Trial Outcomes & Findings for Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib (NCT NCT01908426)

NCT ID: NCT01908426

Last Updated: 2021-05-06

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

707 participants

Primary outcome timeframe

Up to 45 months

Results posted on

2021-05-06

Participant Flow

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

Participant milestones

Participant milestones
Measure	Cabozantinib (XL184) Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets	Placebo Oral cabozantinib-matched placebo tablet once daily Placebo tablets
Overall Study STARTED	470	237
Overall Study COMPLETED	73	26
Overall Study NOT COMPLETED	397	211

Reasons for withdrawal

Reasons for withdrawal
Measure	Cabozantinib (XL184) Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets	Placebo Oral cabozantinib-matched placebo tablet once daily Placebo tablets
Overall Study Adverse Event	98	11
Overall Study Clinical Deterioration	72	38
Overall Study Lack of Efficacy	3	0
Overall Study Lost to Follow-up	0	1
Overall Study Physician Decision	3	3
Overall Study Withdrawal by Subject	11	6
Overall Study Progressive Disease	206	152
Overall Study Protocol Violation	1	0
Overall Study No Study Treatment Given	3	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cabozantinib (XL184) n=470 Participants Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets	Placebo n=237 Participants Oral cabozantinib-matched placebo tablet once daily Placebo tablets	Total n=707 Participants Total of all reporting groups
Age, Continuous	64.0 years n=5 Participants	64.0 years n=7 Participants	64.0 years n=5 Participants
Age, Customized Age, Customized · < 65 years old	240 Participants n=5 Participants	124 Participants n=7 Participants	364 Participants n=5 Participants
Age, Customized Age, Customized · 65 to < 75 years old	158 Participants n=5 Participants	75 Participants n=7 Participants	233 Participants n=5 Participants
Age, Customized Age, Customized · 75 to < 85 years old	67 Participants n=5 Participants	35 Participants n=7 Participants	102 Participants n=5 Participants
Age, Customized Age, Customized · ≥ 85 years old	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Sex: Female, Male Female	91 Participants n=5 Participants	35 Participants n=7 Participants	126 Participants n=5 Participants
Sex: Female, Male Male	379 Participants n=5 Participants	202 Participants n=7 Participants	581 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	18 Participants n=5 Participants	12 Participants n=7 Participants	30 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	417 Participants n=5 Participants	215 Participants n=7 Participants	632 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	35 Participants n=5 Participants	10 Participants n=7 Participants	45 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	159 Participants n=5 Participants	82 Participants n=7 Participants	241 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Black or African American	8 Participants n=5 Participants	11 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) White	264 Participants n=5 Participants	130 Participants n=7 Participants	394 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	36 Participants n=5 Participants	13 Participants n=7 Participants	49 Participants n=5 Participants
Geographic Region Australia / New Zealand	15 Participants n=5 Participants	11 Participants n=7 Participants	26 Participants n=5 Participants
Geographic Region Asia	116 Participants n=5 Participants	59 Participants n=7 Participants	175 Participants n=5 Participants
Geographic Region Europe	231 Participants n=5 Participants	108 Participants n=7 Participants	339 Participants n=5 Participants
Geographic Region North America (USA / Canada)	108 Participants n=5 Participants	59 Participants n=7 Participants	167 Participants n=5 Participants
Presence of extrahepatic spread of disease and/or macrovascular invasion (stratification per IxRS) Yes	368 Participants n=5 Participants	186 Participants n=7 Participants	554 Participants n=5 Participants
Presence of extrahepatic spread of disease and/or macrovascular invasion (stratification per IxRS) No	102 Participants n=5 Participants	51 Participants n=7 Participants	153 Participants n=5 Participants
Etiology of disease (stratification factor per IxRS), HBV (with or without known HCV)	182 Participants n=5 Participants	90 Participants n=7 Participants	272 Participants n=5 Participants
Etiology of disease (stratification factor per IxRS), HCV (without known HBV)	100 Participants n=5 Participants	51 Participants n=7 Participants	151 Participants n=5 Participants
Etiology of disease (stratification factor per IxRS), Other (neither HBV nor HCV)	188 Participants n=5 Participants	96 Participants n=7 Participants	284 Participants n=5 Participants
Geographic region (stratification factor per IxRS) Asia	116 Participants n=5 Participants	59 Participants n=7 Participants	175 Participants n=5 Participants
Geographic region (stratification factor per IxRS) Other Regions	354 Participants n=5 Participants	178 Participants n=7 Participants	532 Participants n=5 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0	245 Participants n=5 Participants	131 Participants n=7 Participants	376 Participants n=5 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1	224 Participants n=5 Participants	106 Participants n=7 Participants	330 Participants n=5 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Smoking history Current	78 Participants n=5 Participants	42 Participants n=7 Participants	120 Participants n=5 Participants
Smoking history Former	229 Participants n=5 Participants	122 Participants n=7 Participants	351 Participants n=5 Participants
Smoking history Never	160 Participants n=5 Participants	71 Participants n=7 Participants	231 Participants n=5 Participants
Smoking history Missing	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Alcohol use Current	65 Participants n=5 Participants	30 Participants n=7 Participants	95 Participants n=5 Participants
Alcohol use Former	223 Participants n=5 Participants	124 Participants n=7 Participants	347 Participants n=5 Participants
Alcohol use Never	176 Participants n=5 Participants	81 Participants n=7 Participants	257 Participants n=5 Participants
Alcohol use Missing	6 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants
Weight	69 kg n=5 Participants	71.5 kg n=7 Participants	70.25 kg n=5 Participants
Body Mass Index (BMI)	24.1 kg / m^2 n=5 Participants	24.9 kg / m^2 n=7 Participants	24.5 kg / m^2 n=5 Participants

PRIMARY outcome

Timeframe: Up to 45 months

Population: 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.

Outcome measures

Outcome measures
Measure	Cabozantinib (XL184) n=470 Participants Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets	Placebo n=237 Participants Oral cabozantinib-matched placebo tablet once daily Placebo tablets
Overall Survival (OS)	10.2 months Interval 9.1 to 12.0	8.0 months Interval 6.8 to 9.4

SECONDARY outcome

Timeframe: Up to 45 months

Population: The prespecified primary analysis of PFS was based on the first 707 randomized subjects (470 cabozantinib, 237 placebo).

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.

Outcome measures

Outcome measures
Measure	Cabozantinib (XL184) n=470 Participants Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets	Placebo n=237 Participants Oral cabozantinib-matched placebo tablet once daily Placebo tablets
Progression-Free Survival (PFS)	5.2 months Interval 4.0 to 5.5	1.9 months Interval 1.9 to 1.9

SECONDARY outcome

Timeframe: ORR is measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation of study treatment (up to 45 months)

Population: 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

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.

Outcome measures

Outcome measures
Measure	Cabozantinib (XL184) n=470 Participants Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets	Placebo n=237 Participants Oral cabozantinib-matched placebo tablet once daily Placebo tablets
Objective Response Rate (ORR)	18 Participants	1 Participants

Adverse Events

Cabozantinib (XL184)

Serious events: 232 serious events

Other events: 445 other events

Deaths: 314 deaths

Placebo

Serious events: 87 serious events

Other events: 173 other events

Deaths: 167 deaths

Serious adverse events

Other adverse events

Additional Information

Exelixis Medical Information

Exelixis, Inc.

Phone: 855-292-3935

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Cabozantinib (XL184) n=467 participants at risk Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets	Placebo n=237 participants at risk Oral cabozantinib-matched placebo tablet once daily Placebo tablets
Blood and lymphatic system disorders Anaemia	0.86% 4/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Blood and lymphatic system disorders Febrile neutropenia	0.43% 2/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Blood and lymphatic system disorders Leukopenia	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Blood and lymphatic system disorders Lymphopenia	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Blood and lymphatic system disorders Neutropenia	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Blood and lymphatic system disorders Thrombocytopenia	1.1% 5/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Cardiac disorders Acute myocardial infarction	0.43% 2/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Cardiac disorders Atrial fibrillation	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Cardiac disorders Atrial flutter	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Cardiac disorders Myocardial infarction	0.00% 0/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Endocrine disorders Hypothyroidisim	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Eye disorders Retinal vein thrombosis	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Eye disorders Sudden visual loss	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Abdominal Pain	1.3% 6/467 • Up to 61 weeks 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).	3.8% 9/237 • Up to 61 weeks 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).
Gastrointestinal disorders Abdominal pain upper	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Anal fistula	0.43% 2/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Ascites	2.6% 12/467 • Up to 61 weeks 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).	1.3% 3/237 • Up to 61 weeks 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).
Gastrointestinal disorders Colitis	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Constipation	0.43% 2/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Diarrhoea	1.1% 5/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Gastrointestinal disorders Duodenal perforation	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Duodenal ulcer haemorrhage	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Enterocolitis	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Gastric haemorrhage	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Gastric perforation	0.43% 2/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Gastric varices haemorrhage	0.21% 1/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Gastrointestinal disorders Gastritis erosive	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Gastrointestinal haemorrhage	0.86% 4/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Gastrointestinal disorders Gastrointestinal ulcer haemorrhage	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Gastrointestinal disorders Haematemesis	0.21% 1/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Gastrointestinal disorders Ileus	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Intestinal haemorrhage	0.00% 0/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Gastrointestinal disorders Intestinal obstruction	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Intestinal perforation	0.00% 0/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Gastrointestinal disorders Large intestine perforation	0.43% 2/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Mallory-Weiss syndrome	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Melaena	0.43% 2/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Mesenteric atermy thrombosis	0.21% 1/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Gastrointestinal disorders Nausea	0.43% 2/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).

Other adverse events
Measure	Cabozantinib (XL184) n=467 participants at risk Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets	Placebo n=237 participants at risk Oral cabozantinib-matched placebo tablet once daily Placebo tablets
Blood and lymphatic system disorders Thrombocytopenia	10.9% 51/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Endocrine disorders Hypothyroidism	8.1% 38/467 • Up to 61 weeks 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).	0.42% 1/237 • Up to 61 weeks 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).
Gastrointestinal disorders Diarrhoea	53.7% 251/467 • Up to 61 weeks 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).	18.1% 43/237 • Up to 61 weeks 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).
Gastrointestinal disorders Dyspepsia	10.1% 47/467 • Up to 61 weeks 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).	3.0% 7/237 • Up to 61 weeks 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).
Gastrointestinal disorders Nausea	31.5% 147/467 • Up to 61 weeks 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).	17.3% 41/237 • Up to 61 weeks 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).
Gastrointestinal disorders Stomatitis	13.5% 63/467 • Up to 61 weeks 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).	2.1% 5/237 • Up to 61 weeks 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).
Gastrointestinal disorders Vomiting	25.3% 118/467 • Up to 61 weeks 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).	10.1% 24/237 • Up to 61 weeks 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).
General disorders Asthenia	21.2% 99/467 • Up to 61 weeks 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).	7.2% 17/237 • Up to 61 weeks 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).
General disorders Fatigue	44.8% 209/467 • Up to 61 weeks 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).	29.5% 70/237 • Up to 61 weeks 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).
General disorders Mucosal inflammation	13.9% 65/467 • Up to 61 weeks 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).	2.1% 5/237 • Up to 61 weeks 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).
Investigations Alanine aminotransferase increased	16.9% 79/467 • Up to 61 weeks 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).	5.5% 13/237 • Up to 61 weeks 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).
Investigations Aspartate aminotransferase increased	22.1% 103/467 • Up to 61 weeks 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).	11.4% 27/237 • Up to 61 weeks 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).
Investigations Platelet count decreased	9.6% 45/467 • Up to 61 weeks 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).	3.0% 7/237 • Up to 61 weeks 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).
Investigations Weight decreased	17.1% 80/467 • Up to 61 weeks 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).	5.9% 14/237 • Up to 61 weeks 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).
Metabolism and nutrition disorders Decreased appetite	48.0% 224/467 • Up to 61 weeks 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).	18.1% 43/237 • Up to 61 weeks 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).
Metabolism and nutrition disorders Hypoalbuminaemia	11.8% 55/467 • Up to 61 weeks 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).	5.1% 12/237 • Up to 61 weeks 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).
Metabolism and nutrition disorders Hypokalaemia	9.4% 44/467 • Up to 61 weeks 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).	1.7% 4/237 • Up to 61 weeks 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).
Metabolism and nutrition disorders Hypomagnesaemia	6.2% 29/467 • Up to 61 weeks 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).	0.00% 0/237 • Up to 61 weeks 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).
Musculoskeletal and connective tissue disorders Muscle spasms	8.4% 39/467 • Up to 61 weeks 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).	1.7% 4/237 • Up to 61 weeks 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).
Musculoskeletal and connective tissue disorders Pain in extremity	9.4% 44/467 • Up to 61 weeks 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).	3.8% 9/237 • Up to 61 weeks 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).
Nervous system disorders Dysgeusia	12.0% 56/467 • Up to 61 weeks 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).	2.1% 5/237 • Up to 61 weeks 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).
Respiratory, thoracic and mediastinal disorders Dysphonia	19.3% 90/467 • Up to 61 weeks 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).	2.1% 5/237 • Up to 61 weeks 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).
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	46.5% 217/467 • Up to 61 weeks 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).	5.1% 12/237 • Up to 61 weeks 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).
Skin and subcutaneous tissue disorders Rash	12.4% 58/467 • Up to 61 weeks 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).	5.9% 14/237 • Up to 61 weeks 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).
Vascular disorders Hypertension	29.3% 137/467 • Up to 61 weeks 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).	5.5% 13/237 • Up to 61 weeks 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).