COMET-2: Study of Cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer

• Sponsor: Exelixis (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01522443
• Collaborator: (none)
• Enrollment: 119
• Locations: 82
• Arms: 2
• Duration (Months): 34.4
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Bone metastases and associated pain are a major cause of morbidity and mortality in castration-resistant prostate cancer (CRPC). Most approved therapies have shown some ability to reduce soft tissue lesions but none meaningfully impacts bone metastases (as demonstrated by lack of resolution of lesions on bone scan with these agents) or the pain associated with these metastases.

This study will evaluate the effect of cabozantinib versus mitoxantrone plus prednisone on pain response and bone scan response in men with CRPC.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer; Castration Resistant Prostate Cancer; Pain; Prostatic Neoplasms	Drug: cabozantinib; Drug: mitoxantrone; Drug: prednisone	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 119 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 Trial of Cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Jan 13, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cabozantinib Subjects randomized to the cabozantinib arm will also receive placebo mitoxantrone injections (color-matched with methylene blue) and placebo prednisone capsules. There will be a maximum of 10 infusions for mitoxantrone placebo.	Drug: cabozantinib; Tablets taken orally once daily.
Active Comparator: Mitoxantrone/prednisone Subjects randomized to the mitoxantrone + prednisone arm will also receive placebo cabozantinib tablets. There will be a maximum of 10 infusions for mitoxantrone.	Drug: mitoxantrone; Given by IV once every 3 weeks.; Drug: prednisone; Taken twice a day orally by mouth. Commercially-obtained prednisone tablets will be over-encapsulated in order to blind identity.

Outcome Measures

Primary Outcome Measures

1. Pain Response at Week 6 Confirmed at Week 12, Week 12 Reported [Pain response was measured at Week 6 and Week 12 by self-reports of subjects]

   The pre-specified primary analysis of Pain Response at Week 6 confirmed at Week 12 was defined as ≥ 30% from baseline in the average daily worst pain intensity score during a 7-day reporting period, with neither a concomitant increase in average daily use of any opioid narcotic type, nor addition of any new opioid narcotic type, relative to baseline. Pain Progression at a given time point is defined as ≥ 30% increase compared with baseline in the average daily worst pain intensity score during a 7-day reporting period or either an increase in the average daily use of any type of opioid narcotic or addition of a new opioid narcotic type compared with baseline.

Secondary Outcome Measures

1. Bone Scan Response (BSR) [BSR was measured at the end of Week 12 as determined by the IRF]

   BSR is defined as >=30% in the bone scan lesion area (BSLA) compared with baseline. Bones scans were evaluated by an independent radiology facility (IRF) for response.

2. Overall Survival (OS) [OS was measured at the time of randomization until 78 deaths]

   OS was defined as the time from randomization to the date of death (due to any cause). Participants that had not died were censored at last known date alive. The analyses for OS occurred after 78/196 deaths (40% of the total required for the pre-specified primary analysis of OS). The data cut-off date was 06 October 2014. Median OS was calculated using Kaplan-Meier estimates.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histological or cytological diagnosis of castration resistant prostate cancer (serum testosterone less than 50 ng/dL).

• Evidence of bone metastasis related to prostate cancer on bone scans.

• Documented pain from bone metastases that requires opioid narcotic intervention.

• Adopted a narcotic regimen that consists of one sustained release opioid agent taken daily for chronic pain and one immediate release opioid agent for breakthrough pain.

• Received prior docetaxel and either abiraterone or MDV3100 treatment and has evidence of investigator assessed prostate cancer progression on each agent independently.

• Maintenance of LHRH agonist or antagonist unless treated with orchiectomy.

• Recovered from toxicities related to any prior treatments, unless the toxicities are clinically non significant or easily manageable.

• Adequate organ and marrow function.

• A left-ventricular ejection fraction (LVEF) of >/= 50% assessed by echocardiogram or MUGA (multigated acquisition scan).

• Capable of understanding and complying with the protocol requirements (including having the ability to access an interactive voice recognition system and self-report pain and narcotic use) and signed the informed consent form.

• Sexually active fertile patients and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 3 months after the last dose of study treatment.

Exclusion Criteria:

• Prior treatment with cabozantinib or mitoxantrone.

• Treatment with docetaxel, abiraterone, or MDV3100 in the last 2 weeks; or with any other type of cytotoxic or investigational anticancer agent in the last 2 weeks.

• Radiation therapy in the last 4 weeks (includes radiation targeting bone metastases), radionuclide treatment in the last 6 weeks, or radiation therapy to the thoracic cavity (unless radiation targets bone metastases) in the past 3 months.

• Treatment with serotonergic psychiatric medication(s) in the last 2 weeks (5 weeks for fluoxetine).

• Known brain metastases or uncontrolled epidural disease.

• Requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or FXa (coagulation factor X) inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (above low dose levels for cardioprotection per local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin are permitted.

• Uncontrolled, significant intercurrent illness including, but not limited to, cardiovascular disorders, gastrointestinal disorders, active infections, non-healing wounds, recent surgery.

• Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage in the last 3 months, or history of other significant bleeding in the past 6 months.

• Cavitating pulmonary lesion(s) or a lesion invading or encasing a major blood vessel.

• Corrected QT interval (QTc) > 500 ms in the last 4 weeks.

• Unable to swallow capsules or tablets or tolerate infusions.

• Previously-identified allergy or hypersensitivity to components of the study treatment formulations investigator or designee.

• History of another malignancy (except non-melanoma skin cancer, adequately treated stage I colon cancer, superficial transitional carcinoma of the bladder) in the past 2 years.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Scottsdale	Arizona	United States	85258
2		La Jolla	California	United States	92093
3		Los Angeles	California	United States	90024
4		Los Angeles	California	United States	90073
5		Marina Del Rey	California	United States	90292
6		San Diego	California	United States	92123
7		San Francisco	California	United States	94115
8		Santa Barbara	California	United States	93105
9		Stanford	California	United States	94305
10		Aurora	Colorado	United States	80012
11		Littleton	Colorado	United States	80122
12		Washington	District of Columbia	United States	20037
13		Boca Raton	Florida	United States	33486
14		Athens	Georgia	United States	30607
15		Chicago	Illinois	United States	60611
16		Indianapolis	Indiana	United States	46202
17		Iowa City	Iowa	United States	52242
18		Westwood	Kansas	United States	66025
19		Louisville	Kentucky	United States	40202
20		New Orleans	Louisiana	United States	70112
21		Baltimore	Maryland	United States	21231
22		Detroit	Michigan	United States	48201
23		Detroit	Michigan	United States	48202
24		Minneapolis	Minnesota	United States	55455
25		Tupelo	Mississippi	United States	38801
26		Saint Louis	Missouri	United States	63110
27		Omaha	Nebraska	United States	68198
28		Las Vegas	Nevada	United States	89109
29		New Brunswick	New Jersey	United States
30		Buffalo	New York	United States	14263
31		New York	New York	United States	10019
32		New York	New York	United States	10022
33		New York	New York	United States	10065
34		Chapel Hill	North Carolina	United States	27516
35		Durham	North Carolina	United States	27710
36		Raleigh	North Carolina	United States	27607
37		Cleveland	Ohio	United States	44195
38		Oklahoma City	Oklahoma	United States	73104
39		Pittsburgh	Pennsylvania	United States	15232
40		Watertown	South Dakota	United States	57201
41		Memphis	Tennessee	United States	38120
42		Nashville	Tennessee	United States	37203
43		Dallas	Texas	United States	75246
44		Round Rock	Texas	United States	78681
45		Salt Lake City	Utah	United States	84112
46		Norfolk	Virginia	United States	23502
47		Seattle	Washington	United States	98104
48		Madison	Wisconsin	United States	53705
49		Milwaukee	Wisconsin	United States	53226
50		Concord	New South Wales	Australia	2139
51		Darlinghurst	New South Wales	Australia	2010
52		Kogarah	New South Wales	Australia	2217
53		Port Macquarie	New South Wales	Australia	2444
54		Randwick	New South Wales	Australia	2031
55		Wahroonga	New South Wales	Australia	2076
56		Milton	Queensland	Australia	4064
57		South Brisbane	Queensland	Australia	4101
58		Woolloongabba	Queensland	Australia	4102
59		Box Hill	Victoria	Australia	3128
60		Wodonga	Victoria	Australia	3690
61		Subiaco	Western Australia	Australia
62		Kelowna	British Columbia	Canada	V1Y 5L3
63		Vancouver	British Columbia	Canada	V57 4E6
64		London	Ontario	Canada	N6A 4L6
65		Toronto	Ontario	Canada	M4N 3M5
66		Toronto	Ontario	Canada	M5G 2M9
67		Dublin		Ireland	24
68		Dublin		Ireland	7
69		Bath	England	United Kingdom	BA1 3NG
70		Cambridge	England	United Kingdom	CB2 0QQ
71		Leeds	England	United Kingdom	LS9 7TF
72		London	England	United Kingdom	NW1 2PG
73		London	England	United Kingdom	SE1 9RT
74		London	England	United Kingdom	W12 0HS
75		Manchester	England	United Kingdom	M20 4BX
76		Sutton	England	United Kingdom	SM2 5PT
77		Wirral	England	United Kingdom	CH63 4JY
78		Aberdeen	Scotland	United Kingdom	AB25 2ZN
79		Edinburgh	Scotland	United Kingdom	EH4 2XU
80		Glasgow	Scotland	United Kingdom	G12 0YN
81		Inverness	Scotland	United Kingdom	RO17
82		Belfast		United Kingdom

Sponsors and Collaborators

• Exelixis

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Exelixis
• ClinicalTrials.gov Identifier: NCT01522443
• Other Study ID Numbers: XL184-306
• First Posted: Jan 31, 2012
• Last Update Posted: May 23, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by Exelixis: prostate cancer; castration resistant prostate cancer; bone pain; CRPC
• Additional relevant MeSH terms: Prostatic Neoplasms; Prednisone; Mitoxantrone

Study Results

Participant Flow

Recruitment Details	First patient enrolled: 15 March 2012, Data cut off date: 06 October 2014. The study was terminated by the Sponsor after 119 subjects were enrolled which was less than the planned sample size of 246 subjects.

Arm/Group Title	Cabozantinib	Mitoxantrone/Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo mitoxantrone injections (color-matched with methylene blue) and placebo prednisone capsules. Cabozantinib (XL184) 60 mg tablets taken orally once daily and mitoxantrone-matched placebo infusion every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.	Subjects randomized to the mitoxantrone + prednisone arm will also receive placebo cabozantinib tablets. Mitoxantrone (12mg/m^2) given by IV once every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.
Period Title: Overall Study
STARTED	61	58
COMPLETED	8	3
NOT COMPLETED	53	55

Baseline Characteristics

Arm/Group Title	Cabozantinib	Mitoxantrone/Prednisone	Total
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo mitoxantrone injections (color-matched with methylene blue) and placebo prednisone capsules. Cabozantinib (XL184) 60 mg tablets taken orally once daily and mitoxantrone-matched placebo infusion every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.	Subjects randomized to the mitoxantrone + prednisone arm will also receive placebo cabozantinib tablets. Mitoxantrone (12mg/m^2) given by IV once every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.	Total of all reporting groups
Overall Participants	61	58	119
Age, Customized (participants) [Number]
<65 years	24 39.3%	26 44.8%	50 42%
65 to <75 years	30 49.2%	26 44.8%	56 47.1%
75 to <85 years	7 11.5%	6 10.3%	13 10.9%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	61 100%	58 100%	119 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.3%	0 0%	2 1.7%
Not Hispanic or Latino	57 93.4%	57 98.3%	114 95.8%
Unknown or Not Reported	2 3.3%	1 1.7%	3 2.5%
Race/Ethnicity, Customized (participants) [Number]
American Indian/Alaska Native	1 1.6%	0 0%	1 0.8%
Asian	1 1.6%	3 5.2%	4 3.4%
Black/African-American	8 13.1%	3 5.2%	11 9.2%
Multiple	1 1.6%	0 0%	1 0.8%
White	49 80.3%	51 87.9%	100 84%
Not Reported	0 0%	1 1.7%	1 0.8%
Other	1 1.6%	0 0%	1 0.8%
Geographic Region (participants) [Number]
North America	44 72.1%	36 62.1%	80 67.2%
Europe	8 13.1%	13 22.4%	21 17.6%
Asia	9 14.8%	9 15.5%	18 15.1%
ECOG Performance Status (per IVRS/IWRS) (participants) [Number]
0-1 (normal to symptoms, but ambulatory)	53 86.9%	52 89.7%	105 88.2%
≥2 (ambulatory to incapable of self-care/death)	8 13.1%	6 10.3%	14 11.8%
Randomization Stratification Factors (per IVRS/IWRS) (participants) [Number]
ECOG = 0-1 and prior cabazitaxel: yes	18 29.5%	18 31%	36 30.3%
ECOG = 0-1 and prior cabazitaxel: no	35 57.4%	34 58.6%	69 58%
ECOG ≥ 2 and prior cabazitaxel: yes	7 11.5%	6 10.3%	13 10.9%
ECOG ≥ 2 and prior cabazitaxel: no	1 1.6%	0 0%	1 0.8%
Time from initial diagnosis to randomization (years) [Median (Full Range) ]
Median (Full Range) [years]	4.7	5.3	5.0
Gleason score at diagnosis (Primary + Secondary) (participants) [Number]
<7	2 3.3%	4 6.9%	6 5%
7	17 27.9%	21 36.2%	38 31.9%
>7	40 65.6%	28 48.3%	68 57.1%
Unknown	2 3.3%	4 6.9%	6 5%
Missing	0 0%	1 1.7%	1 0.8%
Prior prostate surgery/procedure (participants) [Number]
Transurethral resection of the prostate (TURP)	8 13.1%	6 10.3%	14 11.8%
Radical prostatectomy - with	17 27.9%	13 22.4%	30 25.2%
Radical prostatectomy - without	3 4.9%	2 3.4%	5 4.2%
Cyrosurgery	0 0%	1 1.7%	1 0.8%
Bilateral orchiectomy	4 6.6%	2 3.4%	6 5%
Other	55 90.2%	52 89.7%	107 89.9%
Bone-scan lesion area (BSLA) (mm^2) [Median (Full Range) ]
Median (Full Range) [mm^2]	72865.0	72702.5	72865.0
Sites of prostate cancer metastasis (participants) [Number]
Bone	61 100%	58 100%	119 100%
Lymph node	29 47.5%	18 31%	47 39.5%
Visceral (soft tissue; liver)	8 13.1%	8 13.8%	16 13.4%
Visceral (soft tissue; lung)	2 3.3%	5 8.6%	7 5.9%
Other soft tissue	7 11.5%	3 5.2%	10 8.4%
Pain score (BPI Item 3) during Run-In Stage (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	6.00	6.14	6.00
Pain score (BPI Item 3) during Run-In Stage (participants) [Number]
4-5	10 16.4%	15 25.9%	25 21%
>5-6	22 36.1%	13 22.4%	35 29.4%
>6-7	18 29.5%	15 25.9%	33 27.7%
>7-8	11 18%	15 25.9%	26 21.8%
Number of prior anticancer agents (Count of Participants)
2	0 0%	3 5.2%	3 2.5%
3	6 9.8%	4 6.9%	10 8.4%
4	20 32.8%	14 24.1%	34 28.6%
≥5	35 57.4%	37 63.8%	72 60.5%
Prior cabazitaxel (per IVRS/IWRS) (Count of Participants)
Yes	25 41%	24 41.4%	49 41.2%
No	36 59%	34 58.6%	70 58.8%

Outcome Measures

1. Primary Outcome

Title	Pain Response at Week 6 Confirmed at Week 12, Week 12 Reported
Description	The pre-specified primary analysis of Pain Response at Week 6 confirmed at Week 12 was defined as ≥ 30% from baseline in the average daily worst pain intensity score during a 7-day reporting period, with neither a concomitant increase in average daily use of any opioid narcotic type, nor addition of any new opioid narcotic type, relative to baseline. Pain Progression at a given time point is defined as ≥ 30% increase compared with baseline in the average daily worst pain intensity score during a 7-day reporting period or either an increase in the average daily use of any type of opioid narcotic or addition of a new opioid narcotic type compared with baseline.
Time Frame	Pain response was measured at Week 6 and Week 12 by self-reports of subjects

Outcome Measure Data

Analysis Population Description

The primary analysis of pain response was based on the Intent to Treat (ITT) population of 119 participants (61 cabozantinib, 58 mitoxantrone plus prednisone).

Arm/Group Title	Cabozantinib	Mitoxantrone/Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo mitoxantrone injections (color-matched with methylene blue) and placebo prednisone capsules. Cabozantinib (XL184) 60 mg tablets taken orally once daily and mitoxantrone-matched placebo infusion every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.	Subjects randomized to the mitoxantrone + prednisone arm will also receive placebo cabozantinib tablets. Mitoxantrone (12mg/m^2) given by IV once every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.
Measure Participants	61	58
Number (95% Confidence Interval) [percentage of responders]	15	17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cabozantinib, Mitoxantrone/Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.773
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The Cochran-Mantel-Haenszel (CMH) was stratified by the Eastern Cooperative Oncology Group performance status and prior cabazitaxel use.

2. Secondary Outcome

Title	Bone Scan Response (BSR)
Description	BSR is defined as >=30% in the bone scan lesion area (BSLA) compared with baseline. Bones scans were evaluated by an independent radiology facility (IRF) for response.
Time Frame	BSR was measured at the end of Week 12 as determined by the IRF

Outcome Measure Data

Analysis Population Description

Analysis was conducted on the randomized ITT population (61 cabozantinib, 58 mitoxantrone plus prednisone) for BSR at Week 12.

Arm/Group Title	Cabozantinib	Mitoxantrone/Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo mitoxantrone injections (color-matched with methylene blue) and placebo prednisone capsules. Cabozantinib (XL184) 60 mg tablets taken orally once daily and mitoxantrone-matched placebo infusion every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.	Subjects randomized to the mitoxantrone + prednisone arm will also receive placebo cabozantinib tablets. Mitoxantrone (12mg/m^2) given by IV once every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.
Measure Participants	61	58
Number (95% Confidence Interval) [percentage of responders]	31	5.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cabozantinib, Mitoxantrone/Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The Cochran-Mantel-Haenszel (CMH) Test was stratified by baslined Eastern Cooperative Oncology Group performance status and prior cabazitaxel use.

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to the date of death (due to any cause). Participants that had not died were censored at last known date alive. The analyses for OS occurred after 78/196 deaths (40% of the total required for the pre-specified primary analysis of OS). The data cut-off date was 06 October 2014. Median OS was calculated using Kaplan-Meier estimates.
Time Frame	OS was measured at the time of randomization until 78 deaths

Outcome Measure Data

Analysis Population Description

The Intent to Treat (ITT) population was used and included 119 randomized subjects (61 cabozantinib, 58 mitoxantrone plus prednisone) at the time of primary analysis (data cut off date: 06 October 2014).

Arm/Group Title	Cabozantinib	Mitoxantrone/Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo mitoxantrone injections (color-matched with methylene blue) and placebo prednisone capsules. Cabozantinib (XL184) 60 mg tablets taken orally once daily and mitoxantrone-matched placebo infusion every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.	Subjects randomized to the mitoxantrone + prednisone arm will also receive placebo cabozantinib tablets. Mitoxantrone (12mg/m^2) given by IV once every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.
Measure Participants	61	58
Median (95% Confidence Interval) [months]	9.0	7.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cabozantinib, Mitoxantrone/Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.121
	Comments
	Method	Log Rank
	Comments	The Log-Rank Test was stratified by baseline Eastern Cooperative Oncology Group performance status and prior cabazitaxel use.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.44 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 95 weeks
Adverse Event Reporting Description	The safety data includes subjects who were randomized and treated with at least one dose of the study treatment. Of 119 patients, 61 were randomized to receive cabozantinib and 58 mitoxantrone plus prednisone. The Safety population included 117 subjects (60 cabozantinib, 57 mitoxantrone plus prednisone).
Arm/Group Title	Cabozantinib		Mitoxantrone/Prednisone
Arm/Group Description	Subjects randomized to the cabozantinib arm will also receive placebo mitoxantrone injections (color-matched with methylene blue) and placebo prednisone capsules. Cabozantinib (XL184) 60 mg tablets taken orally once daily and mitoxantrone-matched placebo infusion every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.		Subjects randomized to the mitoxantrone + prednisone arm will also receive placebo cabozantinib tablets. Mitoxantrone (12mg/m^2) given by IV once every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily.
All Cause Mortality
	Cabozantinib		Mitoxantrone/Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cabozantinib		Mitoxantrone/Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/60 (26.7%)		15/57 (26.3%)
Blood and lymphatic system disorders
Anaemia	1/60 (1.7%)		0/57 (0%)
Febrile neutropenia	0/60 (0%)		4/57 (7%)
Neutropenia	0/60 (0%)		3/57 (5.3%)
Gastrointestinal disorders
Abdominal pain	0/60 (0%)		2/57 (3.5%)
Diarrhoea	1/60 (1.7%)		1/57 (1.8%)
Large intestine perforation	1/60 (1.7%)		0/57 (0%)
Nausea	2/60 (3.3%)		1/57 (1.8%)
Vomiting	1/60 (1.7%)		1/57 (1.8%)
General disorders
Asthenia	1/60 (1.7%)		1/57 (1.8%)
Malaise	1/60 (1.7%)		0/57 (0%)
Pyrexia	1/60 (1.7%)		1/57 (1.8%)
Infections and infestations
Cellulitis	0/60 (0%)		1/57 (1.8%)
Gastroenteritis viral	1/60 (1.7%)		0/57 (0%)
Neutropenic sepsis	0/60 (0%)		1/57 (1.8%)
Pneumonia	2/60 (3.3%)		1/57 (1.8%)
Investigations
Hepatic enzyme increased	1/60 (1.7%)		0/57 (0%)
Liver function test abnormal	1/60 (1.7%)		0/57 (0%)
Neutrophil count decreased	0/60 (0%)		1/57 (1.8%)
Platelet count decreased	1/60 (1.7%)		0/57 (0%)
Metabolism and nutrition disorders
Dehydration	0/60 (0%)		1/57 (1.8%)
Failure to thrive	0/60 (0%)		1/57 (1.8%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/60 (1.7%)		0/57 (0%)
Nervous system disorders
Depressed level of consciousness	1/60 (1.7%)		0/57 (0%)
Hypoaesthesia	1/60 (1.7%)		0/57 (0%)
Syncope	1/60 (1.7%)		0/57 (0%)
Psychiatric disorders
Confusional state	1/60 (1.7%)		0/57 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	2/60 (3.3%)		2/57 (3.5%)
Vascular disorders
Deep vein thrombosis	1/60 (1.7%)		0/57 (0%)
Hypertension	1/60 (1.7%)		0/57 (0%)
Other (Not Including Serious) Adverse Events
	Cabozantinib		Mitoxantrone/Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/60 (100%)		57/57 (100%)
Endocrine disorders
Hypothyroidism	6/60 (10%)		1/57 (1.8%)
Gastrointestinal disorders
Nausea	38/60 (63.3%)		24/57 (42.1%)
Diarrhoea	27/60 (45%)		17/57 (29.8%)
Constipation	24/60 (40%)		19/57 (33.3%)
Vomiting	23/60 (38.3%)		19/57 (33.3%)
Dyspepsia	9/60 (15%)		4/57 (7%)
Oral pain	7/60 (11.7%)		1/57 (1.8%)
Glossodynia	4/60 (6.7%)		0/57 (0%)
Retching	3/60 (5%)		0/57 (0%)
General disorders
Fatigue	34/60 (56.7%)		27/57 (47.4%)
Asthenia	14/60 (23.3%)		4/57 (7%)
Sinusitis	3/60 (5%)		0/57 (0%)
Investigations
Weight decreased	25/60 (41.7%)		8/57 (14%)
Aspartate aminotransferase increased	12/60 (20%)		2/57 (3.5%)
Alanine aminotransferase increased	10/60 (16.7%)		0/57 (0%)
Blood alkaline phosphatase increased	8/60 (13.3%)		2/57 (3.5%)
Neutrophil count decreased	6/60 (10%)		2/57 (3.5%)
Lymphocyte count decreased	4/60 (6.7%)		0/57 (0%)
Blood bilirubin increased	3/60 (5%)		0/57 (0%)
Metabolism and nutrition disorders
Decreased appetite	28/60 (46.7%)		23/57 (40.4%)
Hypokalaemia	13/60 (21.7%)		4/57 (7%)
Hypomagnesaemia	8/60 (13.3%)		1/57 (1.8%)
Hyponatraemia	6/60 (10%)		2/57 (3.5%)
Musculoskeletal stiffness	3/60 (5%)		0/57 (0%)
Psychiatric disorders
Depression	14/60 (23.3%)		8/57 (14%)
Insomnia	9/60 (15%)		5/57 (8.8%)
Depressed mood	3/60 (5%)		0/57 (0%)
Renal and urinary disorders
Proteinuria	4/60 (6.7%)		0/57 (0%)
Urinary retention	3/60 (5%)		0/57 (0%)
Respiratory, thoracic and mediastinal disorders
Dysphonia	10/60 (16.7%)		1/57 (1.8%)
Oropharyngeal pain	8/60 (13.3%)		1/57 (1.8%)
Dyspnoea exertional	3/60 (5%)		0/57 (0%)
Skin and subcutaneous tissue disorders
Dry skin	9/60 (15%)		3/57 (5.3%)
Palmar-plantar erythrodysaesthesia syndrome	9/60 (15%)		0/57 (0%)
Skin ulcer	6/60 (10%)		0/57 (0%)
Blister	3/60 (5%)		0/57 (0%)
Erythema	3/60 (5%)		0/57 (0%)
Petechiae	3/60 (5%)		0/57 (0%)
Skin discolouration	3/60 (5%)		0/57 (0%)
Vascular disorders
Hypertension	18/60 (30%)		0/57 (0%)
Pallor	3/60 (5%)		0/57 (0%)

Limitations/Caveats

Enrollment was stopped before planned study population size of 246 was reached (only 119 enrolled).

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.