Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM)

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ClinicalTrials.gov Identifier: NCT00704730

Recruitment Status : Completed

First Posted : June 25, 2008

Results First Posted : September 9, 2014

Last Update Posted : April 20, 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	Thyroid Cancer
Interventions	Drug: XL184 Drug: Placebo
Enrollment	330

Participant Flow

Recruitment Details	First patient enrolled 10 September 2008, last patient enrolled 27 February 2011. Data cut off date 15 June 2011.
Pre-assignment Details


Arm/Group Title	XL184 (Cabozantinib)	Placebo
Arm/Group Description	XL184 175 mg L-malate salt weight; ...	oral capsules once daily
Arm/Group Description	XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily	oral capsules once daily
Period Title: Overall Study
Started	219 ^[1]	111 ^[1]
Completed	98 ^[2]	15 ^[3]
Not Completed	121	96
Reason Not Completed
Adverse Event	35	9
Death	11	5
Physician Decision	2	0
Did not receive drug	5	2
Disease progression per PI	58	67
data unavailable	1	0
Withdrawal by Subject	9	13
[1] Randomized [2] Continuing treatment at data cutoff for primary analysis, but subsequently discontinued study [3] Continuing study treatment at the time of data cut-off.

Baseline Characteristics

Arm/Group Title		XL184 (Cabozantinib)	Placebo	Total
Arm/Group Description		XL184 175 mg L-malate salt weight; ...	oral capsules once daily	Total of all reporting groups
Arm/Group Description		XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily	oral capsules once daily	Total of all reporting groups
Overall Number of Baseline Participants		219	111	330
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	219 participants	111 participants	330 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	172 78.5%	86 77.5%	258 78.2%
	>=65 years	47 21.5%	25 22.5%	72 21.8%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	219 participants	111 participants	330 participants
		54.4 (13.33)	53.8 (13.39)	54.2 (13.33)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	219 participants	111 participants	330 participants
	Female	68 31.1%	41 36.9%	109 33.0%
	Male	151 68.9%	70 63.1%	221 67.0%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	219 participants	111 participants	330 participants
Austria		8	1	9
Belgium		7	5	12
Brazil		4	3	7
Canada		6	2	8
Chile		0	1	1
Denmark		1	0	1
France		25	5	30
Germany		15	10	25
Greece		1	2	3
Portugal		0	1	1
India		5	1	6
Israel		5	4	9
Italy		28	14	42
Korea, Republic of		3	4	7
Netherlands		5	3	8
Peru		1	0	1
Poland		12	3	15
Russian Federation		8	5	13
Spain		5	3	8
Switzerland		1	0	1
Sweden		6	4	10
United Kingdom		10	9	19
United States		63	31	94

Outcome Measures

1.Primary Outcome


Title	Progression-Free Survival (PFS)
Description	The duration of Progression-Free Survival (PFS) using progression even...
Description	The duration of Progression-Free Survival (PFS) using progression events as determined by Independent Review Committee (IRC) per mRECIST, or death due to any cause. The analysis was conducted after at least 315 subjects were randomized and at least 138 events were observed.
Time Frame	Treatment period consisted of 4-week cycles with radiologic tumor assessment every 12 weeks from date of randomization until date of first documented PD or date of death from any cause, whichever came first, assessed up to 34 months.

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) 330 subjects were randomized and were included in the analysis. A Kaplan-Meyer analysis was performed to estimate the median.


Arm/Group Title	XL184 (Cabozantinib)	Placebo
Arm/Group Description:	XL184 175 mg L-malate salt weight; ...	Oral capsules once daily
Arm/Group Description:	XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily.	Oral capsules once daily
Overall Number of Participants Analyzed	219	111
Median (95% Confidence Interval) Unit of Measure: months
	11.2 (9.3 to 13.7)	4.0 (3.0 to 5.4)

2.Secondary Outcome


Title	Overall Survival (OS) With XL184 Compared With Placebo
Description	Duration of Overall Survival (OS) from the time of randomization to de...
Description	Duration of Overall Survival (OS) from the time of randomization to death due to any cause. A Kaplan-Meier analysis was performed to estimate the median.
Time Frame	The pre-specified interim analysis of Overall Survival (OS) was assessed at 44% of required events. Includes data up to 15June2011. As of this date, the number of deaths required to conduct the primary analysis had not been reached.

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) randomized to either XL184 or placebo


Arm/Group Title	XL184 (Cabozantinib)	Placebo
Arm/Group Description:	XL184 175 mg L-malate salt weight; ...	Oral capsules once daily
Arm/Group Description:	XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily	Oral capsules once daily
Overall Number of Participants Analyzed	219	111
Median (95% Confidence Interval) Unit of Measure: months
	21.1 (16.59 to 28.52)	NA ^[1] (17.41 to NA)

[1]

Median duration OS could not be estimated for placebo at data cut-off June 15, 2011 due to insufficient number of participants with events. At time of analysis of PFS, number of deaths required to conduct primary analysis of OS was not reached.

3.Secondary Outcome


Title	Objective Response Rate (ORR)
Description	The proportion of subjects with a best overall response (BOR) of confi...
Description	The proportion of subjects with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as determined by the Independent Review Committee (IRC.) Per Response Evaluation Criteria in Solid Tumor Criteria (mRECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR) disappearance of all target lesions; Partial Response (PR) ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) ≥ 20% increase in the sum of the longest diameter of target lesions. Overall Response Rate: ORR=CR +PR
Time Frame	Assessed at the same time as primary analysis of Progression Free Survival (PFS) data. Assessed at baseline and every 12 weeks until Progressive Disease (PD) up to 34 months.

Outcome Measure Data

Analysis Population Description

The primary analysis Objective Response Rate (ORR) was performed among subset of Intent To Treat (ITT) subjects with measurable disease at baseline (N = 208 cabozantinib, N = 104 placebo) based upon response determined by Independent Radiology Committee (IRC.) Subjects without post-baseline adequate tumor assessments - counted as nonresponders.


Arm/Group Title	XL184 (Cabozantinib)	Placebo
Arm/Group Description:	XL184 175 mg L-malate salt weight; ...	Oral capsules once daily
Arm/Group Description:	XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily	Oral capsules once daily
Overall Number of Participants Analyzed	208	104
Measure Type: Number Unit of Measure: % of participants
	28	0

4.Secondary Outcome


Title	Duration of Objective Response (OR): Independent Radiology Committee (IRC) Determined
Description	For those subjects with Independent Radiology Committee (IRC) determin...
Description	For those subjects with Independent Radiology Committee (IRC) determined Objective Response Rate (ORR), the amount of time from documentation of Objective Response (OR) until Progressive Disease (PD) by mRECIST or death due to any cause.
Time Frame	From time of first documentation of Objective Response (OR), confirmed at a later visit ≥28 days later as Progressive Disease (PD) as defined by mRECIST or death due to any cause, assessed up to 34 months.

Outcome Measure Data

Analysis Population Description

The primary analysis of Objective Response Rate (ORR) was performed among the subset of Intent To Treat (ITT) subjects with measurable disease at baseline and was based upon response as determined by the Independent Review Committee (IRC.) Subjects who did not have post-baseline adequate tumor assessments were counted as nonresponders.


Arm/Group Title	XL184 (Cabozantinib)	Placebo
Arm/Group Description:	XL184 175 mg L-malate salt weight; ...	Oral capsules once daily
Arm/Group Description:	XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily	Oral capsules once daily
Overall Number of Participants Analyzed	58	0
Median (95% Confidence Interval) Unit of Measure: months
	14.6 (11.1 to 17.5)

5.Secondary Outcome


Title	Biochemical Response Calcitonin (CTN) %
Description	For each on-treatment tumor marker assessment from each subject, the b...
Description	For each on-treatment tumor marker assessment from each subject, the biochemical response of CTN was determined based on percent increase or decrease from baseline. Best biochemical response over course of treatment was determined from evaluation of subject's time point response data. Biochemical response criteria: Complete Response (CR) - decrease in tumor marker into normal range from baseline value; Partial Response (PR) - decrease of >50% from baseline value when baseline value is above normal range; Stable Disease (SD) - no more than a 50% increase and no more than a 50% decrease from baseline value above normal range; Progressive Disease (PD) - increase of >50% from baseline value when baseline value is above normal range / or increase from low or normal range at baseline to above normal range; Not Evaluable (NE) - missing baseline value / or baseline value is not elevated and response is not PD / or response can not be determined due to change in assay format.
Time Frame	Serum tumor markers CTN evaluated from blood samples collected at screening and every 12 weeks (±5 days from randomization) until date of first documented progression or date of death from any cause, whichever came first, assessed for up to 34 months.

Outcome Measure Data

Analysis Population Description

Population was intent to treat (ITT), randomized to either XL184 or placebo. For the CTN measure the analysis population differs from the ITT population of 219 XL184 and 111 Placebo. Three subjects did not provide samples for CTN. The biomarker analysis was based on available samples, not on ITT.


Arm/Group Title	XL184 (Cabozantinib)	Placebo
Arm/Group Description:	XL184 175 mg L-malate salt weight; ...	Oral capsules once daily
Arm/Group Description:	XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily	Oral capsules once daily
Overall Number of Participants Analyzed	217	110
Measure Type: Number Unit of Measure: % participants
	22.6	0.9

6.Secondary Outcome


Title	Biochemical Response Carcinoembryonic Antigen (CEA) %
Description	For each on-treatment tumor marker assessment from each subject, the b...
Description	For each on-treatment tumor marker assessment from each subject, the biochemical response of CEA was determined based on percent increase or decrease from baseline. Best biochemical response over the course of treatment was determined from evaluation of each subject's time point response data. Biochemical response: Complete Response (CR)- Decrease in tumor marker into normal range from baseline value; Partial Response (PR)- Decrease of >50% from baseline value when baseline value is above normal range; Stable Disease (SD)- No more than a 50% increase and no more than a 50% decrease from baseline value above normal range; Progressive Disease (PD)- Increase of >50% from baseline value when baseline value is above normal range / or increase from low or normal range at baseline to above normal range; Not Evaluable (NE)- Missing baseline value / or baseline value is not elevated and response is not Progressive Disease (PD) / or response can not be determined due to change in assay format.
Time Frame	Serum tumor markers CEA evaluated from blood samples collected at screening and every 12 weeks (± 5 days from randomization) until date of first documented progression or date of death from any cause, whichever came first, assessed for up to 34 months.

Outcome Measure Data

Analysis Population Description

For the CEA measure the analysis population differs from the Intent To Treat (ITT) population of 219 XL184 and 111 Placebo. One subject did not provide samples for CEA. The biomarker analysis was based on available samples, not on ITT.


Arm/Group Title	XL184 (Cabozantinib)	Placebo
Arm/Group Description:	XL184 175 mg L-malate salt weight; ...	Oral capsules once daily
Arm/Group Description:	XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily	Oral capsules once daily
Overall Number of Participants Analyzed	218	111
Measure Type: Number Unit of Measure: % of participants
	21.6	0.9

Adverse Events

Time Frame	From baseline at regular intervals through to the date of the primary analysis
Adverse Event Reporting Description	The safety data includes subjects who were randomized and treated. Of 330 subjects, 219 were randomized to receive XL184, 111 placebo. Seven subjects were randomized and not treated; there were 214 subjects treated with XL184 and 109 subjects who received placebo.

Arm/Group Title	XL184 (Cabozantinib)		Placebo
Arm/Group Description	XL184 175 mg L-malate salt weight; ...		oral capsules once daily
Arm/Group Description	XL184 175 mg L-malate salt weight; 138 mg freebase equivalent weight, oral capsules once daily		oral capsules once daily
All-Cause Mortality
	XL184 (Cabozantinib)		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events Serious Adverse Events
	XL184 (Cabozantinib)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/214 (42.06%)		25/109 (22.94%)
Blood and lymphatic system disorders
Haemolytic uraemic syndrome ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Pancytopenia ^† 1	1/214 (0.47%)	1	1/109 (0.92%)	1
Thrombocytopenia ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Cardiac disorders
Atrial fibrillation ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Atrial flutter ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Cardiac arrest ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Cardiopulmonary failure ^† 1	1/214 (0.47%)	1	1/109 (0.92%)	1
Left ventricular dysfunction ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Supraventricular tachycardia ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Ear and labyrinth disorders
Hypoacusis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Endocrine disorders
Ectopic acth syndrome ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Anal fissure ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Anal fistula ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Aphthous stomatitis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Ascites ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Diarrhoea ^† 1	3/214 (1.40%)	3	1/109 (0.92%)	1
Duodenal ulcer haemorrhage ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Dysphagia ^† 1	5/214 (2.34%)	5	2/109 (1.83%)	2
Enterocolitis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Gastric perforation ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Gastrointestinal disorder ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Gingival bleeding ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Glossodynia ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Haemorrhoidal haemorrhage ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Haemorrhoids ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Intestinal haemorrhage ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Large intestine perforation ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Nausea ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Oesophageal fistula ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Oesophageal ulcer ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Pancreatitis ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Pancreatitis chronic ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Peritonitis ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Pneumoperitonem ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Proctalgia ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Vomiting ^† 1	4/214 (1.87%)	4	1/109 (0.92%)	1
General disorders
Asthenia ^† 1	2/214 (0.93%)	2	2/109 (1.83%)	2
Chest pain ^† 1	1/214 (0.47%)	1	1/109 (0.92%)	1
Death ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Fatigue ^† 1	4/214 (1.87%)	4	1/109 (0.92%)	1
General physical health deterioration ^† 1	1/214 (0.47%)	1	2/109 (1.83%)	2
Injection site haematoma ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Mucosal inflammation ^† 1	6/214 (2.80%)	6	0/109 (0.00%)	0
Multi-organ failure ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Non-cardiac chest pain ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Oedema peripheral ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Performance status decreased ^† 1	2/214 (0.93%)	2	1/109 (0.92%)	1
Pyrexia ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Sudden death ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Hepatobiliary disorders
Hepatic cirrhosis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Hepatic failure ^† 1	1/214 (0.47%)	1	1/109 (0.92%)	1
Hepatitis toxic ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Immune system disorders
Hypersensitivity ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Infections and infestations
Anal abscess ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Appendicitis perforated ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Aspergilloma ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Bronchitis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Bronchopneumonia ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Clostridial infection ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Device related infection ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Fungal oesophagitis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Gastrointestinal infection ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Infectious mononucleosis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Lower respiratory tract infection ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Lung abscess ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Peridiverticular abscess ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Pneumonia ^† 1	7/214 (3.27%)	7	3/109 (2.75%)	3
Pneumonia bacterial ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Salmonellosis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Sepsis ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Septic shock ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Tracheitis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Upper respiratory tract infection ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Urinary tract infection ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Wound infection ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Respiratory tract infection ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Injury, poisoning and procedural complications
Lower limb fracture ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Post procedural haemorrhage ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Spinal compression fracture ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Tracheal haemorrhage ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Investigations
Blood amylase increased ^† 1	1/214 (0.47%)	1	1/109 (0.92%)	1
Blood lactate dehydrogenase increased ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
C-reactive protein increased ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Electrocardiogram QT prolonged ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Electrocardiogram ST segment depression ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Eosinophil count increased ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Haemoglobin decreased ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Lipase increased ^† 1	3/214 (1.40%)	3	1/109 (0.92%)	1
Liver function test abnormal ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Transaminases increased ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Dehydration ^† 1	5/214 (2.34%)	5	1/109 (0.92%)	1
Hypercalcaemia ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Hypocalcaemia ^† 1	6/214 (2.80%)	6	0/109 (0.00%)	0
Hypokalaemia ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Hyponatraemia ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Back pain ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Bone pain ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Muscle spasms ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Neck pain ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Osteonecrosis of jaw ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Metastases to oesophagus ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Metastases to trachea ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Metastatic pain ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Neoplasm progression ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Tumor pain ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Nervous system disorders
Cerebral infarction ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Cervicobrachial syndrome ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Convulsion ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Hepatic encephalopathy ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Hypoxic-ischaemic encephalopathy ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Loss of consciousness ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Posterior reversible encephalopathy syndrome ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Syncope ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Transient ischaemic attack ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Vocal cord paralysis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Psychiatric disorders
Agitation ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Confusional state ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Delirium ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Suicide attempt ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Renal and urinary disorders
Acute prerenal failure ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Nephrotic syndrome ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Proteinuria ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Renal failure ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acquired tracheo-oesophageal fistula ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Acute respiratory distress syndrome ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Acute respiratory failure ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Aspiration ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Atelectasis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Bronchial haemorrhage ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Dyspnoea ^† 1	2/214 (0.93%)	2	6/109 (5.50%)	6
Epistaxis ^† 1	2/214 (0.93%)	2	1/109 (0.92%)	1
Haemoptysis ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Laryngeal oedema ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Lung infiltration ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Nasal septum perforation ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Obstructive airways disorder ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Pharyngeal oedema ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Pleuritic pain ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
Pneumomediastinum ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Pneumonia aspiration ^† 1	4/214 (1.87%)	4	1/109 (0.92%)	1
Pneumothorax ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Pulmonary embolism ^† 1	5/214 (2.34%)	5	0/109 (0.00%)	0
Pulmonary haemorrhage ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Pulmonary necrosis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Rales ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Respiratory failure ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Respiratory tract haemorrhage ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Tracheal fistula ^† 1	2/214 (0.93%)	2	0/109 (0.00%)	0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Rash ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Vascular disorders
Arterial thrombosis limb ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Deep vein thrombosis ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Haemorrhage ^† 1	1/214 (0.47%)	1	0/109 (0.00%)	0
Hypertension ^† 1	5/214 (2.34%)	5	0/109 (0.00%)	0
Hypotension ^† 1	3/214 (1.40%)	3	0/109 (0.00%)	0
Shock ^† 1	0/214 (0.00%)	0	1/109 (0.92%)	1
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (14.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	XL184 (Cabozantinib)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	213/214 (99.53%)		102/109 (93.58%)
Blood and lymphatic system disorders
Anaemia ^† 1	14/214 (6.54%)	14	10/109 (9.17%)	10
Leukopenia ^† 1	11/214 (5.14%)	11	2/109 (1.83%)	2
Endocrine disorders
Hypothyroidism ^† 1	20/214 (9.35%)	20	1/109 (0.92%)	1
Gastrointestinal disorders
Abdominal pain ^† 1	34/214 (15.89%)	34	7/109 (6.42%)	7
Abdominal pain upper ^† 1	16/214 (7.48%)	16	6/109 (5.50%)	6
Constipation ^† 1	57/214 (26.64%)	57	6/109 (5.50%)	6
Diarrhoea ^† 1	135/214 (63.08%)	135	36/109 (33.03%)	36
Dry mouth ^† 1	28/214 (13.08%)	28	9/109 (8.26%)	9
Dyspepsia ^† 1	24/214 (11.21%)	24	0/109 (0.00%)	0
Dysphagia ^† 1	25/214 (11.68%)	25	7/109 (6.42%)	7
Flatulence ^† 1	15/214 (7.01%)	15	4/109 (3.67%)	4
Glossodynia ^† 1	21/214 (9.81%)	21	0/109 (0.00%)	0
Haemorrhoids ^† 1	17/214 (7.94%)	17	3/109 (2.75%)	3
Nausea ^† 1	92/214 (42.99%)	92	23/109 (21.10%)	23
Oral pain ^† 1	29/214 (13.55%)	29	1/109 (0.92%)	1
Stomatitis ^† 1	62/214 (28.97%)	62	3/109 (2.75%)	3
Vomiting ^† 1	51/214 (23.83%)	51	2/109 (1.83%)	2
General disorders
Asthenia ^† 1	43/214 (20.09%)	43	14/109 (12.84%)	14
Fatigue ^† 1	86/214 (40.19%)	86	31/109 (28.44%)	31
Mucosal inflamation ^† 1	46/214 (21.50%)	46	4/109 (3.67%)	4
Oedema peripheral ^† 1	20/214 (9.35%)	20	13/109 (11.93%)	13
Pain ^† 1	12/214 (5.61%)	12	4/109 (3.67%)	4
Pyrexia ^† 1	19/214 (8.88%)	19	7/109 (6.42%)	7
Infections and infestations
Nasopharyngitis ^† 1	10/214 (4.67%)	10	8/109 (7.34%)	8
Upper respiratory tract infection ^† 1	17/214 (7.94%)	17	4/109 (3.67%)	4
Urinary tract infection ^† 1	16/214 (7.48%)	16	3/109 (2.75%)	3
Investigations
Alanine aminotransferase increased ^† 1	46/214 (21.50%)	46	6/109 (5.50%)	6
Aspartate aminotransferase increased ^† 1	46/214 (21.50%)	46	6/109 (5.50%)	6
Blood alkaline phosphatase increased ^† 1	17/214 (7.94%)	17	3/109 (2.75%)	3
Blood amylase increased ^† 1	14/214 (6.54%)	14	11/109 (10.09%)	11
Blood lactate dehydrogenase increased ^† 1	39/214 (18.22%)	39	3/109 (2.75%)	3
Blood thyroid stimulating hormone increased ^† 1	28/214 (13.08%)	28	3/109 (2.75%)	3
Lipase increased ^† 1	23/214 (10.75%)	23	13/109 (11.93%)	13
Weight decreased ^† 1	102/214 (47.66%)	102	11/109 (10.09%)	11
Metabolism and nutrition disorders
Decreased appetite ^† 1	98/214 (45.79%)	98	17/109 (15.60%)	17
Dehydration ^† 1	12/214 (5.61%)	12	1/109 (0.92%)	1
Hypocalcaemia ^† 1	43/214 (20.09%)	43	5/109 (4.59%)	5
Hypokalaemia ^† 1	22/214 (10.28%)	22	4/109 (3.67%)	4
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	28/214 (13.08%)	28	8/109 (7.34%)	8
Back pain ^† 1	32/214 (14.95%)	32	12/109 (11.01%)	12
Bone pain ^† 1	11/214 (5.14%)	11	5/109 (4.59%)	5
Joint swelling ^† 1	2/214 (0.93%)	2	6/109 (5.50%)	6
Muscle spasms ^† 1	26/214 (12.15%)	26	5/109 (4.59%)	5
Musculoskeletal chest pain ^† 1	19/214 (8.88%)	19	4/109 (3.67%)	4
Musculoskeletal pain ^† 1	12/214 (5.61%)	12	6/109 (5.50%)	6
Myalgia ^† 1	13/214 (6.07%)	13	4/109 (3.67%)	4
Neck pain ^† 1	15/214 (7.01%)	15	5/109 (4.59%)	5
Pain in extremity ^† 1	33/214 (15.42%)	33	12/109 (11.01%)	12
Nervous system disorders
Dizziness ^† 1	29/214 (13.55%)	29	8/109 (7.34%)	8
Dysgeusia ^† 1	73/214 (34.11%)	73	6/109 (5.50%)	6
Headache ^† 1	39/214 (18.22%)	39	9/109 (8.26%)	9
Neuropathy peripheral ^† 1	11/214 (5.14%)	11	0/109 (0.00%)	0
Paraesthesia ^† 1	16/214 (7.48%)	16	2/109 (1.83%)	2
Peripheral sensory neuropathy ^† 1	14/214 (6.54%)	14	0/109 (0.00%)	0
Psychiatric disorders
Anxiety ^† 1	19/214 (8.88%)	19	2/109 (1.83%)	2
Depression ^† 1	14/214 (6.54%)	14	3/109 (2.75%)	3
Insomnia ^† 1	23/214 (10.75%)	23	7/109 (6.42%)	7
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	26/214 (12.15%)	26	14/109 (12.84%)	14
Dysphonia ^† 1	43/214 (20.09%)	43	10/109 (9.17%)	10
Dyspnoea ^† 1	27/214 (12.62%)	27	18/109 (16.51%)	18
Epistaxis ^† 1	19/214 (8.88%)	19	12/109 (11.01%)	12
Oropharyngeal pain ^† 1	38/214 (17.76%)	38	5/109 (4.59%)	5
Skin and subcutaneous tissue disorders
Alopecia ^† 1	35/214 (16.36%)	35	2/109 (1.83%)	2
Dermatitis acneiform ^† 1	14/214 (6.54%)	14	2/109 (1.83%)	2
Dry skin ^† 1	41/214 (19.16%)	41	3/109 (2.75%)	3
Erythema ^† 1	23/214 (10.75%)	23	2/109 (1.83%)	2
Hair colour changes ^† 1	72/214 (33.64%)	72	1/109 (0.92%)	1
Hyperhidrosis ^† 1	4/214 (1.87%)	4	6/109 (5.50%)	6
Hyperkeratosis ^† 1	16/214 (7.48%)	16	0/109 (0.00%)	0
Palmar-plantar erythrodysaesthesia syndrome ^† 1	105/214 (49.07%)	105	2/109 (1.83%)	2
Pruritus ^† 1	13/214 (6.07%)	13	7/109 (6.42%)	7
Rash ^† 1	41/214 (19.16%)	41	11/109 (10.09%)	11
Vascular disorders
Hypertension ^† 1	62/214 (28.97%)	62	4/109 (3.67%)	4
Hypotension ^† 1	11/214 (5.14%)	11	0/109 (0.00%)	0
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (14.0)

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.

PIs may publish trial results generated at his/ her site with sponsor's prior written consent and only after results of the trial from all participating sites have been released in a multi-center publication coordinated by the sponsor.

Results Point of Contact

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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):

Schlumberger M, Elisei R, Muller S, Schoffski P, Brose M, Shah M, Licitra L, Krajewska J, Kreissl MC, Niederle B, Cohen EEW, Wirth L, Ali H, Clary DO, Yaron Y, Mangeshkar M, Ball D, Nelkin B, Sherman S. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol. 2017 Nov 1;28(11):2813-2819. doi: 10.1093/annonc/mdx479.

Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, Niederle B, Cohen EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, Nelkin B, Sherman SI. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013 Oct 10;31(29):3639-46. doi: 10.1200/JCO.2012.48.4659. Epub 2013 Sep 3. Erratum In: J Clin Oncol. 2014 Jun 10;32(17):1864.

Layout table for additonal information

Responsible Party:	Exelixis
ClinicalTrials.gov Identifier:	NCT00704730
Other Study ID Numbers:	XL184-301
First Submitted:	June 23, 2008
First Posted:	June 25, 2008
Results First Submitted:	April 8, 2014
Results First Posted:	September 9, 2014
Last Update Posted:	April 20, 2021

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