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 : Completed

First Posted : July 25, 2013

Results First Posted : March 1, 2019

Last Update Posted : May 6, 2021

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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

Participant Flow

Recruitment Details	First patient enrolled: 26 September 2013, Data cut-off date: 01 June 2017
Pre-assignment Details


Arm/Group Title	Cabozantinib (XL184)	Placebo
Arm/Group Description	Cabozantinib (XL184) 60 mg tablet o...	Oral cabozantinib-matched placebo t...
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

Baseline Characteristics

Arm/Group Title		Cabozantinib (XL184)	Placebo	Total
Arm/Group Description		Cabozantinib (XL184) 60 mg tablet o...	Oral cabozantinib-matched placebo t...	Total of all reporting groups
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
Baseline Analysis Population Description		[Not Specified]
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)

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS)
Description	The primary analysis of OS is defined as the time from randomization t...
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

Outcome Measure Data

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
Arm/Group Description:	Cabozantinib (XL184) 60 mg tablet o...	Oral cabozantinib-matched placebo t...
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)

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)
Description	Duration of PFS is defined as the time of randomization to the earlier...
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

Outcome Measure Data

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
Arm/Group Description:	Cabozantinib (XL184) 60 mg tablet o...	Oral cabozantinib-matched placebo t...
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)

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)
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0...
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)

Outcome Measure Data

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
Arm/Group Description:	Cabozantinib (XL184) 60 mg tablet o...	Oral cabozantinib-matched placebo t...
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%

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]

Adverse Events

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
Arm/Group Description	Cabozantinib (XL184) 60 mg tablet o...	Oral cabozantinib-matched placebo t...
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%)
Serious Adverse Events 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
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

Limitations and Caveats

[Not Specified]

More Information

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

Layout table for Results Point of Contact information

Name/Title:	Exelixis Medical Information
Organization:	Exelixis, Inc.
Phone:	855-292-3935
EMail:	druginfo@exelixis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Freemantle N, Mollon P, Meyer T, Cheng AL, El-Khoueiry AB, Kelley RK, Baron AD, Benzaghou F, Mangeshkar M, Abou-Alfa GK. Quality of life assessment of cabozantinib in patients with advanced hepatocellular carcinoma in the CELESTIAL trial. Eur J Cancer. 2022 Jun;168:91-98. doi: 10.1016/j.ejca.2022.03.021. Epub 2022 Apr 26.

El-Khoueiry AB, Meyer T, Cheng AL, Rimassa L, Sen S, Milwee S, Kelley RK, Abou-Alfa GK. Safety and efficacy of cabozantinib for patients with advanced hepatocellular carcinoma who advanced to Child-Pugh B liver function at study week 8: a retrospective analysis of the CELESTIAL randomised controlled trial. BMC Cancer. 2022 Apr 9;22(1):377. doi: 10.1186/s12885-022-09453-z.

Kelley RK, Miksad R, Cicin I, Chen Y, Klumpen HJ, Kim S, Lin ZZ, Youkstetter J, Hazra S, Sen S, Cheng AL, El-Khoueiry AB, Meyer T, Abou-Alfa GK. Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade. Br J Cancer. 2022 Mar;126(4):569-575. doi: 10.1038/s41416-021-01532-5. Epub 2021 Oct 7.

Trojan J, Mollon P, Daniele B, Marteau F, Martin L, Li Y, Xu Q, Piscaglia F, Zaucha R, Sarker D, Lim HY, Venerito M. Comparative Efficacy of Cabozantinib and Ramucirumab After Sorafenib for Patients with Hepatocellular Carcinoma and Alpha-fetoprotein >/= 400 ng/mL: A Matching-Adjusted Indirect Comparison. Adv Ther. 2021 May;38(5):2472-2490. doi: 10.1007/s12325-021-01700-2. Epub 2021 Apr 6.

Kelley RK, Ryoo BY, Merle P, Park JW, Bolondi L, Chan SL, Lim HY, Baron AD, Parnis F, Knox J, Cattan S, Yau T, Lougheed JC, Milwee S, El-Khoueiry AB, Cheng AL, Meyer T, Abou-Alfa GK. Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial. ESMO Open. 2020 Aug;5(4):e000714. doi: 10.1136/esmoopen-2020-000714.

Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klumpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJMoa1717002.

Layout table for additonal information

Responsible Party:	Exelixis
ClinicalTrials.gov Identifier:	NCT01908426
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:	May 6, 2021

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