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

Sponsor
Exelixis (Industry)
Overall Status
Completed
CT.gov ID
NCT01908426
Collaborator
(none)
707
Enrollment
104
Locations
2
Arms
87.6
Duration (Months)
6.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with placebo on overall survival in subjects with advanced hepatocellular carcinoma who have received prior sorafenib.

Condition or Disease Intervention/Treatment Phase
  • Drug: Cabozantinib tablets
  • Drug: Placebo tablets
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
707 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Randomized, Double-blind, Controlled Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib
Study Start Date :
Sep 26, 2013
Actual Primary Completion Date :
Oct 16, 2017
Actual Study Completion Date :
Jan 12, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cabozantinib (XL184)

Cabozantinib (XL184) 60 mg tablet once daily

Drug: Cabozantinib tablets
Other Names:
  • XL184

    		•
    Placebo Comparator: Placebo

    Oral cabozantinib-matched placebo tablet once daily

    Drug: Placebo tablets

    Outcome Measures

    Primary Outcome Measures

    1. Overall Survival (OS) [Up to 45 months]

      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.

    Secondary Outcome Measures

    1. Progression-Free Survival (PFS) [Up to 45 months]

      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.

    2. Objective Response Rate (ORR) [ORR is measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation of study treatment (up to 45 months)]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Select Inclusion Criteria:

    1. Histological or cytological diagnosis of HCC.

    2. The subject has disease that is not amenable to a curative treatment approach.

    3. Received prior sorafenib.

    4. Progression following at least 1 prior systemic treatment for HCC.

    5. Recovery to from toxicities related to any prior treatments.

    6. ECOG performance status of 0 or 1.

    7. Adequate hematologic and renal function, based upon meeting protocol defined laboratory criteria within 7 days before randomization.

    8. Child-Pugh Score of A.

    9. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection.

    10. Sexually active fertile subjects(male and female)must agree to use medically accepted methods of contraception during the course of the study and for 4 months after the last dose of study treatment.

    11. Female subjects of childbearing potential must not be pregnant at screening.

    Select Exclusion Criteria:

    1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.

    2. Receipt of more than 2 prior systemic therapies for advanced HCC.

    3. Any type of anticancer agent (including investigational) within 2 weeks before randomization.

    4. Radiation therapy within 4 weeks (2 weeks for radiation for bone metastases) or radionuclide treatment within 6 weeks of randomization.

    5. Prior cabozantinib treatment.

    6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before randomization.

    7. Concomitant anticoagulation, at therapeutic doses, with anticoagulants.

    8. Serious illness other than cancer that would preclude safe participation in the study.

    9. Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding.

    10. Moderate or severe ascites.

    11. Pregnant or lactating females.

    12. Diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low-grade tumors.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Corona California United States 92879
    2 Los Angeles California United States 90033
    3 San Diego California United States 92123
    4 San Francisco California United States 94115
    5 Gainesville Florida United States 32610
    6 Atlanta Georgia United States 30318
    7 Honolulu Hawaii United States 96815
    8 Chicago Illinois United States 60637
    9 Burlington Massachusetts United States 01805
    10 Rochester Minnesota United States 55905
    11 Kansas City Missouri United States 64128
    12 Saint Louis Missouri United States 63110
    13 Las Vegas Nevada United States 89109
    14 East Orange New Jersey United States 07018
    15 New York New York United States 10032
    16 New York New York United States 10065
    17 Valhalla New York United States 10595
    18 Dallas Texas United States 75246
    19 San Antonio Texas United States 78215
    20 Seattle Washington United States 98104
    21 Seattle Washington United States 98109
    22 Spokane Washington United States 99208
    23 Camperdown New South Wales Australia 2050
    24 Concord New South Wales Australia 2139
    25 Darlinghurst New South Wales Australia 2010
    26 Kogarah New South Wales Australia 2217
    27 Westmead New South Wales Australia 2145
    28 Kurralta Park South Australia Australia 5037
    29 Melbourne Victoria Australia 3050
    30 Perth Western Australia Australia 6000
    31 Edegem Antwerpen Belgium 2650
    32 La Louvière Hainaut Belgium 7100
    33 Gent Oost-Vlaanderen Belgium 9000
    34 Liege Belgium 4000
    35 Calgary Alberta Canada T2N 4N2
    36 Toronto Ontario Canada M5G 2M9
    37 Saskatoon Saskatchewan Canada S7N 4H4
    38 Nice Alpes-Maritimes France 6202
    39 Amiens Somme France 80054
    40 Creteil Val-de-Marne France 94010
    41 Besançon France 25000
    42 Bordeaux France 33075
    43 Clermont-Ferrand France 63003
    44 Lille France 59037
    45 Lyon France 69317
    46 Esslingen am Neckar Baden-Württemberg Germany 73730
    47 Tübingen Baden-Württemberg Germany 72076
    48 München Bayern Germany 81675
    49 Frankfurt am Main Hessen Germany 60590
    50 Magdeburg Sachsen-Anhalt Germany 39120
    51 Berlin Germany 13353
    52 Freiburg Germany
    53 Hong Kong Hong Kong
    54 Dublin Ireland 7
    55 Bologna Emilia-Romagna Italy 40138
    56 Faenza Emilia-Romagna Italy 48018
    57 Meldola Emilia-Romagna Italy 47014
    58 Rimini Emilia-Romagna Italy 47900
    59 Roma Lazio Italy 128
    60 Roma Lazio Italy 168
    61 Genova Liguria Italy 16132
    62 Milan Lombardia Italy 20122
    63 Rozzano Lombardia Italy 20089
    64 Palermo Sicilia Italy 90127
    65 Padova Veneto Italy 35128
    66 Goyang Gyeonggido Korea, Republic of 410-769
    67 Busan Korea, Republic of 602-739
    68 Seongnam Korea, Republic of 463-707
    69 Seoul Korea, Republic of 110-744
    70 Seoul Korea, Republic of 120-752
    71 Seoul Korea, Republic of 135-710
    72 Seoul Korea, Republic of 136-705
    73 Seoul Korea, Republic of 137-701
    74 Seoul Korea, Republic of 138-736
    75 Suwon-si Korea, Republic of 443-721
    76 Maastricht Limburg Netherlands 6229 HX
    77 Amsterdam Noord-Holland Netherlands 1081 HV
    78 Amsterdam Noord-Holland Netherlands 1105 AZ
    79 Leiden Zuid-Holland Netherlands 2333 ZA
    80 Auckland North Island New Zealand 1003
    81 Olsztyn Warminsko-Mazurskie Poland 10-513
    82 Myslowice Poland 41-400
    83 Poznan Poland 60-569
    84 Cluj-Napoca Cluj Romania 400015
    85 Brasov Romania 500019
    86 Singapore Singapore 119074
    87 Singapore Singapore 169610
    88 Singapore Singapore 308433
    89 Elche Alicante Spain 3293
    90 Majadahonda Madrid Spain 28222
    91 Torrejon de Ardoz Madrid Spain 28850
    92 Madrid Spain 28007
    93 Madrid Spain 28041
    94 Zaragoza Spain 50009
    95 Liuying Township Tainan Taiwan 736
    96 Taichung Taiwan 40705
    97 Taipei Taiwan 100
    98 Edirne Turkey 22030
    99 Gaziantep Turkey 27100
    100 Wirral England United Kingdom CH63 4JY
    101 Birmingham United Kingdom B15 2TH
    102 London United Kingdom NW3 2QG
    103 London United Kingdom SE5 9RS
    104 Manchester United Kingdom M20 4BX

    Sponsors and Collaborators

    • Exelixis

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Exelixis
    ClinicalTrials.gov Identifier:
    NCT01908426
    Other Study ID Numbers:
    • XL184-309
    First Posted:
    Jul 25, 2013
    Last Update Posted:
    May 6, 2021
    Last Verified:
    Apr 1, 2021
    Keywords provided by Exelixis
    cabozantinib
    XL184
    liver cancer
    hepatocellular carcinoma
    tyrosine kinase inhibitor
    MET kinase
    vascular endothelial growth factor receptor 2 (VEGFR2)
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Hepatocellular

    Study Results

    Participant Flow

    Recruitment Details First patient enrolled: 26 September 2013, Data cut-off date: 01 June 2017
    Pre-assignment Detail
    Arm/Group Title Cabozantinib (XL184) Placebo
    Arm/Group Description Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets Oral cabozantinib-matched placebo tablet once daily Placebo tablets
    Period Title: Overall Study
    STARTED 470 237
    COMPLETED 73 26
    NOT COMPLETED 397 211

    Baseline Characteristics

    Arm/Group Title Cabozantinib (XL184) Placebo Total
    Arm/Group Description Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets Oral cabozantinib-matched placebo tablet once daily Placebo tablets Total of all reporting groups
    Overall Participants 470 237 707
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    64.0
    64.0
    64.0
    Age, Customized (Count of Participants)
    < 65 years old
    240
    51.1%
    124
    52.3%
    364
    51.5%
    65 to < 75 years old
    158
    33.6%
    75
    31.6%
    233
    33%
    75 to < 85 years old
    67
    14.3%
    35
    14.8%
    102
    14.4%
    ≥ 85 years old
    5
    1.1%
    3
    1.3%
    8
    1.1%
    Sex: Female, Male (Count of Participants)
    Female
    91
    19.4%
    35
    14.8%
    126
    17.8%
    Male
    379
    80.6%
    202
    85.2%
    581
    82.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    18
    3.8%
    12
    5.1%
    30
    4.2%
    Not Hispanic or Latino
    417
    88.7%
    215
    90.7%
    632
    89.4%
    Unknown or Not Reported
    35
    7.4%
    10
    4.2%
    45
    6.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    159
    33.8%
    82
    34.6%
    241
    34.1%
    Native Hawaiian or Other Pacific Islander
    3
    0.6%
    0
    0%
    3
    0.4%
    Black or African American
    8
    1.7%
    11
    4.6%
    19
    2.7%
    White
    264
    56.2%
    130
    54.9%
    394
    55.7%
    More than one race
    0
    0%
    1
    0.4%
    1
    0.1%
    Unknown or Not Reported
    36
    7.7%
    13
    5.5%
    49
    6.9%
    Geographic Region (Count of Participants)
    Australia / New Zealand
    15
    3.2%
    11
    4.6%
    26
    3.7%
    Asia
    116
    24.7%
    59
    24.9%
    175
    24.8%
    Europe
    231
    49.1%
    108
    45.6%
    339
    47.9%
    North America (USA / Canada)
    108
    23%
    59
    24.9%
    167
    23.6%
    Presence of extrahepatic spread of disease and/or macrovascular invasion (stratification per IxRS) (Count of Participants)
    Yes
    368
    78.3%
    186
    78.5%
    554
    78.4%
    No
    102
    21.7%
    51
    21.5%
    153
    21.6%
    Etiology of disease (stratification factor per IxRS), (Count of Participants)
    HBV (with or without known HCV)
    182
    38.7%
    90
    38%
    272
    38.5%
    HCV (without known HBV)
    100
    21.3%
    51
    21.5%
    151
    21.4%
    Other (neither HBV nor HCV)
    188
    40%
    96
    40.5%
    284
    40.2%
    Geographic region (stratification factor per IxRS) (Count of Participants)
    Asia
    116
    24.7%
    59
    24.9%
    175
    24.8%
    Other Regions
    354
    75.3%
    178
    75.1%
    532
    75.2%
    Eastern Cooperative Oncology Group Performance Status (ECOG PS) (Count of Participants)
    0
    245
    52.1%
    131
    55.3%
    376
    53.2%
    1
    224
    47.7%
    106
    44.7%
    330
    46.7%
    2
    1
    0.2%
    0
    0%
    1
    0.1%
    Smoking history (Count of Participants)
    Current
    78
    16.6%
    42
    17.7%
    120
    17%
    Former
    229
    48.7%
    122
    51.5%
    351
    49.6%
    Never
    160
    34%
    71
    30%
    231
    32.7%
    Missing
    3
    0.6%
    2
    0.8%
    5
    0.7%
    Alcohol use (Count of Participants)
    Current
    65
    13.8%
    30
    12.7%
    95
    13.4%
    Former
    223
    47.4%
    124
    52.3%
    347
    49.1%
    Never
    176
    37.4%
    81
    34.2%
    257
    36.4%
    Missing
    6
    1.3%
    2
    0.8%
    8
    1.1%
    Weight (kg) [Median (Full Range) ]
    Median (Full Range) [kg]
    69
    71.5
    70.25
    Body Mass Index (BMI) (kg / m^2) [Median (Full Range) ]
    Median (Full Range) [kg / m^2]
    24.1
    24.9
    24.5

    Outcome Measures

    1. Primary Outcome
    Title Overall Survival (OS)
    Description The primary analysis of OS is defined as the time from randomization to death from any cause. The analysis was based on a second planned interim analysis prespecified to be performed at approximately the 75% information fraction (ie, at approximately 466 deaths). The data cutoff date for this event-driven analysis in the Intent to Treat (ITT) population was 01 June 2017. Median OS was calculated using the Kaplan-Meier estimates.
    Time Frame Up to 45 months

    Outcome Measure Data

    Analysis Population Description
    The ITT population was used and included 707 randomized subjects (470 cabozantinib, 237 placebo) in the second interim analysis with a cutoff date of 01 June 2017.
    Arm/Group Title Cabozantinib (XL184) Placebo
    Arm/Group Description Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets Oral cabozantinib-matched placebo tablet once daily Placebo tablets
    Measure Participants 470 237
    Median (95% Confidence Interval) [months]
    10.2
    8.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Cabozantinib (XL184), Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0049
    Comments
    Method Log Rank
    Comments The Log-Rank Test was stratified by etiology of disease, geo. region, presence of extrahepatic spread of disease and/or macrovascular invasion.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.76
    Confidence Interval (2-Sided) 95%
    0.63 to 0.92
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Progression-Free Survival (PFS)
    Description Duration of PFS is defined as the time of randomization to the earlier of the following events, progressive disease as determined by Investigator (per RECIST 1.0, which is defined by a ≥ 20% increase in the sum of the longest diameter of target lesions from baseline) or death due to any cause. A Kaplan- Meier analysis was performed to estimate the median duration.
    Time Frame Up to 45 months

    Outcome Measure Data

    Analysis Population Description
    The prespecified primary analysis of PFS was based on the first 707 randomized subjects (470 cabozantinib, 237 placebo).
    Arm/Group Title Cabozantinib (XL184) Placebo
    Arm/Group Description Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets Oral cabozantinib-matched placebo tablet once daily Placebo tablets
    Measure Participants 470 237
    Median (95% Confidence Interval) [months]
    5.2
    1.9
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Cabozantinib (XL184), Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments
    Method Log Rank
    Comments The Log Rank Test was stratified by etiology of disease, geographic region, presence of extrahepatic spread of disease and/or macrovascular invasion.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.44
    Confidence Interval (2-Sided) 95%
    0.36 to 0.52
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Objective Response Rate (ORR)
    Description Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    Time Frame ORR is measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation of study treatment (up to 45 months)

    Outcome Measure Data

    Analysis Population Description
    The analysis of ORR was performed in the ITT population (all randomized: 470 cabozantinib, 237 placebo) based upon response determined by Investigator per RECIST 1.1
    Arm/Group Title Cabozantinib (XL184) Placebo
    Arm/Group Description Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets Oral cabozantinib-matched placebo tablet once daily Placebo tablets
    Measure Participants 470 237
    Count of Participants [Participants]
    18
    3.8%
    1
    0.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Cabozantinib (XL184), Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0086
    Comments
    Method Cochran-Mantel-Haenszel
    Comments

    Adverse Events

    Time Frame Up to 61 weeks
    Adverse Event Reporting Description The safety data includes subjects who were randomized and treated. Of 707 patients, 470 were randomized to received cabozantinib and 237 to placebo. Three subjects in the cabozantinib arm were randomized but did not receive study drug. Thus, a total of 704 subjects received study treatment in the Safety Population (467 cabozantinib, 237 placebo).
    Arm/Group Title Cabozantinib (XL184) Placebo
    Arm/Group Description Cabozantinib (XL184) 60 mg tablet once daily Cabozantinib tablets Oral cabozantinib-matched placebo tablet once daily Placebo tablets
    All Cause Mortality
    Cabozantinib (XL184) Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 314/467 (67.2%) 167/237 (70.5%)
    Serious Adverse Events
    Cabozantinib (XL184) Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 232/467 (49.7%) 87/237 (36.7%)
    Blood and lymphatic system disorders
    Anaemia 4/467 (0.9%) 1/237 (0.4%)
    Febrile neutropenia 2/467 (0.4%) 0/237 (0%)
    Leukopenia 1/467 (0.2%) 0/237 (0%)
    Lymphopenia 1/467 (0.2%) 0/237 (0%)
    Neutropenia 1/467 (0.2%) 0/237 (0%)
    Thrombocytopenia 5/467 (1.1%) 0/237 (0%)
    Cardiac disorders
    Acute myocardial infarction 2/467 (0.4%) 0/237 (0%)
    Atrial fibrillation 1/467 (0.2%) 0/237 (0%)
    Atrial flutter 1/467 (0.2%) 0/237 (0%)
    Myocardial infarction 0/467 (0%) 1/237 (0.4%)
    Endocrine disorders
    Hypothyroidisim 1/467 (0.2%) 0/237 (0%)
    Eye disorders
    Retinal vein thrombosis 1/467 (0.2%) 0/237 (0%)
    Sudden visual loss 1/467 (0.2%) 0/237 (0%)
    Gastrointestinal disorders
    Abdominal Pain 6/467 (1.3%) 9/237 (3.8%)
    Abdominal pain upper 1/467 (0.2%) 0/237 (0%)
    Anal fistula 2/467 (0.4%) 0/237 (0%)
    Ascites 12/467 (2.6%) 3/237 (1.3%)
    Colitis 1/467 (0.2%) 0/237 (0%)
    Constipation 2/467 (0.4%) 0/237 (0%)
    Diarrhoea 5/467 (1.1%) 1/237 (0.4%)
    Duodenal perforation 1/467 (0.2%) 0/237 (0%)
    Duodenal ulcer haemorrhage 1/467 (0.2%) 0/237 (0%)
    Enterocolitis 1/467 (0.2%) 0/237 (0%)
    Gastric haemorrhage 1/467 (0.2%) 0/237 (0%)
    Gastric perforation 2/467 (0.4%) 0/237 (0%)
    Gastric varices haemorrhage 1/467 (0.2%) 1/237 (0.4%)
    Gastritis erosive 1/467 (0.2%) 0/237 (0%)
    Gastrointestinal haemorrhage 4/467 (0.9%) 1/237 (0.4%)
    Gastrointestinal ulcer haemorrhage 1/467 (0.2%) 0/237 (0%)
    Gastrooesophageal reflux disease 0/467 (0%) 1/237 (0.4%)
    Haematemesis 1/467 (0.2%) 1/237 (0.4%)
    Ileus 1/467 (0.2%) 0/237 (0%)
    Intestinal haemorrhage 0/467 (0%) 1/237 (0.4%)
    Intestinal obstruction 1/467 (0.2%) 0/237 (0%)
    Intestinal perforation 0/467 (0%) 1/237 (0.4%)
    Large intestine perforation 2/467 (0.4%) 0/237 (0%)
    Mallory-Weiss syndrome 1/467 (0.2%) 0/237 (0%)
    Melaena 2/467 (0.4%) 0/237 (0%)
    Mesenteric atermy thrombosis 1/467 (0.2%) 0/237 (0%)
    Nausea 2/467 (0.4%) 1/237 (0.4%)
    Oesophageal varices haemorrhage 7/467 (1.5%) 5/237 (2.1%)
    Oesophagitis 1/467 (0.2%) 0/237 (0%)
    Pancreatic pseudocyst 1/467 (0.2%) 0/237 (0%)
    Pancreatitis 2/467 (0.4%) 1/237 (0.4%)
    Pancreatitis acute 3/467 (0.6%) 0/237 (0%)
    Peritoneal haemorrhage 0/467 (0%) 1/237 (0.4%)
    Portal hypertensive gastropathy 1/467 (0.2%) 0/237 (0%)
    Proctalgia 1/467 (0.2%) 0/237 (0%)
    Rectal haemorrhage 3/467 (0.6%) 2/237 (0.8%)
    Rectal ulcer haemorrhage 0/467 (0%) 1/237 (0.4%)
    Thrombosis mesenteric vessel 1/467 (0.2%) 0/237 (0%)
    Upper gastrointestinal haemorrhage 3/467 (0.6%) 2/237 (0.8%)
    Vomiting 4/467 (0.9%) 4/237 (1.7%)
    General disorders
    Asthenia 9/467 (1.9%) 0/237 (0%)
    Chest pain 1/467 (0.2%) 0/237 (0%)
    Death 1/467 (0.2%) 1/237 (0.4%)
    Fatigue 6/467 (1.3%) 1/237 (0.4%)
    General physical health deterioration 17/467 (3.6%) 8/237 (3.4%)
    Influenza like illness 1/467 (0.2%) 0/237 (0%)
    Infusion site extravasation 1/467 (0.2%) 0/237 (0%)
    Local swelling 0/467 (0%) 1/237 (0.4%)
    Multi-organ failure 2/467 (0.4%) 0/237 (0%)
    Non-cardiac chest pain 1/467 (0.2%) 0/237 (0%)
    Oedema 2/467 (0.4%) 0/237 (0%)
    Oedema peripheral 3/467 (0.6%) 0/237 (0%)
    Pain 2/467 (0.4%) 0/237 (0%)
    Pyrexia 4/467 (0.9%) 1/237 (0.4%)
    Hepatobiliary disorders
    Acute hepatic failure 1/467 (0.2%) 0/237 (0%)
    Bile duct obstruction 3/467 (0.6%) 0/237 (0%)
    Bile duct stenosis 0/467 (0%) 1/237 (0.4%)
    Bile duct stone 0/467 (0%) 1/237 (0.4%)
    Cholangitis 3/467 (0.6%) 0/237 (0%)
    Cholangitis acute 0/467 (0%) 1/237 (0.4%)
    Cholelithiasis 1/467 (0.2%) 0/237 (0%)
    Cholestasis 0/467 (0%) 1/237 (0.4%)
    Chronic hepatic failure 0/467 (0%) 1/237 (0.4%)
    Dilatation intrahepatic duct acquired 0/467 (0%) 1/237 (0.4%)
    Gallbladder perforation 1/467 (0.2%) 0/237 (0%)
    Hepatic cirrhosis 1/467 (0.2%) 0/237 (0%)
    Hepatic failure 8/467 (1.7%) 8/237 (3.4%)
    Hepatic lesion 0/467 (0%) 2/237 (0.8%)
    Hepatic pain 0/467 (0%) 1/237 (0.4%)
    Hepatorenal syndrome 1/467 (0.2%) 1/237 (0.4%)
    Hyperbilirubinaemia 2/467 (0.4%) 1/237 (0.4%)
    Ischaemic hepatitis 1/467 (0.2%) 0/237 (0%)
    Jaundice 0/467 (0%) 2/237 (0.8%)
    Liver disorder 1/467 (0.2%) 0/237 (0%)
    Portail vein thrombosis 3/467 (0.6%) 0/237 (0%)
    Infections and infestations
    Abscess jaw 1/467 (0.2%) 0/237 (0%)
    Anal abscess 3/467 (0.6%) 0/237 (0%)
    Bacteraemia 1/467 (0.2%) 1/237 (0.4%)
    Biliary sepsis 0/467 (0%) 2/237 (0.8%)
    Biliary tract infection 1/467 (0.2%) 0/237 (0%)
    Bronchitis 1/467 (0.2%) 0/237 (0%)
    Campylobacter gastroenteritis 1/467 (0.2%) 0/237 (0%)
    Cellulitis of male external genital organ 1/467 (0.2%) 0/237 (0%)
    Clostridium dificile colitis 1/467 (0.2%) 0/237 (0%)
    Clostridium dificile infection 1/467 (0.2%) 1/237 (0.4%)
    Empyema 1/467 (0.2%) 0/237 (0%)
    Gangrene 1/467 (0.2%) 0/237 (0%)
    Gastroenteritis 2/467 (0.4%) 1/237 (0.4%)
    Gastroenteritis viral 1/467 (0.2%) 0/237 (0%)
    Gastroenteritis viral infection 0/467 (0%) 1/237 (0.4%)
    Herpes zoster 1/467 (0.2%) 0/237 (0%)
    Infection 1/467 (0.2%) 1/237 (0.4%)
    Liver abscess 1/467 (0.2%) 0/237 (0%)
    Lower respiratory tract infection 0/467 (0%) 1/237 (0.4%)
    Lung infection 1/467 (0.2%) 0/237 (0%)
    Peritonitis 1/467 (0.2%) 0/237 (0%)
    Pneumonia 16/467 (3.4%) 6/237 (2.5%)
    Pneumonia bacterial 0/467 (0%) 1/237 (0.4%)
    Sepsis 3/467 (0.6%) 2/237 (0.8%)
    Sepsis syndrome 1/467 (0.2%) 0/237 (0%)
    Septic shock 1/467 (0.2%) 1/237 (0.4%)
    Staphylococcal sepsis 1/467 (0.2%) 0/237 (0%)
    Subcutaneous abscess 2/467 (0.4%) 0/237 (0%)
    Upper respiratory tract infection 1/467 (0.2%) 0/237 (0%)
    Urinary tract infection 3/467 (0.6%) 1/237 (0.4%)
    Urosepsis 1/467 (0.2%) 0/237 (0%)
    Wound sepsis 1/467 (0.2%) 0/237 (0%)
    Injury, poisoning and procedural complications
    Compression fracture 1/467 (0.2%) 0/237 (0%)
    Fall 3/467 (0.6%) 0/237 (0%)
    Femur fracture 1/467 (0.2%) 0/237 (0%)
    Hip fracture 0/467 (0%) 1/237 (0.4%)
    Intestinal anastomosis complication 1/467 (0.2%) 0/237 (0%)
    Lumbar vertebral fracture 1/467 (0.2%) 0/237 (0%)
    Multiple fractures 1/467 (0.2%) 0/237 (0%)
    Overdose 1/467 (0.2%) 0/237 (0%)
    Post procedural haemorrhage 0/467 (0%) 1/237 (0.4%)
    Radius fracture 1/467 (0.2%) 0/237 (0%)
    Road traffic accident 0/467 (0%) 1/237 (0.4%)
    Toxicity to various agents 1/467 (0.2%) 0/237 (0%)
    Vascular pseudoaneurysm 1/467 (0.2%) 0/237 (0%)
    Investigations
    Alanine aminotransferase increased 1/467 (0.2%) 0/237 (0%)
    Amylase increased 1/467 (0.2%) 0/237 (0%)
    Aspartate aminotransferase increased 3/467 (0.6%) 0/237 (0%)
    Blood bilirubin increased 3/467 (0.6%) 0/237 (0%)
    Blood creatine increased 1/467 (0.2%) 0/237 (0%)
    Gamma-glutamytransferase increased 1/467 (0.2%) 0/237 (0%)
    Lymphcyte count decreased 1/467 (0.2%) 0/237 (0%)
    Neutrophil count decreased 1/467 (0.2%) 0/237 (0%)
    Oesophaggogastroduodenoscopy 0/467 (0%) 1/237 (0.4%)
    Oxygen saturation decreased 1/467 (0.2%) 0/237 (0%)
    Weight decreased 1/467 (0.2%) 0/237 (0%)
    Metabolism and nutrition disorders
    Cachexia 1/467 (0.2%) 0/237 (0%)
    Decreased appetite 4/467 (0.9%) 0/237 (0%)
    Dehydration 4/467 (0.9%) 2/237 (0.8%)
    Diabetes mellitus inadequate control 1/467 (0.2%) 0/237 (0%)
    Failure to thrive 1/467 (0.2%) 0/237 (0%)
    Hyperammonaemia 0/467 (0%) 1/237 (0.4%)
    Hypercalcaemia 0/467 (0%) 1/237 (0.4%)
    Hyperglycaemia 1/467 (0.2%) 0/237 (0%)
    Hypocalcaemia 2/467 (0.4%) 0/237 (0%)
    Hypokalaemia 1/467 (0.2%) 1/237 (0.4%)
    Hypomagnesaemia 2/467 (0.4%) 0/237 (0%)
    Hyponatraemia 5/467 (1.1%) 0/237 (0%)
    Hypophagia 0/467 (0%) 1/237 (0.4%)
    Musculoskeletal and connective tissue disorders
    Back pain 1/467 (0.2%) 0/237 (0%)
    Bone pain 2/467 (0.4%) 1/237 (0.4%)
    Fistula 0/467 (0%) 1/237 (0.4%)
    Intervertebral disc protusion 1/467 (0.2%) 0/237 (0%)
    Musculoskletal chest pain 0/467 (0%) 1/237 (0.4%)
    Musculoskeletal pain 1/467 (0.2%) 1/237 (0.4%)
    Myalgia 1/467 (0.2%) 0/237 (0%)
    Pain in extremity 1/467 (0.2%) 0/237 (0%)
    Rhabdomyolysis 1/467 (0.2%) 0/237 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia 1/467 (0.2%) 0/237 (0%)
    Cancer pain 1/467 (0.2%) 0/237 (0%)
    Head and neck cancer 1/467 (0.2%) 0/237 (0%)
    Hepatic neoplasm 1/467 (0.2%) 0/237 (0%)
    Hepatocellular carcinoma 39/467 (8.4%) 22/237 (9.3%)
    Intracranial tumour haemorrhage 1/467 (0.2%) 0/237 (0%)
    Liver carcinoma ruptured 0/467 (0%) 1/237 (0.4%)
    Lymphangiosis carcinomatosa 0/467 (0%) 1/237 (0.4%)
    Metastases to bone 1/467 (0.2%) 0/237 (0%)
    Metastases to central nervous system 2/467 (0.4%) 3/237 (1.3%)
    Metastases to lung 3/467 (0.6%) 0/237 (0%)
    Metastases to spine 1/467 (0.2%) 2/237 (0.8%)
    Metastatic pain 2/467 (0.4%) 0/237 (0%)
    Squamous cell carcinoma 1/467 (0.2%) 0/237 (0%)
    Tumor associated fever 1/467 (0.2%) 0/237 (0%)
    Tumor compression 1/467 (0.2%) 0/237 (0%)
    Tumor haemorrhage 1/467 (0.2%) 0/237 (0%)
    Nervous system disorders
    Aphasia 1/467 (0.2%) 0/237 (0%)
    Cerebral haemorrhage 1/467 (0.2%) 0/237 (0%)
    Cerebral infarction 0/467 (0%) 1/237 (0.4%)
    Cerebrovascular accident 4/467 (0.9%) 0/237 (0%)
    Cervicobrachial syndrome 1/467 (0.2%) 0/237 (0%)
    Convulsion 1/467 (0.2%) 0/237 (0%)
    Dizziness 1/467 (0.2%) 0/237 (0%)
    Encephalopathy 1/467 (0.2%) 0/237 (0%)
    Hepatic encephalopathy 15/467 (3.2%) 1/237 (0.4%)
    Hyperammonaemic encephalopathy 1/467 (0.2%) 0/237 (0%)
    Ischaemic stroke 2/467 (0.4%) 0/237 (0%)
    Somnolence 1/467 (0.2%) 0/237 (0%)
    Spinal cord compression 3/467 (0.6%) 1/237 (0.4%)
    Syncope 2/467 (0.4%) 0/237 (0%)
    Psychiatric disorders
    Completed suicide 1/467 (0.2%) 0/237 (0%)
    Delirium 1/467 (0.2%) 0/237 (0%)
    Mental status changes 1/467 (0.2%) 1/237 (0.4%)
    Renal and urinary disorders
    Azotaemia 0/467 (0%) 1/237 (0.4%)
    Calculus ureteric 0/467 (0%) 1/237 (0.4%)
    Haematuria 1/467 (0.2%) 0/237 (0%)
    Prerenal failure 1/467 (0.2%) 0/237 (0%)
    Renal failure 1/467 (0.2%) 1/237 (0.4%)
    Renal failure acture 2/467 (0.4%) 2/237 (0.8%)
    Reproductive system and breast disorders
    Pelvic pain 1/467 (0.2%) 1/237 (0.4%)
    Scrotal pain 1/467 (0.2%) 0/237 (0%)
    Testicular swelling 1/467 (0.2%) 0/237 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 1/467 (0.2%) 0/237 (0%)
    Acute respiratory failure 0/467 (0%) 1/237 (0.4%)
    Asthma 1/467 (0.2%) 0/237 (0%)
    Chronic obstructive pulmonary disease 0/467 (0%) 2/237 (0.8%)
    Dyspnoea 10/467 (2.1%) 2/237 (0.8%)
    Epistaxis 3/467 (0.6%) 0/237 (0%)
    Haemoptysis 2/467 (0.4%) 3/237 (1.3%)
    Lung disorder 1/467 (0.2%) 0/237 (0%)
    Oesophagobronchial fistula 1/467 (0.2%) 0/237 (0%)
    Pleural effusion 2/467 (0.4%) 1/237 (0.4%)
    Pneumonia aspiration 0/467 (0%) 1/237 (0.4%)
    Pneumonitis 0/467 (0%) 1/237 (0.4%)
    Pneumothorax 2/467 (0.4%) 0/237 (0%)
    Pulmonary embolism 3/467 (0.6%) 2/237 (0.8%)
    Pulmonary haemorrhage 1/467 (0.2%) 1/237 (0.4%)
    Pulmonary infarction 1/467 (0.2%) 0/237 (0%)
    Respiratory failure 2/467 (0.4%) 0/237 (0%)
    Respiratory crisis (verbatim) 1/467 (0.2%) 0/237 (0%)
    Skin and subcutaneous tissue disorders
    Diabetic ulcer 1/467 (0.2%) 0/237 (0%)
    Palmar-plantar erythrodysaesthesia 6/467 (1.3%) 0/237 (0%)
    Rash 1/467 (0.2%) 0/237 (0%)
    Vascular disorders
    Aneurysm 1/467 (0.2%) 0/237 (0%)
    Deep vein thrombosis 2/467 (0.4%) 0/237 (0%)
    Haematoma 1/467 (0.2%) 0/237 (0%)
    Hypertension 2/467 (0.4%) 1/237 (0.4%)
    Hypotension 1/467 (0.2%) 0/237 (0%)
    Orthostatic hypotension 1/467 (0.2%) 0/237 (0%)
    Peripheral artery thrombosis 0/467 (0%) 1/237 (0.4%)
    Peripheral ischaemia 1/467 (0.2%) 0/237 (0%)
    Thrombosis 1/467 (0.2%) 0/237 (0%)
    Venous thrombosis 0/467 (0%) 1/237 (0.4%)
    Other (Not Including Serious) Adverse Events
    Cabozantinib (XL184) Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 445/467 (95.3%) 173/237 (73%)
    Blood and lymphatic system disorders
    Thrombocytopenia 51/467 (10.9%) 1/237 (0.4%)
    Endocrine disorders
    Hypothyroidism 38/467 (8.1%) 1/237 (0.4%)
    Gastrointestinal disorders
    Diarrhoea 251/467 (53.7%) 43/237 (18.1%)
    Dyspepsia 47/467 (10.1%) 7/237 (3%)
    Nausea 147/467 (31.5%) 41/237 (17.3%)
    Stomatitis 63/467 (13.5%) 5/237 (2.1%)
    Vomiting 118/467 (25.3%) 24/237 (10.1%)
    General disorders
    Asthenia 99/467 (21.2%) 17/237 (7.2%)
    Fatigue 209/467 (44.8%) 70/237 (29.5%)
    Mucosal inflammation 65/467 (13.9%) 5/237 (2.1%)
    Investigations
    Alanine aminotransferase increased 79/467 (16.9%) 13/237 (5.5%)
    Aspartate aminotransferase increased 103/467 (22.1%) 27/237 (11.4%)
    Platelet count decreased 45/467 (9.6%) 7/237 (3%)
    Weight decreased 80/467 (17.1%) 14/237 (5.9%)
    Metabolism and nutrition disorders
    Decreased appetite 224/467 (48%) 43/237 (18.1%)
    Hypoalbuminaemia 55/467 (11.8%) 12/237 (5.1%)
    Hypokalaemia 44/467 (9.4%) 4/237 (1.7%)
    Hypomagnesaemia 29/467 (6.2%) 0/237 (0%)
    Musculoskeletal and connective tissue disorders
    Muscle spasms 39/467 (8.4%) 4/237 (1.7%)
    Pain in extremity 44/467 (9.4%) 9/237 (3.8%)
    Nervous system disorders
    Dysgeusia 56/467 (12%) 5/237 (2.1%)
    Respiratory, thoracic and mediastinal disorders
    Dysphonia 90/467 (19.3%) 5/237 (2.1%)
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome 217/467 (46.5%) 12/237 (5.1%)
    Rash 58/467 (12.4%) 14/237 (5.9%)
    Vascular disorders
    Hypertension 137/467 (29.3%) 13/237 (5.5%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Our agreements with investigators vary; constant is our right to review results communications prior to public release, and embargo communications for a period of ≤ 60 days from submittal for review. We do not prohibit investigators from publishing, but we may require previously undisclosed confidential information, other than study results, to be removed from publications, and single-center publications are postponed until after publication of the trial's primary multicenter publication.

    Results Point of Contact

    Name/Title Exelixis Medical Information
    Organization Exelixis, Inc.
    Phone 855-292-3935
    Email druginfo@exelixis.com
    Responsible Party:
    Exelixis
    ClinicalTrials.gov Identifier:
    NCT01908426
    Other Study ID Numbers:
    • XL184-309
    First Posted:
    Jul 25, 2013
    Last Update Posted:
    May 6, 2021
    Last Verified:
    Apr 1, 2021