Cabozantinib-S-Malate Compared With Temozolomide or Dacarbazine in Treating Patients With Metastatic Melanoma of the Eye That Cannot Be Removed by Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01835145
• Collaborator: Exelisis (Other)
• Enrollment: 47
• Locations: 228
• Arms: 2
• Actual Duration (Months): 75
• Patients Per Site: 0.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well cabozantinib-s-malate works compared with temozolomide or dacarbazine in treating patients with melanoma of the eye (ocular melanoma) that has spread to other parts of the body and cannot be removed by surgery. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide and dacarbazine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether cabozantinib-s-malate works better than temozolomide or dacarbazine in treating patients with melanoma of the eye.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Uveal Melanoma; Stage III Uveal Melanoma AJCC v7; Stage IIIA Uveal Melanoma AJCC v7; Stage IIIB Uveal Melanoma AJCC v7; Stage IIIC Uveal Melanoma AJCC v7; Stage IV Uveal Melanoma AJCC v7	Drug: Cabozantinib S-malate; Drug: Dacarbazine; Other: Laboratory Biomarker Analysis; Drug: Temozolomide	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Compare the progression-free survival rate at 4 months (PFS4) of patients with ocular melanoma treated with cabozantinib-s-malate (cabozantinib) or temozolomide (or dacarbazine).

SECONDARY OBJECTIVES:

1. Estimate the distribution of progression-free survival (PFS) times. II. Estimate the distribution of overall survival (OS) times. III. Estimate the confirmed response rate as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

2. Assess the safety of these agents by examining the toxicity profile. V. Correlate the response of MET molecular status.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive temozolomide PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive dacarbazine intravenously (IV) over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Study Comparing the MET Inhibitor Cabozantinib to Temozolomide/Dacarbazine in Ocular Melanoma
• Actual Study Start Date: Jul 31, 2013
• Actual Primary Completion Date: Oct 21, 2016
• Actual Study Completion Date: Nov 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (cabozantinib-s-malate) Patients receive cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Cabozantinib S-malate; Given PO; Other Names: BMS-907351 Cabometyx Cometriq XL-184 XL184 ; Other: Laboratory Biomarker Analysis; Correlative studies
Experimental: Arm II (temozolomide or dacarbazine) Patients receive temozolomide PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: Dacarbazine; Given IV; Other Names: 4-(Dimethyltriazeno)imidazole-5-carboxamide 5-(Dimethyltriazeno)imidazole-4-carboxamide Asercit Biocarbazine Dacarbazina Dacarbazina Almirall Dacarbazine - DTIC Dacatic Dakarbazin Deticene Detimedac DIC Dimethyl (triazeno) imidazolecarboxamide Dimethyl Triazeno Imidazol Carboxamide Dimethyl Triazeno Imidazole Carboxamide dimethyl-triazeno-imidazole carboxamide Dimethyl-triazeno-imidazole-carboximide DTIC DTIC-Dome Fauldetic Imidazole Carboxamide Imidazole Carboxamide Dimethyltriazeno WR-139007 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Temozolomide; Given PO; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac TMZ

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients Without a Progression Free Survival Event at 4 Months (PFS4) [At 4 months]

   A patient will be declared a PFS4 success if they are on study and progression free for at least 4 months. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. The success for each arm will be calculated independently as the number of successes divided by the total number of evaluable patients. A one-sided chi-squared test for a difference in PFS4 proportions will be used to test for a difference between arms.

Secondary Outcome Measures

1. Confirmed Response Rate as Determined by the RECIST Criteria (Version 1.1) [Up to 2 years]

   The confirmed response rates will be estimated by dividing the number of confirmed responders by the number of evaluable patients. 95% confidence intervals will be calculated.

2. Percentage of Patients Who Experienced Grade 3+ Adverse Events Regardless of Attribution [Up to 2 years]

   percentage of patients who experienced grade 3+ adverse events regardless of attribution, graded according to the National Cancer Institute CTCAE version 4.0

3. Overall Survival (OS) [Number of days from registration until death, assessed up to 2 years]

   The distribution of OS time will be estimated using the method of Kaplan Meier.

4. PFS [Number of days from registration until disease progression (or death), assessed up to 2 years]

   The distribution of PFS time will be estimated using the method of Kaplan Meier and is defined as the number of days from registration until disease progression (or death). Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Other Outcome Measures

1. Pre-treatment GNAQ/GNA11 and Potentially Other Mutations in Tissue [Baseline]

   The proportions of patients within these groups pre-treatment will be presented with 90% exact binomial confidence intervals. These findings will be correlated with overall survival using a Student's T-test.

2. Pre-treatment Immune Gene Expression in Tissue Defined as T Cell-inflamed, Intermediate and Non-T Cell-inflamed [Baseline]

   The proportions of patients within these groups pre-treatment will be presented with 90% exact binomial confidence intervals. These findings will be correlated with overall survival using a Student's T-test.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed uveal melanoma that is metastatic or unresectable; if histologic or cytologic confirmation of the primary is not available, confirmation of the primary diagnosis of uveal melanoma by the treating investigator can be clinically obtained, as per standard practice for uveal melanoma; pathologic confirmation of diagnosis will be performed at the participating site

• Measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan or magnetic resonance imaging (MRI)

• Prior systemic therapies allowed, except for those treatments directed toward, or with activity against, c-Met or vascular endothelial growth factor/receptor (VEGF/R), and the chemotherapy agents temozolomide and dacarbazine; prior treatment must have been no earlier than 3 weeks prior to starting treatment with cabozantinib with exceptions noted below and the following: at least 4 weeks since prior hepatic infusion or at least 2 weeks since radiation therapy

• No cytotoxic chemotherapy including investigational cytotoxic chemotherapy or biologic agents (e.g., cytokines or antibodies) within the last 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment; at least 6 weeks must have elapsed if the last regimen included an anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody; patients must have experienced disease progression on their prior therapy in the opinion of the treating investigator

• No prior radiation therapy within the last 4 weeks, except as below

• To the thoracic cavity, abdomen, or pelvis within 12 weeks before the first dose of study treatment, or has ongoing complications, or is without complete recovery to < grade 1 toxicity

• To bone or brain metastasis within 14 days before the first dose of study treatment

• To any other site(s) within 28 days before the first dose of study treatment

• Prior radiation treatment may have included no more than 3000 centigray (cGy) to fields including substantial bone marrow

• No prior radionuclide treatment within 6 weeks of the first dose of study treatment

• No prior treatment with a small molecule kinase inhibitor or a hormonal therapy within 14 days or 5 half-lives (whichever is longer)

• No concomitant anti-cancer therapy unless specified above

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• A corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before randomization; Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =< 500 ms, the patient meets eligibility in this regard

• Common Terminology Criteria for Adverse Events (CTCAE) recovered to baseline or CTCAE =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)

• No active brain metastases or epidural disease; patients with brain metastases previously treated with whole brain radiation or radiosurgery or patients with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 12 weeks before starting study treatment; baseline brain imaging with contrast-enhanced CT or MRI scans for patients with known brain metastases is required to confirm eligibility

• No clinically significant gastrointestinal bleeding within 24 weeks before the first dose of study treatment

• No hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 12 weeks before the first dose of study treatment

• No signs indicative of pulmonary hemorrhage within 12 weeks before the first dose of study treatment

• No prior radiographic evidence of cavitating pulmonary lesion(s)

• No tumor in contact with, invading or encasing any major blood vessels

• No evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of treatment

• The patient may not have uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

• Cardiovascular disorders including:

• Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening

• Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mmHg systolic, or > 90 mmHg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment

• Any history of congenital long QT syndrome

• Any of the following within 24 weeks before the first dose of study treatment:

• Unstable angina pectoris

• Clinically-significant cardiac arrhythmias

• Stroke (including transient ischemic attack [TIA], or other ischemic event)

• Myocardial infarction

• Thromboembolic event requiring therapeutic anticoagulation (Note: patients with a venous filter [e.g. vena cava filter] are not eligible for this study)

• Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

• Any of the following within 28 days before the first dose of study treatment

• Intra-abdominal tumor/metastases invading GI mucosa

• Active peptic ulcer disease

• Inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis

• Malabsorption syndrome

• Any of the following within 24 weeks before the first dose of study treatment:

• Abdominal fistula

• Gastrointestinal perforation

• Intra-abdominal abscess; Note: complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 24 weeks before the first dose of study treatment

• Bowel obstruction or gastric outlet obstruction

• Other clinically significant disorders such as:

• Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment

• History of organ transplant

• Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment

• History of major surgery as follows:

• Major surgery in past 8 weeks of the first dose of cabozantinib if there were no wound healing complications or within 24 weeks of the first dose of cabozantinib if there were wound complications

• Minor surgery within 4 weeks of the first dose of cabozantinib if there were no wound healing complications or within 12 weeks of the first dose of cabozantinib if there were wound complications

• In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery

• Active infection requiring systemic treatment within 28 days before the first dose of study treatment

• No concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted; please note that drugs that strongly induce or inhibit cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) or are associated with a risk of Torsades are not allowed; chronic concomitant treatment of CYP3A4 inducers is not allowed (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort); as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; the following drugs are strong inhibitors of CYP3A4 and are not allowed during the treatment with cabozantinib:

• Boceprevir

• Indinavir

• Nelfinavir

• Lopinavir/ritonavir

• Saquinavir

• Telaprevir

• Ritonavir

• Clarithromycin

• Conivaptan

• Itraconazole

• Ketoconazole

• Mibefradil

• Nefazodone

• Posaconazole

• Voriconazole

• Telithromycin

• Drugs with possible or conditional risk of torsades should be used with caution knowing that cabozantinib could prolong the QT interval

• Patients who are pregnant or nursing are not eligible; women of child bearing potential must have a negative serum or urine pregnancy test within 16 days prior to registration; women of child-bearing potential include:

• Any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months)

• Women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35m IU/mL

• Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy)

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, temozolomide and dacarbazine

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 × upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5.0 × institutional upper limit of normal (for patients with metastases); AST (SGOT)/ALT (SGPT) =< 2.5 × institutional upper limit of normal (for patients without metastases)

• Serum creatinine =< 1.5 × ULN, OR calculated creatinine clearance >= 30 mL/minute (modified Cockcroft and Gault formula)

• Hemoglobin >= 9 g/dL

• Serum albumin >= 2.8 g/dL

• Urine protein/creatinine ratio (UPCR) =< 1; if urine/protein creatinine (UPC) >= 1, then a 24-hour urine protein must be assessed; eligible patients must have a 24-hour urine protein value < 1 g/L

• Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH however free T4 and free thyroxine index (FTI) are normal and patient is clinically euthyroid, patient is eligible

• Prothrombin time (PT)/international normalized ratio (INR) must be =< 1.2 x the laboratory ULN

• No clinical or radiographic evidence of pancreatitis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	Anchorage Radiation Therapy Center	Anchorage	Alaska	United States	99504
3	Alaska Breast Care and Surgery LLC	Anchorage	Alaska	United States	99508
4	Alaska Oncology and Hematology LLC	Anchorage	Alaska	United States	99508
5	Alaska Women's Cancer Care	Anchorage	Alaska	United States	99508
6	Anchorage Oncology Centre	Anchorage	Alaska	United States	99508
7	Katmai Oncology Group	Anchorage	Alaska	United States	99508
8	Providence Alaska Medical Center	Anchorage	Alaska	United States	99508
9	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California	United States	91505
10	Beebe Medical Center	Lewes	Delaware	United States	19958
11	Christiana Gynecologic Oncology LLC	Newark	Delaware	United States	19713
12	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware	United States	19713
13	Helen F Graham Cancer Center	Newark	Delaware	United States	19713
14	Medical Oncology Hematology Consultants PA	Newark	Delaware	United States	19713
15	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
16	Beebe Health Campus	Rehoboth Beach	Delaware	United States	19971
17	TidalHealth Nanticoke / Allen Cancer Center	Seaford	Delaware	United States	19973
18	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware	United States	19801
19	Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
20	Jupiter Medical Center	Jupiter	Florida	United States	33458
21	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
22	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
23	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho	United States	83814
24	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho	United States	83619
25	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho	United States	83642
26	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho	United States	83686
27	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho	United States	83854
28	Kootenai Cancer Clinic	Sandpoint	Idaho	United States	83864
29	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho	United States	83301
30	Northwestern University	Chicago	Illinois	United States	60611
31	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
32	Hematology Oncology Associates of Illinois-Highland Park	Highland Park	Illinois	United States	60035
33	Presence Saint Mary's Hospital	Kankakee	Illinois	United States	60901
34	AMG Libertyville - Oncology	Libertyville	Illinois	United States	60048
35	Loyola University Medical Center	Maywood	Illinois	United States	60153
36	Garneau, Stewart C MD (UIA Investigator)	Moline	Illinois	United States	61265
37	Porubcin, Michael MD (UIA Investigator)	Moline	Illinois	United States	61265
38	Spector, David MD (UIA Investigator)	Moline	Illinois	United States	61265
39	Trinity Medical Center	Moline	Illinois	United States	61265
40	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
41	Illinois Cancer Specialists-Niles	Niles	Illinois	United States	60714
42	Hematology Oncology Associates of Illinois - Skokie	Skokie	Illinois	United States	60076
43	Mary Greeley Medical Center	Ames	Iowa	United States	50010
44	McFarland Clinic PC - Ames	Ames	Iowa	United States	50010
45	Constantinou, Costas L MD (UIA Investigator)	Bettendorf	Iowa	United States	52722
46	McFarland Clinic PC-Boone	Boone	Iowa	United States	50036
47	McFarland Clinic PC-Trinity Cancer Center	Fort Dodge	Iowa	United States	50501
48	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
49	McFarland Clinic PC-Jefferson	Jefferson	Iowa	United States	50129
50	McFarland Clinic PC-Marshalltown	Marshalltown	Iowa	United States	50158
51	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
52	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51102
53	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
54	Menorah Medical Center	Overland Park	Kansas	United States	66209
55	Saint Luke's South Hospital	Overland Park	Kansas	United States	66213
56	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas	United States	66208
57	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
58	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
59	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
60	Bronson Battle Creek	Battle Creek	Michigan	United States	49017
61	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49829
62	Cancer Research Consortium of West Michigan NCORP	Grand Rapids	Michigan	United States	49503
63	Mercy Health Saint Mary's	Grand Rapids	Michigan	United States	49503
64	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
65	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
66	Mercy Health Mercy Campus	Muskegon	Michigan	United States	49444
67	Lakeland Hospital Niles	Niles	Michigan	United States	49120
68	Spectrum Health Reed City Hospital	Reed City	Michigan	United States	49677
69	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan	United States	49085
70	Marie Yeager Cancer Center	Saint Joseph	Michigan	United States	49085
71	Munson Medical Center	Traverse City	Michigan	United States	49684
72	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
73	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
74	Essentia Health Cancer Center	Duluth	Minnesota	United States	55805
75	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota	United States	55805
76	Miller-Dwan Hospital	Duluth	Minnesota	United States	55805
77	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
78	Unity Hospital	Fridley	Minnesota	United States	55432
79	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
80	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
81	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
82	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
83	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
84	Health Partners Inc	Minneapolis	Minnesota	United States	55454
85	New Ulm Medical Center	New Ulm	Minnesota	United States	56073
86	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
87	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
88	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
89	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
90	Regions Hospital	Saint Paul	Minnesota	United States	55101
91	United Hospital	Saint Paul	Minnesota	United States	55102
92	Saint Francis Regional Medical Center	Shakopee	Minnesota	United States	55379
93	Lakeview Hospital	Stillwater	Minnesota	United States	55082
94	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
95	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
96	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
97	Cox Cancer Center Branson	Branson	Missouri	United States	65616
98	Centerpoint Medical Center LLC	Independence	Missouri	United States	64057
99	Mercy Hospital Joplin	Joplin	Missouri	United States	64804
100	Saint Luke's Hospital of Kansas City	Kansas City	Missouri	United States	64111
101	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri	United States	64118
102	Research Medical Center	Kansas City	Missouri	United States	64132
103	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri	United States	64086
104	Liberty Radiation Oncology Center	Liberty	Missouri	United States	64068
105	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri	United States	65401
106	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
107	Saint Joseph Oncology Inc	Saint Joseph	Missouri	United States	64507
108	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
109	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
110	Cancer Research for the Ozarks NCORP	Springfield	Missouri	United States	65804
111	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
112	CoxHealth South Hospital	Springfield	Missouri	United States	65807
113	Community Hospital of Anaconda	Anaconda	Montana	United States	59711
114	Billings Clinic Cancer Center	Billings	Montana	United States	59101
115	Saint Vincent Healthcare	Billings	Montana	United States	59101
116	Montana Cancer Consortium NCORP	Billings	Montana	United States	59102
117	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
118	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana	United States	59701
119	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
120	Great Falls Clinic	Great Falls	Montana	United States	59405
121	Saint Peter's Community Hospital	Helena	Montana	United States	59601
122	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
123	Saint Patrick Hospital - Community Hospital	Missoula	Montana	United States	59802
124	Community Medical Hospital	Missoula	Montana	United States	59804
125	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
126	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
127	Cancer and Blood Specialists-Henderson	Henderson	Nevada	United States	89052
128	Comprehensive Cancer Centers of Nevada - Henderson	Henderson	Nevada	United States	89052
129	Las Vegas Cancer Center-Henderson	Henderson	Nevada	United States	89052
130	Comprehensive Cancer Centers of Nevada-Southeast Henderson	Henderson	Nevada	United States	89074
131	GenesisCare USA - Henderson	Henderson	Nevada	United States	89074
132	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
133	Cancer and Blood Specialists-Shadow	Las Vegas	Nevada	United States	89106
134	Radiation Oncology Centers of Nevada Central	Las Vegas	Nevada	United States	89106
135	GenesisCare USA - Las Vegas	Las Vegas	Nevada	United States	89109
136	HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway	Las Vegas	Nevada	United States	89109
137	HealthCare Partners Medical Group Oncology/Hematology-San Martin	Las Vegas	Nevada	United States	89113
138	Radiation Oncology Centers of Nevada Southeast	Las Vegas	Nevada	United States	89119
139	Cancer Therapy and Integrative Medicine	Las Vegas	Nevada	United States	89121
140	Cancer and Blood Specialists-Tenaya	Las Vegas	Nevada	United States	89128
141	Comprehensive Cancer Centers of Nevada - Northwest	Las Vegas	Nevada	United States	89128
142	GenesisCare USA - Vegas Tenaya	Las Vegas	Nevada	United States	89128
143	HealthCare Partners Medical Group Oncology/Hematology-Tenaya	Las Vegas	Nevada	United States	89128
144	Comprehensive Cancer Centers of Nevada-Summerlin	Las Vegas	Nevada	United States	89144
145	Las Vegas Cancer Center-Medical Center	Las Vegas	Nevada	United States	89148-2405
146	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89148
147	GenesisCare USA - Fort Apache	Las Vegas	Nevada	United States	89148
148	OptumCare Cancer Care at Fort Apache	Las Vegas	Nevada	United States	89148
149	HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills	Las Vegas	Nevada	United States	89149
150	Comprehensive Cancer Centers of Nevada - Central Valley	Las Vegas	Nevada	United States	89169
151	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada	United States	89169
152	Morristown Medical Center	Morristown	New Jersey	United States	07960
153	Overlook Hospital	Summit	New Jersey	United States	07902
154	Duke University Medical Center	Durham	North Carolina	United States	27710
155	Vidant Oncology-Kinston	Kinston	North Carolina	United States	28501
156	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
157	The Christ Hospital	Cincinnati	Ohio	United States	45219
158	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
159	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
160	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma	United States	74146
161	Saint Charles Health System	Bend	Oregon	United States	97701
162	Clackamas Radiation Oncology Center	Clackamas	Oregon	United States	97015
163	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon	United States	97015
164	Bay Area Hospital	Coos Bay	Oregon	United States	97420
165	Providence Milwaukie Hospital	Milwaukie	Oregon	United States	97222
166	Providence Newberg Medical Center	Newberg	Oregon	United States	97132
167	Providence Willamette Falls Medical Center	Oregon City	Oregon	United States	97045
168	Providence Portland Medical Center	Portland	Oregon	United States	97213
169	Providence Saint Vincent Medical Center	Portland	Oregon	United States	97225
170	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
171	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina	United States	29316
172	Prisma Health Cancer Institute - Easley	Easley	South Carolina	United States	29640
173	Greenville Health System Cancer Institute-Andrews	Greenville	South Carolina	United States	29601
174	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina	United States	29605
175	Prisma Health Cancer Institute - Faris	Greenville	South Carolina	United States	29605
176	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina	United States	29605
177	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina	United States	29615
178	Prisma Health Cancer Institute - Greer	Greer	South Carolina	United States	29650
179	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina	United States	29672
180	Bristol Regional Medical Center	Bristol	Tennessee	United States	37620
181	Wellmont Medical Associates Oncology and Hematology-Johnson City	Johnson City	Tennessee	United States	37604
182	Ballad Health Cancer Care - Kingsport	Kingsport	Tennessee	United States	37660
183	Wellmont Holston Valley Hospital and Medical Center	Kingsport	Tennessee	United States	37660
184	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
185	Southwest VA Regional Cancer Center	Norton	Virginia	United States	24273
186	Providence Regional Cancer System-Aberdeen	Aberdeen	Washington	United States	98520
187	Cancer Care Center at Island Hospital	Anacortes	Washington	United States	98221
188	Swedish Cancer Institute-Eastside Oncology Hematology	Bellevue	Washington	United States	98005
189	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington	United States	98225
190	Providence Regional Cancer System-Centralia	Centralia	Washington	United States	98531
191	Swedish Cancer Institute-Edmonds	Edmonds	Washington	United States	98026
192	Providence Regional Cancer Partnership	Everett	Washington	United States	98201
193	Swedish Cancer Institute-Issaquah	Issaquah	Washington	United States	98029
194	Providence Regional Cancer System-Lacey	Lacey	Washington	United States	98503
195	PeaceHealth Saint John Medical Center	Longview	Washington	United States	98632
196	Minor and James Medical PLLC	Seattle	Washington	United States	98104
197	Pacific Gynecology Specialists	Seattle	Washington	United States	98104
198	Swedish Medical Center-Ballard Campus	Seattle	Washington	United States	98107
199	Kaiser Permanente Washington	Seattle	Washington	United States	98112
200	Swedish Medical Center-First Hill	Seattle	Washington	United States	98122-4307
201	Providence Regional Cancer System-Shelton	Shelton	Washington	United States	98584
202	MultiCare Deaconess Cancer and Blood Specialty Center - Valley	Spokane Valley	Washington	United States	99216
203	MultiCare Deaconess Cancer and Blood Specialty Center - Downtown	Spokane	Washington	United States	99204
204	PeaceHealth Southwest Medical Center	Vancouver	Washington	United States	98664
205	Compass Oncology Vancouver	Vancouver	Washington	United States	98684
206	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington	United States	99362
207	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington	United States	98902
208	Providence Regional Cancer System-Yelm	Yelm	Washington	United States	98597
209	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
210	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
211	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
212	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin	United States	54303
213	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
214	Holy Family Memorial Hospital	Manitowoc	Wisconsin	United States	54221
215	Bay Area Medical Center	Marinette	Wisconsin	United States	54143
216	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
217	Cancer Center of Western Wisconsin	New Richmond	Wisconsin	United States	54017
218	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin	United States	54154
219	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin	United States	53081
220	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
221	Rocky Mountain Oncology	Casper	Wyoming	United States	82609
222	Big Horn Basin Cancer Center	Cody	Wyoming	United States	82414
223	Billings Clinic-Cody	Cody	Wyoming	United States	82414
224	Welch Cancer Center	Sheridan	Wyoming	United States	82801
225	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
226	University Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
227	CHUM - Hopital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
228	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4

Sponsors and Collaborators

• National Cancer Institute (NCI)
• Exelisis

Investigators

• Principal Investigator: Jason J Luke, Alliance for Clinical Trials in Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01835145
• Other Study ID Numbers: NCI-2013-00821; NCI-2013-00821; CALGB-A091201; A091201; A091201; A091201; U10CA180821; U10CA031946
• First Posted: Apr 18, 2013
• Last Update Posted: Aug 4, 2022
• Last Verified: Aug 1, 2022

• Additional relevant MeSH terms: Melanoma; Uveal Neoplasms; Temozolomide; Dacarbazine; Imidazole

Study Results

Participant Flow

Arm/Group Title	Arm I (Cabozantinib-s-malate)	Arm II (Temozolomide or Dacarbazine)
Arm/Group Description	Patients receive 60 mg cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive 150 mg/m^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive 1000 mg/m^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	32	15
COMPLETED	31	15
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Arm I (Cabozantinib-s-malate)	Arm II (Temozolomide or Dacarbazine)	Total
Arm/Group Description	Patients receive 60 mg cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive 150 mg/m^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. >> >> If temozolomide is not available, patients receive 1000 mg/m^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	31	15	46
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60	67	62.5
Sex: Female, Male (Count of Participants)
Female	14 45.2%	6 40%	20 43.5%
Male	17 54.8%	9 60%	26 56.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	31 100%	15 100%	46 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Canada	8 25.8%	3 20%	11 23.9%
United States	23 74.2%	12 80%	35 76.1%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients Without a Progression Free Survival Event at 4 Months (PFS4)
Description	A patient will be declared a PFS4 success if they are on study and progression free for at least 4 months. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. The success for each arm will be calculated independently as the number of successes divided by the total number of evaluable patients. A one-sided chi-squared test for a difference in PFS4 proportions will be used to test for a difference between arms.
Time Frame	At 4 months

Outcome Measure Data

Analysis Population Description

All patients that began protocol treatment were included in this analysis.

Arm/Group Title	Arm I (Cabozantinib-s-malate)	Arm II (Temozolomide or Dacarbazine)
Arm/Group Description	Patients receive 60 mg cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive 150 mg/m^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. > > If temozolomide is not available, patients receive 1000 mg/m^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	31	15
Number (95% Confidence Interval) [proportion of participants]	.323 1%	.267 1.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Cabozantinib-s-malate), Arm II (Temozolomide or Dacarbazine)
	Comments	A one-sided chi-squared test for a difference in PFS4 rates will be used to test for a difference between arms.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Confirmed Response Rate as Determined by the RECIST Criteria (Version 1.1)
Description	The confirmed response rates will be estimated by dividing the number of confirmed responders by the number of evaluable patients. 95% confidence intervals will be calculated.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Cabozantinib-s-malate)	Arm II (Temozolomide or Dacarbazine)
Arm/Group Description	Patients receive 60 mg cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive 150 mg/m^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive 1000 mg/m^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	31	15
Count of Participants [Participants]	0 0%	0 0%

3. Secondary Outcome

Title	Percentage of Patients Who Experienced Grade 3+ Adverse Events Regardless of Attribution
Description	percentage of patients who experienced grade 3+ adverse events regardless of attribution, graded according to the National Cancer Institute CTCAE version 4.0
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Cabozantinib-s-malate)	Arm II (Temozolomide or Dacarbazine)
Arm/Group Description	Patients receive 60 mg cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive 150 mg/m^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. > > If temozolomide is not available, patients receive 1000 mg/m^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	31	15
Number [percentage of patients]	51.6	20

4. Secondary Outcome

Title	Overall Survival (OS)
Description	The distribution of OS time will be estimated using the method of Kaplan Meier.
Time Frame	Number of days from registration until death, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Cabozantinib-s-malate)	Arm II (Temozolomide or Dacarbazine)
Arm/Group Description	Patients receive 60 mg cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive 150 mg/m^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. > > If temozolomide is not available, patients receive 1000 mg/m^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	31	15
Median (95% Confidence Interval) [months]	6.3	7.2

5. Secondary Outcome

Title	PFS
Description	The distribution of PFS time will be estimated using the method of Kaplan Meier and is defined as the number of days from registration until disease progression (or death). Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
Time Frame	Number of days from registration until disease progression (or death), assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Cabozantinib-s-malate)	Arm II (Temozolomide or Dacarbazine)
Arm/Group Description	Patients receive 60 mg cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive 150 mg/m^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. > > If temozolomide is not available, patients receive 1000 mg/m^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	31	15
Median (95% Confidence Interval) [months]	2.0	1.9

6. Other Pre-specified Outcome

Title	Pre-treatment GNAQ/GNA11 and Potentially Other Mutations in Tissue
Description	The proportions of patients within these groups pre-treatment will be presented with 90% exact binomial confidence intervals. These findings will be correlated with overall survival using a Student's T-test.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Pre-treatment Immune Gene Expression in Tissue Defined as T Cell-inflamed, Intermediate and Non-T Cell-inflamed
Description	The proportions of patients within these groups pre-treatment will be presented with 90% exact binomial confidence intervals. These findings will be correlated with overall survival using a Student's T-test.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Arm I (Cabozantinib-s-malate)		Arm II (Temozolomide)		Arm II (Dacarbazine)
Arm/Group Description	Patients receive 60 mg cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.		Patients receive 150 mg/m^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.		Patients receive 1000 mg/m^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Arm I (Cabozantinib-s-malate)		Arm II (Temozolomide)		Arm II (Dacarbazine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/31 (6.5%)		1/11 (9.1%)		0/4 (0%)
Serious Adverse Events
	Arm I (Cabozantinib-s-malate)		Arm II (Temozolomide)		Arm II (Dacarbazine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/31 (48.4%)		6/11 (54.5%)		2/4 (50%)
Endocrine disorders
Hyperthyroidism	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/31 (3.2%)	1	2/11 (18.2%)	2	0/4 (0%)	0
Diarrhea	1/31 (3.2%)	1	2/11 (18.2%)	2	1/4 (25%)	1
Nausea	1/31 (3.2%)	2	1/11 (9.1%)	1	1/4 (25%)	1
Oral pain	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
General disorders
Death NOS	2/31 (6.5%)	2	0/11 (0%)	0	0/4 (0%)	0
Fatigue	2/31 (6.5%)	2	0/11 (0%)	0	0/4 (0%)	0
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	2/31 (6.5%)	2	0/11 (0%)	0	0/4 (0%)	0
Portal vein thrombosis	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Immune system disorders
Anaphylaxis	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Infections and infestations
Appendicitis perforated	0/31 (0%)	0	1/11 (9.1%)	2	0/4 (0%)	0
Enterocolitis infectious	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Lung infection	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Investigations
Alanine aminotransferase increased	4/31 (12.9%)	5	0/11 (0%)	0	0/4 (0%)	0
Alkaline phosphatase increased	2/31 (6.5%)	2	0/11 (0%)	0	0/4 (0%)	0
Aspartate aminotransferase increased	4/31 (12.9%)	5	1/11 (9.1%)	1	0/4 (0%)	0
Blood bilirubin increased	2/31 (6.5%)	2	0/11 (0%)	0	0/4 (0%)	0
Creatinine increased	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Ejection fraction decreased	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Lipase increased	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Neutrophil count decreased	1/31 (3.2%)	1	0/11 (0%)	0	1/4 (25%)	1
Platelet count decreased	0/31 (0%)	0	0/11 (0%)	0	1/4 (25%)	1
Metabolism and nutrition disorders
Dehydration	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Hypoalbuminemia	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Hyponatremia	2/31 (6.5%)	2	0/11 (0%)	0	0/4 (0%)	0
Hypophosphatemia	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Metabolism and nutrition disorders - Other, specify	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Nervous system disorders
Headache	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Renal and urinary disorders
Chronic kidney disease	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Sore throat	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Vascular disorders
Hypertension	2/31 (6.5%)	3	0/11 (0%)	0	0/4 (0%)	0
Thromboembolic event	4/31 (12.9%)	4	1/11 (9.1%)	1	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I (Cabozantinib-s-malate)		Arm II (Temozolomide)		Arm II (Dacarbazine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/31 (96.8%)		11/11 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Anemia	2/31 (6.5%)	4	6/11 (54.5%)	9	0/4 (0%)	0
Cardiac disorders
Cardiac disorders - Other, specify	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Left ventricular systolic dysfunction	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Palpitations	2/31 (6.5%)	3	0/11 (0%)	0	0/4 (0%)	0
Sinus bradycardia	0/31 (0%)	0	1/11 (9.1%)	3	0/4 (0%)	0
Ear and labyrinth disorders
Tinnitus	1/31 (3.2%)	2	0/11 (0%)	0	0/4 (0%)	0
Endocrine disorders
Hyperthyroidism	2/31 (6.5%)	2	0/11 (0%)	0	0/4 (0%)	0
Hypothyroidism	3/31 (9.7%)	17	2/11 (18.2%)	6	0/4 (0%)	0
Eye disorders
Dry eye	0/31 (0%)	0	1/11 (9.1%)	5	0/4 (0%)	0
Gastrointestinal disorders
Abdominal distension	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Abdominal pain	2/31 (6.5%)	2	3/11 (27.3%)	6	0/4 (0%)	0
Constipation	3/31 (9.7%)	6	3/11 (27.3%)	6	0/4 (0%)	0
Diarrhea	15/31 (48.4%)	41	4/11 (36.4%)	6	2/4 (50%)	5
Dry mouth	4/31 (12.9%)	5	1/11 (9.1%)	3	0/4 (0%)	0
Dyspepsia	2/31 (6.5%)	4	2/11 (18.2%)	3	0/4 (0%)	0
Dysphagia	0/31 (0%)	0	2/11 (18.2%)	3	0/4 (0%)	0
Flatulence	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Gastroesophageal reflux disease	1/31 (3.2%)	2	0/11 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders - Other, specify	0/31 (0%)	0	1/11 (9.1%)	4	0/4 (0%)	0
Mucositis oral	4/31 (12.9%)	5	0/11 (0%)	0	0/4 (0%)	0
Nausea	11/31 (35.5%)	20	6/11 (54.5%)	16	1/4 (25%)	1
Oral pain	2/31 (6.5%)	2	1/11 (9.1%)	4	0/4 (0%)	0
Vomiting	6/31 (19.4%)	6	4/11 (36.4%)	6	1/4 (25%)	3
General disorders
Chills	0/31 (0%)	0	1/11 (9.1%)	3	1/4 (25%)	6
Edema limbs	1/31 (3.2%)	1	1/11 (9.1%)	1	0/4 (0%)	0
Fatigue	20/31 (64.5%)	51	10/11 (90.9%)	31	3/4 (75%)	5
General disorders and administration site conditions - Other, specify	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Non-cardiac chest pain	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Pain	3/31 (9.7%)	5	1/11 (9.1%)	1	0/4 (0%)	0
Hepatobiliary disorders
Portal vein thrombosis	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Infections and infestations
Sinusitis	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Skin infection	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Upper respiratory infection	0/31 (0%)	0	1/11 (9.1%)	2	0/4 (0%)	0
Urinary tract infection	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Injury, poisoning and procedural complications
Fall	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Investigations
Alanine aminotransferase increased	21/31 (67.7%)	71	6/11 (54.5%)	17	1/4 (25%)	3
Alkaline phosphatase increased	5/31 (16.1%)	9	3/11 (27.3%)	6	0/4 (0%)	0
Aspartate aminotransferase increased	26/31 (83.9%)	85	10/11 (90.9%)	26	2/4 (50%)	4
Blood bilirubin increased	6/31 (19.4%)	10	3/11 (27.3%)	4	2/4 (50%)	3
Creatinine increased	2/31 (6.5%)	4	1/11 (9.1%)	4	0/4 (0%)	0
Electrocardiogram QT corrected interval prolonged	1/31 (3.2%)	1	0/11 (0%)	0	1/4 (25%)	1
Hemoglobin increased	1/31 (3.2%)	1	1/11 (9.1%)	1	0/4 (0%)	0
Investigations - Other, specify	1/31 (3.2%)	3	2/11 (18.2%)	10	0/4 (0%)	0
Lipase increased	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Lymphocyte count decreased	2/31 (6.5%)	3	3/11 (27.3%)	7	0/4 (0%)	0
Neutrophil count decreased	7/31 (22.6%)	13	2/11 (18.2%)	6	2/4 (50%)	5
Platelet count decreased	12/31 (38.7%)	27	5/11 (45.5%)	9	2/4 (50%)	6
Weight loss	6/31 (19.4%)	9	2/11 (18.2%)	9	0/4 (0%)	0
White blood cell decreased	3/31 (9.7%)	5	4/11 (36.4%)	8	0/4 (0%)	0
Metabolism and nutrition disorders
Anorexia	7/31 (22.6%)	14	3/11 (27.3%)	10	0/4 (0%)	0
Dehydration	3/31 (9.7%)	3	0/11 (0%)	0	0/4 (0%)	0
Hyperglycemia	4/31 (12.9%)	6	1/11 (9.1%)	1	0/4 (0%)	0
Hyperkalemia	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Hypoalbuminemia	3/31 (9.7%)	3	4/11 (36.4%)	9	0/4 (0%)	0
Hypokalemia	1/31 (3.2%)	1	2/11 (18.2%)	4	0/4 (0%)	0
Hyponatremia	3/31 (9.7%)	4	3/11 (27.3%)	5	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	3/31 (9.7%)	4	1/11 (9.1%)	1	0/4 (0%)	0
Back pain	1/31 (3.2%)	2	2/11 (18.2%)	4	0/4 (0%)	0
Generalized muscle weakness	2/31 (6.5%)	2	1/11 (9.1%)	1	0/4 (0%)	0
Musculoskeletal and connective tissue disorder - Other, specify	1/31 (3.2%)	10	0/11 (0%)	0	0/4 (0%)	0
Myalgia	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Neck pain	1/31 (3.2%)	2	2/11 (18.2%)	4	0/4 (0%)	0
Pain in extremity	0/31 (0%)	0	1/11 (9.1%)	2	0/4 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Nervous system disorders
Dizziness	2/31 (6.5%)	6	1/11 (9.1%)	1	0/4 (0%)	0
Dysgeusia	4/31 (12.9%)	11	1/11 (9.1%)	1	0/4 (0%)	0
Headache	2/31 (6.5%)	4	1/11 (9.1%)	3	0/4 (0%)	0
Hypersomnia	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Nervous system disorders - Other, specify	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Peripheral sensory neuropathy	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Psychiatric disorders
Depression	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Insomnia	1/31 (3.2%)	1	1/11 (9.1%)	3	0/4 (0%)	0
Renal and urinary disorders
Hematuria	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Proteinuria	6/31 (19.4%)	10	0/11 (0%)	0	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/31 (0%)	0	2/11 (18.2%)	2	0/4 (0%)	0
Dyspnea	0/31 (0%)	0	2/11 (18.2%)	8	0/4 (0%)	0
Epistaxis	1/31 (3.2%)	1	0/11 (0%)	0	0/4 (0%)	0
Hoarseness	1/31 (3.2%)	1	2/11 (18.2%)	5	0/4 (0%)	0
Laryngeal inflammation	0/31 (0%)	0	1/11 (9.1%)	5	0/4 (0%)	0
Productive cough	0/31 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0
Sore throat	2/31 (6.5%)	2	0/11 (0%)	0	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Dry skin	3/31 (9.7%)	9	1/11 (9.1%)	1	0/4 (0%)	0
Nail discoloration	1/31 (3.2%)	4	0/11 (0%)	0	0/4 (0%)	0
Palmar-plantar erythrodysesthesia syndrome	2/31 (6.5%)	5	1/11 (9.1%)	1	0/4 (0%)	0
Pruritus	1/31 (3.2%)	2	0/11 (0%)	0	0/4 (0%)	0
Rash acneiform	1/31 (3.2%)	1	2/11 (18.2%)	2	0/4 (0%)	0
Rash maculo-papular	1/31 (3.2%)	2	1/11 (9.1%)	1	0/4 (0%)	0
Skin and subcutaneous tissue disorders - Other, specify	3/31 (9.7%)	4	1/11 (9.1%)	3	0/4 (0%)	0
Vascular disorders
Hot flashes	0/31 (0%)	0	1/11 (9.1%)	3	0/4 (0%)	0
Hypertension	18/31 (58.1%)	61	5/11 (45.5%)	17	1/4 (25%)	2
Hypotension	1/31 (3.2%)	1	1/11 (9.1%)	1	0/4 (0%)	0
Thromboembolic event	1/31 (3.2%)	4	0/11 (0%)	0	0/4 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.