was used and included 707 randomized subjects (470 cabozantinib, 237 placebo) in the second interim analysis with a cutoff date of 01 June 2017.
Arm/Group Title Cabozantinib (XL184) Placebo
Hide Arm/Group Description:

Cabozantinib (XL184) 60 mg tablet once daily

Cabozantinib tablets

Oral cabozantinib-matched placebo tablet once daily

Placebo tablets

Overall Number of Participants Analyzed 470 237
Median (95% Confidence Interval)
Unit of Measure: months
10.2
(9.1 to 12.0)
8.0
(6.8 to 9.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cabozantinib (XL184), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0049
Comments [Not Specified]
Method Log Rank
Comments The Log-Rank Test was stratified by etiology of disease, geo. region, presence of extrahepatic spread of disease and/or macrovascular invasion.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.63 to 0.92
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Progression-Free Survival (PFS)
Hide Description Duration of PFS is defined as the time of randomization to the earlier of the following events, progressive disease as determined by Investigator (per RECIST 1.0, which is defined by a ≥ 20% increase in the sum of the longest diameter of target lesions from baseline) or death due to any cause. A Kaplan- Meier analysis was performed to estimate the median duration.
Time Frame Up to 45 months
Hide Outcome Measure Data
Hide Analysis Population Description
The prespecified primary analysis of PFS was based on the first 707 randomized subjects (470 cabozantinib, 237 placebo).
Arm/Group Title Cabozantinib (XL184) Placebo
Hide Arm/Group Description:

Cabozantinib (XL184) 60 mg tablet once daily

Cabozantinib tablets

Oral cabozantinib-matched placebo tablet once daily

Placebo tablets

Overall Number of Participants Analyzed 470 237
Median (95% Confidence Interval)
Unit of Measure: months
5.2
(4.0 to 5.5)
1.9
(1.9 to 1.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cabozantinib (XL184), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments [Not Specified]
Method Log Rank
Comments The Log Rank Test was stratified by etiology of disease, geographic region, presence of extrahepatic spread of disease and/or macrovascular invasion.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.44
Confidence Interval (2-Sided) 95%
0.36 to 0.52
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Objective Response Rate (ORR)
Hide Description Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame ORR is measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation of study treatment (up to 45 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis of ORR was performed in the ITT population (all randomized: 470 cabozantinib, 237 placebo) based upon response determined by Investigator per RECIST 1.1
Arm/Group Title Cabozantinib (XL184) Placebo
Hide Arm/Group Description:

Cabozantinib (XL184) 60 mg tablet once daily

Cabozantinib tablets

Oral cabozantinib-matched placebo tablet once daily

Placebo tablets

Overall Number of Participants Analyzed 470 237
Measure Type: Count of Participants
Unit of Measure: Participants
18
   3.8%
1
   0.4%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cabozantinib (XL184), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0086
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Time Frame Up to 61 weeks
Adverse Event Reporting Description The safety data includes subjects who were randomized and treated. Of 707 patients, 470 were randomized to received cabozantinib and 237 to placebo. Three subjects in the cabozantinib arm were randomized but did not receive study drug. Thus, a total of 704 subjects received study treatment in the Safety Population (467 cabozantinib, 237 placebo).
 
Arm/Group Title Cabozantinib (XL184) Placebo
Hide Arm/Group Description

Cabozantinib (XL184) 60 mg tablet once daily

Cabozantinib tablets

Oral cabozantinib-matched placebo tablet once daily

Placebo tablets

All-Cause Mortality
Cabozantinib (XL184) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   314/467 (67.24%)   167/237 (70.46%) 
Show Serious Adverse Events Hide Serious Adverse Events
Cabozantinib (XL184) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   232/467 (49.68%)   87/237 (36.71%) 
Blood and lymphatic system disorders     
Anaemia  1  4/467 (0.86%)  1/237 (0.42%) 
Febrile neutropenia  1  2/467 (0.43%)  0/237 (0.00%) 
Leukopenia  1  1/467 (0.21%)  0/237 (0.00%) 
Lymphopenia  1  1/467 (0.21%)  0/237 (0.00%) 
Neutropenia  1  1/467 (0.21%)  0/237 (0.00%) 
Thrombocytopenia  1  5/467 (1.07%)  0/237 (0.00%) 
Cardiac disorders     
Acute myocardial infarction  1  2/467 (0.43%)  0/237 (0.00%) 
Atrial fibrillation  1  1/467 (0.21%)  0/237 (0.00%) 
Atrial flutter  1  1/467 (0.21%)  0/237 (0.00%) 
Myocardial infarction  1  0/467 (0.00%)  1/237 (0.42%) 
Endocrine disorders     
Hypothyroidisim  1  1/467 (0.21%)  0/237 (0.00%) 
Eye disorders     
Retinal vein thrombosis  1  1/467 (0.21%)  0/237 (0.00%) 
Sudden visual loss  1  1/467 (0.21%)  0/237 (0.00%) 
Gastrointestinal disorders     
Abdominal Pain  1  6/467 (1.28%)  9/237 (3.80%) 
Abdominal pain upper  1  1/467 (0.21%)  0/237 (0.00%) 
Anal fistula  1  2/467 (0.43%)  0/237 (0.00%) 
Ascites  1  12/467 (2.57%)  3/237 (1.27%) 
Colitis  1  1/467 (0.21%)  0/237 (0.00%) 
Constipation  1  2/467 (0.43%)  0/237 (0.00%) 
Diarrhoea  1  5/467 (1.07%)  1/237 (0.42%) 
Duodenal perforation  1  1/467 (0.21%)  0/237 (0.00%) 
Duodenal ulcer haemorrhage  1  1/467 (0.21%)  0/237 (0.00%) 
Enterocolitis  1  1/467 (0.21%)  0/237 (0.00%) 
Gastric haemorrhage  1  1/467 (0.21%)  0/237 (0.00%) 
Gastric perforation  1  2/467 (0.43%)  0/237 (0.00%) 
Gastric varices haemorrhage  1  1/467 (0.21%)  1/237 (0.42%) 
Gastritis erosive  1  1/467 (0.21%)  0/237 (0.00%) 
Gastrointestinal haemorrhage  1  4/467 (0.86%)  1/237 (0.42%) 
Gastrointestinal ulcer haemorrhage  1  1/467 (0.21%)  0/237 (0.00%) 
Gastrooesophageal reflux disease  1  0/467 (0.00%)  1/237 (0.42%) 
Haematemesis  1  1/467 (0.21%)  1/237 (0.42%) 
Ileus  1  1/467 (0.21%)  0/237 (0.00%) 
Intestinal haemorrhage  1  0/467 (0.00%)  1/237 (0.42%) 
Intestinal obstruction  1  1/467 (0.21%)  0/237 (0.00%) 
Intestinal perforation  1  0/467 (0.00%)  1/237 (0.42%) 
Large intestine perforation  1  2/467 (0.43%)  0/237 (0.00%) 
Mallory-Weiss syndrome  1  1/467 (0.21%)  0/237 (0.00%) 
Melaena  1  2/467 (0.43%)  0/237 (0.00%) 
Mesenteric atermy thrombosis  1  1/467 (0.21%)  0/237 (0.00%) 
Nausea  1  2/467 (0.43%)  1/237 (0.42%) 
Oesophageal varices haemorrhage  1  7/467 (1.50%)  5/237 (2.11%) 
Oesophagitis  1  1/467 (0.21%)  0/237 (0.00%) 
Pancreatic pseudocyst  1  1/467 (0.21%)  0/237 (0.00%) 
Pancreatitis  1  2/467 (0.43%)  1/237 (0.42%) 
Pancreatitis acute  1  3/467 (0.64%)  0/237 (0.00%) 
Peritoneal haemorrhage  1  0/467 (0.00%)  1/237 (0.42%) 
Portal hypertensive gastropathy  1  1/467 (0.21%)  0/237 (0.00%) 
Proctalgia  1  1/467 (0.21%)  0/237 (0.00%) 
Rectal haemorrhage  1  3/467 (0.64%)  2/237 (0.84%) 
Rectal ulcer haemorrhage  1  0/467 (0.00%)  1/237 (0.42%) 
Thrombosis mesenteric vessel  1  1/467 (0.21%)  0/237 (0.00%) 
Upper gastrointestinal haemorrhage  1  3/467 (0.64%)  2/237 (0.84%) 
Vomiting  1  4/467 (0.86%)  4/237 (1.69%) 
General disorders     
Asthenia  1  9/467 (1.93%)  0/237 (0.00%) 
Chest pain  1  1/467 (0.21%)  0/237 (0.00%) 
Death  1  1/467 (0.21%)  1/237 (0.42%) 
Fatigue  1  6/467 (1.28%)  1/237 (0.42%) 
General physical health deterioration  1  17/467 (3.64%)  8/237 (3.38%) 
Influenza like illness  1  1/467 (0.21%)  0/237 (0.00%) 
Infusion site extravasation  1  1/467 (0.21%)  0/237 (0.00%) 
Local swelling  1  0/467 (0.00%)  1/237 (0.42%) 
Multi-organ failure  1  2/467 (0.43%)  0/237 (0.00%) 
Non-cardiac chest pain  1  1/467 (0.21%)  0/237 (0.00%) 
Oedema  1  2/467 (0.43%)  0/237 (0.00%) 
Oedema peripheral  1  3/467 (0.64%)  0/237 (0.00%) 
Pain  1  2/467 (0.43%)  0/237 (0.00%) 
Pyrexia  1  4/467 (0.86%)  1/237 (0.42%) 
Hepatobiliary disorders     
Acute hepatic failure  1  1/467 (0.21%)  0/237 (0.00%) 
Bile duct obstruction  1  3/467 (0.64%)  0/237 (0.00%) 
Bile duct stenosis  1  0/467 (0.00%)  1/237 (0.42%) 
Bile duct stone  1  0/467 (0.00%)  1/237 (0.42%) 
Cholangitis  1  3/467 (0.64%)  0/237 (0.00%) 
Cholangitis acute  1  0/467 (0.00%)  1/237 (0.42%) 
Cholelithiasis  1  1/467 (0.21%)  0/237 (0.00%) 
Cholestasis  1  0/467 (0.00%)  1/237 (0.42%) 
Chronic hepatic failure  1  0/467 (0.00%)  1/237 (0.42%) 
Dilatation intrahepatic duct acquired  1  0/467 (0.00%)  1/237 (0.42%) 
Gallbladder perforation  1  1/467 (0.21%)  0/237 (0.00%) 
Hepatic cirrhosis  1  1/467 (0.21%)  0/237 (0.00%) 
Hepatic failure  1  8/467 (1.71%)  8/237 (3.38%) 
Hepatic lesion  1  0/467 (0.00%)  2/237 (0.84%) 
Hepatic pain  1  0/467 (0.00%)  1/237 (0.42%) 
Hepatorenal syndrome  1  1/467 (0.21%)  1/237 (0.42%) 
Hyperbilirubinaemia  1  2/467 (0.43%)  1/237 (0.42%) 
Ischaemic hepatitis  1  1/467 (0.21%)  0/237 (0.00%) 
Jaundice  1  0/467 (0.00%)  2/237 (0.84%) 
Liver disorder  1  1/467 (0.21%)  0/237 (0.00%) 
Portail vein thrombosis  1  3/467 (0.64%)  0/237 (0.00%) 
Infections and infestations     
Abscess jaw  1  1/467 (0.21%)  0/237 (0.00%) 
Anal abscess  1  3/467 (0.64%)  0/237 (0.00%) 
Bacteraemia  1  1/467 (0.21%)  1/237 (0.42%) 
Biliary sepsis  1  0/467 (0.00%)  2/237 (0.84%) 
Biliary tract infection  1  1/467 (0.21%)  0/237 (0.00%) 
Bronchitis  1  1/467 (0.21%)  0/237 (0.00%) 
Campylobacter gastroenteritis  1  1/467 (0.21%)  0/237 (0.00%) 
Cellulitis of male external genital organ  1  1/467 (0.21%)  0/237 (0.00%) 
Clostridium dificile colitis  1  1/467 (0.21%)  0/237 (0.00%) 
Clostridium dificile infection  1  1/467 (0.21%)  1/237 (0.42%) 
Empyema  1  1/467 (0.21%)  0/237 (0.00%) 
Gangrene  1  1/467 (0.21%)  0/237 (0.00%) 
Gastroenteritis  1  2/467 (0.43%)  1/237 (0.42%) 
Gastroenteritis viral  1  1/467 (0.21%)  0/237 (0.00%) 
Gastroenteritis viral infection  1  0/467 (0.00%)  1/237 (0.42%) 
Herpes zoster  1  1/467 (0.21%)  0/237 (0.00%) 
Infection  1  1/467 (0.21%)  1/237 (0.42%) 
Liver abscess  1  1/467 (0.21%)  0/237 (0.00%) 
Lower respiratory tract infection  1  0/467 (0.00%)  1/237 (0.42%) 
Lung infection  1  1/467 (0.21%)  0/237 (0.00%) 
Peritonitis  1  1/467 (0.21%)  0/237 (0.00%) 
Pneumonia  1  16/467 (3.43%)  6/237 (2.53%) 
Pneumonia bacterial  1  0/467 (0.00%)  1/237 (0.42%) 
Sepsis  1  3/467 (0.64%)  2/237 (0.84%) 
Sepsis syndrome  1  1/467 (0.21%)  0/237 (0.00%) 
Septic shock  1  1/467 (0.21%)  1/237 (0.42%) 
Staphylococcal sepsis  1  1/467 (0.21%)  0/237 (0.00%) 
Subcutaneous abscess  1  2/467 (0.43%)  0/237 (0.00%) 
Upper respiratory tract infection  1  1/467 (0.21%)  0/237 (0.00%) 
Urinary tract infection  1  3/467 (0.64%)  1/237 (0.42%) 
Urosepsis  1  1/467 (0.21%)  0/237 (0.00%) 
Wound sepsis  1  1/467 (0.21%)  0/237 (0.00%) 
Injury, poisoning and procedural complications     
Compression fracture  1  1/467 (0.21%)  0/237 (0.00%) 
Fall  1  3/467 (0.64%)  0/237 (0.00%) 
Femur fracture  1  1/467 (0.21%)  0/237 (0.00%) 
Hip fracture  1  0/467 (0.00%)  1/237 (0.42%) 
Intestinal anastomosis complication  1  1/467 (0.21%)  0/237 (0.00%) 
Lumbar vertebral fracture  1  1/467 (0.21%)  0/237 (0.00%) 
Multiple fractures  1  1/467 (0.21%)  0/237 (0.00%) 
Overdose  1  1/467 (0.21%)  0/237 (0.00%) 
Post procedural haemorrhage  1  0/467 (0.00%)  1/237 (0.42%) 
Radius fracture  1  1/467 (0.21%)  0/237 (0.00%) 
Road traffic accident  1  0/467 (0.00%)  1/237 (0.42%) 
Toxicity to various agents  1  1/467 (0.21%)  0/237 (0.00%) 
Vascular pseudoaneurysm  1  1/467 (0.21%)  0/237 (0.00%) 
Investigations     
Alanine aminotransferase increased  1  1/467 (0.21%)  0/237 (0.00%) 
Amylase increased  1  1/467 (0.21%)  0/237 (0.00%) 
Aspartate aminotransferase increased  1  3/467 (0.64%)  0/237 (0.00%) 
Blood bilirubin increased  1  3/467 (0.64%)  0/237 (0.00%) 
Blood creatine increased  1  1/467 (0.21%)  0/237 (0.00%) 
Gamma-glutamytransferase increased  1  1/467 (0.21%)  0/237 (0.00%) 
Lymphcyte count decreased  1  1/467 (0.21%)  0/237 (0.00%) 
Neutrophil count decreased  1  1/467 (0.21%)  0/237 (0.00%) 
Oesophaggogastroduodenoscopy  1  0/467 (0.00%)  1/237 (0.42%) 
Oxygen saturation decreased  1  1/467 (0.21%)  0/237 (0.00%) 
Weight decreased  1  1/467 (0.21%)  0/237 (0.00%) 
Metabolism and nutrition disorders     
Cachexia  1  1/467 (0.21%)  0/237 (0.00%) 
Decreased appetite  1  4/467 (0.86%)  0/237 (0.00%) 
Dehydration  1  4/467 (0.86%)  2/237 (0.84%) 
Diabetes mellitus inadequate control  1  1/467 (0.21%)  0/237 (0.00%) 
Failure to thrive  1  1/467 (0.21%)  0/237 (0.00%) 
Hyperammonaemia  1  0/467 (0.00%)  1/237 (0.42%) 
Hypercalcaemia  1  0/467 (0.00%)  1/237 (0.42%) 
Hyperglycaemia  1  1/467 (0.21%)  0/237 (0.00%) 
Hypocalcaemia  1  2/467 (0.43%)  0/237 (0.00%) 
Hypokalaemia  1  1/467 (0.21%)  1/237 (0.42%) 
Hypomagnesaemia  1  2/467 (0.43%)  0/237 (0.00%) 
Hyponatraemia  1  5/467 (1.07%)  0/237 (0.00%) 
Hypophagia  1  0/467 (0.00%)  1/237 (0.42%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  1/467 (0.21%)  0/237 (0.00%) 
Bone pain  1  2/467 (0.43%)  1/237 (0.42%) 
Fistula  1  0/467 (0.00%)  1/237 (0.42%) 
Intervertebral disc protusion  1  1/467 (0.21%)  0/237 (0.00%) 
Musculoskletal chest pain  1  0/467 (0.00%)  1/237 (0.42%) 
Musculoskeletal pain  1  1/467 (0.21%)  1/237 (0.42%) 
Myalgia  1  1/467 (0.21%)  0/237 (0.00%) 
Pain in extremity  1  1/467 (0.21%)  0/237 (0.00%) 
Rhabdomyolysis  1  1/467 (0.21%)  0/237 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Acute lymphocytic leukaemia  1  1/467 (0.21%)  0/237 (0.00%) 
Cancer pain  1  1/467 (0.21%)  0/237 (0.00%) 
Head and neck cancer  1  1/467 (0.21%)  0/237 (0.00%) 
Hepatic neoplasm  1  1/467 (0.21%)  0/237 (0.00%) 
Hepatocellular carcinoma  1  39/467 (8.35%)  22/237 (9.28%) 
Intracranial tumour haemorrhage  1  1/467 (0.21%)  0/237 (0.00%) 
Liver carcinoma ruptured  1  0/467 (0.00%)  1/237 (0.42%) 
Lymphangiosis carcinomatosa  1  0/467 (0.00%)  1/237 (0.42%) 
Metastases to bone  1  1/467 (0.21%)  0/237 (0.00%) 
Metastases to central nervous system  1  2/467 (0.43%)  3/237 (1.27%) 
Metastases to lung  1  3/467 (0.64%)  0/237 (0.00%) 
Metastases to spine  1  1/467 (0.21%)  2/237 (0.84%) 
Metastatic pain  1  2/467 (0.43%)  0/237 (0.00%) 
Squamous cell carcinoma  1  1/467 (0.21%)  0/237 (0.00%) 
Tumor associated fever  1  1/467 (0.21%)  0/237 (0.00%) 
Tumor compression  1  1/467 (0.21%)  0/237 (0.00%) 
Tumor haemorrhage  1  1/467 (0.21%)  0/237 (0.00%) 
Nervous system disorders     
Aphasia  1  1/467 (0.21%)  0/237 (0.00%) 
Cerebral haemorrhage  1  1/467 (0.21%)  0/237 (0.00%) 
Cerebral infarction  1  0/467 (0.00%)  1/237 (0.42%) 
Cerebrovascular accident  1  4/467 (0.86%)  0/237 (0.00%) 
Cervicobrachial syndrome  1  1/467 (0.21%)  0/237 (0.00%) 
Convulsion  1  1/467 (0.21%)  0/237 (0.00%) 
Dizziness  1  1/467 (0.21%)  0/237 (0.00%) 
Encephalopathy  1  1/467 (0.21%)  0/237 (0.00%) 
Hepatic encephalopathy  1  15/467 (3.21%)  1/237 (0.42%) 
Hyperammonaemic encephalopathy  1  1/467 (0.21%)  0/237 (0.00%) 
Ischaemic stroke  1  2/467 (0.43%)  0/237 (0.00%) 
Somnolence  1  1/467 (0.21%)  0/237 (0.00%) 
Spinal cord compression  1  3/467 (0.64%)  1/237 (0.42%) 
Syncope  1  2/467 (0.43%)  0/237 (0.00%) 
Psychiatric disorders     
Completed suicide  1  1/467 (0.21%)  0/237 (0.00%) 
Delirium  1  1/467 (0.21%)  0/237 (0.00%) 
Mental status changes  1  1/467 (0.21%)  1/237 (0.42%) 
Renal and urinary disorders     
Azotaemia  1  0/467 (0.00%)  1/237 (0.42%) 
Calculus ureteric  1  0/467 (0.00%)  1/237 (0.42%) 
Haematuria  1  1/467 (0.21%)  0/237 (0.00%) 
Prerenal failure  1  1/467 (0.21%)  0/237 (0.00%) 
Renal failure  1  1/467 (0.21%)  1/237 (0.42%) 
Renal failure acture  1  2/467 (0.43%)  2/237 (0.84%) 
Reproductive system and breast disorders     
Pelvic pain  1  1/467 (0.21%)  1/237 (0.42%) 
Scrotal pain  1  1/467 (0.21%)  0/237 (0.00%) 
Testicular swelling  1  1/467 (0.21%)  0/237 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  1/467 (0.21%)  0/237 (0.00%) 
Acute respiratory failure  1  0/467 (0.00%)  1/237 (0.42%) 
Asthma  1  1/467 (0.21%)  0/237 (0.00%) 
Chronic obstructive pulmonary disease  1  0/467 (0.00%)  2/237 (0.84%) 
Dyspnoea  1  10/467 (2.14%)  2/237 (0.84%) 
Epistaxis  1  3/467 (0.64%)  0/237 (0.00%) 
Haemoptysis  1  2/467 (0.43%)  3/237 (1.27%) 
Lung disorder  1  1/467 (0.21%)  0/237 (0.00%) 
Oesophagobronchial fistula  1  1/467 (0.21%)  0/237 (0.00%) 
Pleural effusion  1  2/467 (0.43%)  1/237 (0.42%) 
Pneumonia aspiration  1  0/467 (0.00%)  1/237 (0.42%) 
Pneumonitis  1  0/467 (0.00%)  1/237 (0.42%) 
Pneumothorax  1  2/467 (0.43%)  0/237 (0.00%) 
Pulmonary embolism  1  3/467 (0.64%)  2/237 (0.84%) 
Pulmonary haemorrhage  1  1/467 (0.21%)  1/237 (0.42%) 
Pulmonary infarction  1  1/467 (0.21%)  0/237 (0.00%) 
Respiratory failure  1  2/467 (0.43%)  0/237 (0.00%) 
Respiratory crisis (verbatim)  1  1/467 (0.21%)  0/237 (0.00%) 
Skin and subcutaneous tissue disorders     
Diabetic ulcer  1  1/467 (0.21%)  0/237 (0.00%) 
Palmar-plantar erythrodysaesthesia  1  6/467 (1.28%)  0/237 (0.00%) 
Rash  1  1/467 (0.21%)  0/237 (0.00%) 
Vascular disorders     
Aneurysm  1  1/467 (0.21%)  0/237 (0.00%) 
Deep vein thrombosis  1  2/467 (0.43%)  0/237 (0.00%) 
Haematoma  1  1/467 (0.21%)  0/237 (0.00%) 
Hypertension  1  2/467 (0.43%)  1/237 (0.42%) 
Hypotension  1  1/467 (0.21%)  0/237 (0.00%) 
Orthostatic hypotension  1  1/467 (0.21%)  0/237 (0.00%) 
Peripheral artery thrombosis  1  0/467 (0.00%)  1/237 (0.42%) 
Peripheral ischaemia  1  1/467 (0.21%)  0/237 (0.00%) 
Thrombosis  1  1/467 (0.21%)  0/237 (0.00%) 
Venous thrombosis  1  0/467 (0.00%)  1/237 (0.42%) 
1
Term from vocabulary, MedDRA (17.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cabozantinib (XL184) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   445/467 (95.29%)   173/237 (73.00%) 
Blood and lymphatic system disorders     
Thrombocytopenia  1  51/467 (10.92%)  1/237 (0.42%) 
Endocrine disorders     
Hypothyroidism  1  38/467 (8.14%)  1/237 (0.42%) 
Gastrointestinal disorders     
Diarrhoea  1  251/467 (53.75%)  43/237 (18.14%) 
Dyspepsia  1  47/467 (10.06%)  7/237 (2.95%) 
Nausea  1  147/467 (31.48%)  41/237 (17.30%) 
Stomatitis  1  63/467 (13.49%)  5/237 (2.11%) 
Vomiting  1  118/467 (25.27%)  24/237 (10.13%) 
General disorders     
Asthenia  1  99/467 (21.20%)  17/237 (7.17%) 
Fatigue  1  209/467 (44.75%)  70/237 (29.54%) 
Mucosal inflammation  1  65/467 (13.92%)  5/237 (2.11%) 
Investigations     
Alanine aminotransferase increased  1  79/467 (16.92%)  13/237 (5.49%) 
Aspartate aminotransferase increased  1  103/467 (22.06%)  27/237 (11.39%) 
Platelet count decreased  1  45/467 (9.64%)  7/237 (2.95%) 
Weight decreased  1  80/467 (17.13%)  14/237 (5.91%) 
Metabolism and nutrition disorders     
Decreased appetite  1  224/467 (47.97%)  43/237 (18.14%) 
Hypoalbuminaemia  1  55/467 (11.78%)  12/237 (5.06%) 
Hypokalaemia  1  44/467 (9.42%)  4/237 (1.69%) 
Hypomagnesaemia  1  29/467 (6.21%)  0/237 (0.00%) 
Musculoskeletal and connective tissue disorders     
Muscle spasms  1  39/467 (8.35%)  4/237 (1.69%) 
Pain in extremity  1  44/467 (9.42%)  9/237 (3.80%) 
Nervous system disorders     
Dysgeusia  1  56/467 (11.99%)  5/237 (2.11%) 
Respiratory, thoracic and mediastinal disorders     
Dysphonia  1  90/467 (19.27%)  5/237 (2.11%) 
Skin and subcutaneous tissue disorders     
Palmar-plantar erythrodysaesthesia syndrome  1  217/467 (46.47%)  12/237 (5.06%) 
Rash  1  58/467 (12.42%)  14/237 (5.91%) 
Vascular disorders     
Hypertension  1  137/467 (29.34%)  13/237 (5.49%) 
1
Term from vocabulary, MedDRA (17.0)
Indicates events were collected by systematic assessment
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.
Our agreements with investigators vary; constant is our right to review results communications prior to public release, and embargo communications for a period of ≤ 60 days from submittal for review. We do not prohibit investigators from publishing, but we may require previously undisclosed confidential information, other than study results, to be removed from publications, and single-center publications are postponed until after publication of the trial's primary multicenter publication.
Results Point of Contact
Name/Title: Exelixis Medical Information
Organization: Exelixis, Inc.
Phone: 855-292-3935
Responsible Party: Exelixis
ClinicalTrials.gov Identifier: NCT01908426     History of Changes
Other Study ID Numbers: XL184-309
First Submitted: July 23, 2013
First Posted: July 25, 2013
Results First Submitted: October 16, 2018
Results First Posted: March 1, 2019
Last Update Posted: March 1, 2019