Dasatinib and Bevacizumab in Treating Patients With Recurrent or Progressive High-Grade Glioma or Glioblastoma Multiforme

• Sponsor: Alliance for Clinical Trials in Oncology (Other)
• Overall Status: Completed
• CT.gov ID: NCT00892177
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 144
• Locations: 305
• Arms: 2
• Actual Duration (Months): 117
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also block the growth of the tumor by blocking blood flow to the tumor. It is not yet known whether bevacizumab together with dasatinib are more effective than a placebo in treating patients with recurrent or progressive high-grade glioma or glioblastoma multiforme.

PURPOSE: This randomized phase I/II trial (Phase I completed) is studying the side effects and best dose of dasatinib when given together with bevacizumab and to see how well it works compared to placebo in treating patients with recurrent or progressive high-grade glioma or glioblastoma multiforme.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme	Biological: bevacizumab; Drug: dasatinib; Other: placebo	Phase 2

Detailed Description

OUTLINE: This is a multicenter, phase I, dose-escalation study (Phase I completed) of dasatinib followed by a phase II randomized study. Patients are grouped according to study (1 vs 2). Patients in the phase II portion are stratified according to age (> 70 years of age vs ≤ 70 years of age), and ECOG performance status (0 vs 1 or 2).

Phase I: Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oral dasatinib once or twice daily on days 1-14 until the maximum-tolerated dose (MTD) is determined. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. (Phase I completed) Please see the Arms section for the Phase II treatment regimens.

OBJECTIVES:

PRIMARY OBJECTIVES:

1. Determine the maximum tolerated dose (MTD) of dasatinib in combination with bevacizumab in high grade glioma patients. (Phase I)

2. To assess the safety and adverse events of the dasatinib in combination with bevacizumab in this patient population. (Phase I)

3. To estimate the efficacy of the bevacizumab combination with dasatinib in recurrent glioblastoma multiforme as measured by progression free survival at six months and compare it with the efficacy of bevacizumab alone. (Phase II)

SECONDARY OBJECTIVES:

1. To describe the overall toxicity associated with the dasatinib/bevacizumab combination. (Phase I)

2. To describe any preliminary evidence of antitumor activity. (Phase I)

3. To assess the time to disease progression. (Phase II)

4. To assess the safety and toxicity of the bevacizumab combination with dasatinib in this patient population. (Phase II)

5. To estimate the efficacy of the bevacizumab combination with dasatinib in recurrent glioblastoma multiforme as measured by overall survival time and compare it with the efficacy of bevacizumab alone. (Phase II)

6. To assess the impact of the treatment on the patient's quality of life (QOL) using the overall score from the FACT-Br (Phase II)

Study Design

• Study Type: Interventional
• Actual Enrollment: 144 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase I/Randomized Phase II Double Blind Study of Either Dasatinib or Placebo Combined With Bevacizumab in Recurrent Glioblastoma
• Actual Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Jul 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive bevacizumab on Day 1 and dasatinib on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab; Given intravenously; Drug: dasatinib; Given orally
Active Comparator: Arm II Patients receive bevacizumab on Day 1 and placebo on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab; Given intravenously; Other: placebo; Given orally

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Bevacizumab (Phase I) [14 days]

   The Maximum Tolerated Dose (MTD) will be based on the assessment of dose-limiting toxicities (DLT) during the first 4 weeks of treatment only (i.e., following the first 2 treatment cycles), and will be defined as the dose at which fewer than one-third of patients experience a DLT to study treatment. The MTD is the dose level at which 0/6 or 1/6 patients experience DLT with the next higher dose having at least 2 out of 3 or 2 out of 6 patients encountering DLT.> Three patients will be treated at each dose level, and can be enrolled simultaneously. If one DLT is encountered, an additional 3 patients will be added to that dose level. If at any point two DLTs are encountered within a given dose level, then the MTD has been exceeded and if only three patients have been treated at the next lower dose three more patients are treated at the next lower dose. The number of patients who developed DLTs are reported here by dose level, with the MTD reported in the statistical analysis section.

2. Progression-free Survival at 6 Months (PFS6) (Phase II) [6 months]

   The primary endpoint is the proportion of patients alive and progression-free 6 months after study treatment initiation (PFS6). All eligible consented patients that received treatment will be considered evaluable. Those who die will be considered to have had disease progression unless documented evidence clearly indicates no progression has occurred. PFS6 is defined as the time from start of study therapy to the date of first observation of disease progression or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The PFS6 will be estimated as the number of evaluable patients progression free and still alive at 6 months divided by the total number of evaluable patients. The confidence interval will be calculated according to the Clopper-Pearson Method.

Secondary Outcome Measures

1. Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II) [Up to 3 years]

   Adverse events were collected systematically at the end of each cycle and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Events are scored as: 1="Mild symptoms", 2= "Moderate", 3="Severe", 4="Life-threatening", and 5="Death". The number of patients reporting a grade 3 or higher event regardless of attribution are summarized here. A complete list of all adverse events reported during treatment can be found in the Adverse Events Section.

2. Overall Survival (Phase II) [Up to 3 years]

   Survival time is defined to be the length of time from start of study therapy to death due to any cause. All patients meeting the eligibility criteria that have signed a consent form and begun treatment will be considered evaluable for estimation of the survival distribution. The distribution of overall survival for both arms of the study will be estimated using the Kaplan-Meier method, and be compared using log-rank tests.

3. Time-to-disease Progression (Phase II) [Up to 3 years]

   Time-to-disease progression is defined as the time from start of study therapy to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death unless there is documented evidence that no progression occurred before death. Patients who fail to return for evaluation after beginning therapy will be censored for progression on the last day of therapy or date last known to be alive, whichever is later. Patients who are still alive and have not progressed will be censored for progression at the time of the last tumor assessment. Patients who experience major treatment violations will be censored for progression on the date the treatment violation occurred. The time-to-progression distribution will be estimated using the Kaplan-Meier method.

4. Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II) [Baseline to cycle 10 (20 weeks).]

   FACT-Br questionnaires were used to assess QOL at every other cycle of treatment (prior to cycles 3, 5, 7, etc.). FACT-Br includes 50 questions used to assess patients' self-assessment in 4 broad categories: Physical, Social/Family, Emotional, and Function Well-being. Scores range from 0="Not at all", 1="A little bit", 2="Somewhat", 3="Quite a bit", 4="Very Much". Higher scores can be interpreted as having higher quality of life. The scores for all 50 questions were summed to give a total score per patient per cycle. Therefore the possible range is from 0 to 200. Below is the reported mean and standard deviation for patients at baseline and during cycles 2, 4, 6, 8, and 10.

5. Objective Response (Phase II) [Up to 3 years]

   Objective response to treatment will be determined by the results of neurological exam and the MRI and/or CT measurement of the tumor at each evaluation as is used for all NCCTG neuro-oncology trials. The percentage of patients in each response category will be summarized, 95% confidence intervals calculated, and rates between the 2 arms will be compared using a Fisher's Exact test. For bi-dimensionally measurable disease, CR: total disappearance of all tumor and that patients be on no corticosteroids or on only adrenal replacement maintenance; PR: ≥ 50% reduction in product of perpendicular diameters of contrast enhancement or mass with no new lesions, and stable or decreasing steroid dosing; PD: >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions; REGR: unequivocal reduction in extent of contrast-enhancement, or a decrease in mass effect, no new lesions (for evaluable disease); SD: failure to qualify for CR, PR,REGR or PD.

Eligibility Criteria

Criteria

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

Patient Eligibility:

I. Pre-registration:

1. Central pathology review submission. This review is mandatory prior to registration to confirm eligibility.

II. Registration Inclusion Criteria:

1. ≥18 years of age

2. Study 1: Histologic confirmation of grade 3 or 4 glioma, including astrocytoma, oligodendroglioma, and mixed gliomas, as determined by pre-registration central pathology review.

3. Study 2: Histological confirmation of glioblastoma multiforme (grade 4 astrocytoma) as determined by pre-registration central pathology review. NOTE: Variant gliosarcomas are eligible

4. Evidence of tumor progression by MRI or CT scan following RT or following the most recent anti-tumor therapy. Patients who had surgical treatment at recurrence are eligible if there is imaging evidence of disease progression as compared to the first postoperative scan.

5. Bidimensionally measurable or evaluable disease by MRI or CT scan.

6. ECOG Performance Status (PS) 0, 1, or 2.

7. Patient willing to discontinue use of aspirin or medications that inhibit platelet function ≥ 1 week prior to registration.

8. Previous RT and ≥12 weeks since the completion of RT prior to registration.

9. The following laboratory values obtained ≤ 21 days prior to registration.

• ANC ≥1500

• PLT ≥100,000

• Hgb >9.0 g/dL

• 1. bili ≤1.5 x ULN

• SGOT (AST) ≤ 3 x ULN

• Creatinine ≤ ULN

1. UPC ratio <1. NOTE: Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio ≥1.0, 24-hour urine protein must be obtained and the level should be <1000 mg

2. Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only.

3. Ability to complete questionnaire(s) by themselves or with assistance.

4. Provide informed written consent

5. Willingness to return to enrolling institution for follow-up.

6. Patient willing to provide mandatory tissue samples for research purposes

7. Study 1: Any number of prior chemotherapy regimens for recurrent disease. Study 2: Up to 2 prior chemotherapy regimens with ≤1 regimen for recurrent disease.

III. Exclusion Criteria:

1. Pregnant women, nursing women and men or women of childbearing potential who are unwilling to employ adequate contraception during this study and for up to 6 months after bevacizumab treatment has ended. NOTE: bevacizumab and dasatinib are investigational agents whose genotoxic effects on the developing fetus and newborn are unknown.

2. Prior intratumoral therapy, stereotactic radiosurgery, or interstitial brachytherapy.

EXCEPTION: Separate lesion on MRI which is not part of the previous treatment field, or convincing evidence of recurrent disease, based on biopsy, MRI spectroscopy, or PET scan.

1. Prior treatment with bevacizumab or VEGF-Trap (Aflibercept).

2. Inadequately controlled hypertension (systolic blood pressure of >150 mmHg or diastolic pressure >100 mmHg on anti-hypertensive medications).

NOTE: Patients with well-controlled hypertension are eligible.

1. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

2. Immunocompromised patients (other than that related to the use of corticosteroids). NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this study.

3. Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, or prior surgical procedures affecting absorption) that impairs ability to swallow pills.

4. Receiving therapeutic anticoagulation with Warfarin. NOTE: Prophylactic anticoagulation (i.e., low dose warfarin) of venous or arterial access devices is allowed, provided that INR <1.5. Therapeutic anti-coagulation with low molecular weight heparin is allowed at time of registration.

5. Evidence of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation).

6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.

7. Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.

8. Other active malignancy ≤3 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma in-situ of the cervix. Note: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer.

9. History of myocardial infarction or unstable angina ≤6 months prior to registration.

10. New York Heart Association (NYHA) classification II, III or IV congestive heart failure.

11. Core biopsy or other minor surgical procedures ≤7 days prior to registration. Note: Placement of a vascular access device is allowed.

12. Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to registration or anticipation of need for major surgical procedure during the course of the study.

13. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis ≤6 months prior to registration.

14. History of hypertensive crisis or hypertensive encephalopathy.

15. Known hypersensitivity to any of the components of dasatinib or bevacizumab.

16. Serious, non-healing wound, active ulcer, or untreated bone fracture

17. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤6 months prior to registration.

18. Active or recent history of hemoptysis (≥ ½ teaspoon of bright red blood per episode) ≤30 days prior to registration.

19. History of stroke or transient ischemic attack (TIA) ≤6 months prior to registration.

20. Any evidence of CNS hemorrhage on baseline CT or MRI

21. Any of the following Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes ≤7 days prior to registration (patients must discontinue drug 7 days prior to starting dasatinib)

• Quinidine, procainamide, disopyramide

• Amiodarone, sotalol, ibutilide, dofetilide

• Erythromycin, clarithromycin

• Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

• Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine

• Prochlorperazine

1. Diagnosed congenital long QT syndrome

2. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes)

3. Prolonged QTc interval on pre-entry electrocardiogram (>450 msec)

4. Patients may not have any clinically significant cardiovascular disease including the following:

• Myocardial infarction or ventricular tachyarrhythmia within 6 months.

• Prolonged QTc ≥ 480 msec (Fridericia correction)

• Ejection fraction less than institutional normal

• Major conduction abnormality (unless a cardiac pacemaker is present)

Note: Patients with any cardiopulmonary symptoms of unknown cause (e.g., shortness of breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed in addition to electrocardiogram (ECG) to rule out QTc prolongation. The patient may be referred to a cardiologist at the discretion of the principal investigator. Patients with underlying cardiopulmonary dysfunction should be excluded from the study.

1. Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration

2. Known pleural or pericardial effusion of any grade

3. Concomitant use of H2 blockers or proton pump inhibitors that cannot be discontinued or switched to locally acting agents (i.e. famotidine or omeprazole.)

4. Use of the following Enzyme Inducing Anti-Convulsive (EIAC) medications is prohibited ≤ 7 days prior to registration: carbamazepine (Tegretol®, Tegretol XR®, Carbatrol®), phenytoin (Dilantin®, Phenytek®), fosphenytoin (Cerebyx®), phenobarbital, pentobarbital and primidone (Mysoline®). Note: Many antiepileptic drugs induce hepatic enzymes. Because dasatinib is metabolized by hepatic enzymes, patients taking antiepileptic medications that induce hepatic enzymes (EIACs) are ineligible for this trial. To be eligible for this trial, patients taking EIACs must be switched to non-EIACs ≥ 7 days prior to registration. The following agents are not known to affect dasatinib metabolism and are acceptable for use: valproic acid (Depakote®, Depacon®), gabapentin (Neurontin®), lamotrigine (Lamictal®), topiramate (Topamax®), tiagabine (Gabitril®), zonisamide (Zonegran®), levetiracetam (Keppra®), clonazepam (Klonopin®) and clobazam (Frisium®).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
2	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
3	Palchak David MD	Pismo Beach	California	United States	93449
4	Aurora Presbyterian Hospital	Aurora	Colorado	United States	80012
5	Boulder Community Hospital	Boulder	Colorado	United States	80301-9019
6	Boulder Community Hospital	Boulder	Colorado	United States	80301
7	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
8	St. Anthony Central Hospital	Denver	Colorado	United States	80204
9	Porter Adventist Hospital	Denver	Colorado	United States	80210
10	Presbyterian - St. Luke's Medical Center	Denver	Colorado	United States	80218
11	St. Joseph Hospital	Denver	Colorado	United States	80218
12	Rose Medical Center	Denver	Colorado	United States	80220
13	Swedish Medical Center	Englewood	Colorado	United States	80110
14	North Colorado Medical Center	Greeley	Colorado	United States	80631
15	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
16	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado	United States	80501
17	McKee Medical Center	Loveland	Colorado	United States	80539
18	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado	United States	81004
19	Exempla Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
20	Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center	Hartford	Connecticut	United States	06105
21	Beebe Medical Center	Lewes	Delaware	United States	19958
22	Tunnell Cancer Center at Beebe Medical Center	Lewes	Delaware	United States	19958
23	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
24	Lombardi Comprehensive Cancer Center at Georgetown University Medical Center	Washington	District of Columbia	United States	20007
25	Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
26	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida	United States	33021
27	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
28	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
29	Ella Milbank Foshay Cancer Center at Jupiter Medical Center	Jupiter	Florida	United States	33458
30	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
31	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida	United States	32803-1273
32	John B Amos Cancer Center	Columbus	Georgia	United States	31904
33	Kapiolani Medical Center at Pali Momi	'Aiea	Hawaii	United States	96701
34	Oncare Hawaii, Incorporated - Pali Momi	'Aiea	Hawaii	United States	96701
35	Cancer Research Center of Hawaii	Honolulu	Hawaii	United States	96813
36	Oncare Hawaii Inc-POB II	Honolulu	Hawaii	United States	96813
37	OnCare Hawaii, Incorporated - Lusitana	Honolulu	Hawaii	United States	96813
38	Queen's Cancer Institute at Queen's Medical Center	Honolulu	Hawaii	United States	96813
39	Straub Clinic and Hospital, Incorporated	Honolulu	Hawaii	United States	96813
40	University of Hawaii	Honolulu	Hawaii	United States	96813
41	Kuakini Medical Center	Honolulu	Hawaii	United States	96817
42	OnCare Hawaii, Incorporated - Kuakini	Honolulu	Hawaii	United States	96817
43	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
44	Castle Medical Center	Kailua	Hawaii	United States	96734
45	Kauai Medical Clinic	Lihue	Hawaii	United States	96766
46	Wilcox Memorial Hospital and Kauai Medical Clinic	Lihue	Hawaii	United States	96766
47	Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center	Boise	Idaho	United States	83706
48	Rush-Copley Cancer Care Center	Aurora	Illinois	United States	60504
49	Illinois CancerCare - Bloomington	Bloomington	Illinois	United States	61701
50	Illinois CancerCare - Canton	Canton	Illinois	United States	61520
51	Illinois CancerCare - Carthage	Carthage	Illinois	United States	62321
52	Rush University Medical Center	Chicago	Illinois	United States	60612
53	Eureka Community Hospital	Eureka	Illinois	United States	61530
54	Illinois CancerCare - Eureka	Eureka	Illinois	United States	61530
55	Galesburg Clinic, PC	Galesburg	Illinois	United States	61401
56	Illinois CancerCare - Havana	Havana	Illinois	United States	62644
57	Illinois CancerCare - Kewanee Clinic	Kewanee	Illinois	United States	61443
58	Illinois CancerCare - Macomb	Macomb	Illinois	United States	61455
59	Illinois CancerCare - Monmouth	Monmouth	Illinois	United States	61462
60	BroMenn Regional Medical Center	Normal	Illinois	United States	61761
61	Community Cancer Center	Normal	Illinois	United States	61761
62	Illinois CancerCare - Community Cancer Center	Normal	Illinois	United States	61761
63	Community Hospital of Ottawa	Ottawa	Illinois	United States	61350
64	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
65	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois	United States	61350
66	Ottawa Regional Hospital and Healthcare Center	Ottawa	Illinois	United States	61350
67	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois	United States	61554
68	Illinois CancerCare - Pekin	Pekin	Illinois	United States	61603
69	Proctor Hospital	Peoria	Illinois	United States	61614
70	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61615
71	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois	United States	61615
72	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
73	Illinois CancerCare - Peru	Peru	Illinois	United States	61354
74	Illinois Valley Community Hospital	Peru	Illinois	United States	61354
75	Illinois CancerCare - Princeton	Princeton	Illinois	United States	61356
76	Illinois CancerCare - Spring Valley	Spring Valley	Illinois	United States	61362
77	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
78	St. Francis Hospital Cancer Care Services	Indianapolis	Indiana	United States	46237
79	Reid Hospital & Health Care Services	Richmond	Indiana	United States	47374
80	McFarland Clinic, PC	Ames	Iowa	United States	50010
81	Cedar Rapids Oncology Association	Cedar Rapids	Iowa	United States	52403
82	Mercy Hospital	Cedar Rapids	Iowa	United States	52403
83	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa	United States	52403
84	Medical Oncology and Hematology Associates - West Des Moines	Clive	Iowa	United States	50325
85	Mercy Cancer Center - West Lakes	Clive	Iowa	United States	50325
86	CCOP - Iowa Oncology Research Association	Des Moines	Iowa	United States	50309
87	John Stoddard Cancer Center at Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
88	Medical Oncology and Hematology Associates at John Stoddard Cancer Center	Des Moines	Iowa	United States	50309
89	Medical Oncology and Hematology Associates at Mercy Cancer Center	Des Moines	Iowa	United States	50314
90	Mercy Cancer Center at Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
91	John Stoddard Cancer Center at Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
92	Mercy Cancer Center at Mercy Medical Center - North Iowa	Mason City	Iowa	United States	50401
93	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
94	Mercy Medical Center - Sioux City	Sioux City	Iowa	United States	51102
95	St. Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
96	Methodist West Hospital	West Des Moines	Iowa	United States	50266-7700
97	Mercy Medical Center-West Lakes	West Des Moines	Iowa	United States	50266
98	Cancer Center of Kansas - Chanute	Chanute	Kansas	United States	66720
99	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas	United States	66720
100	Cancer Center of Kansas - Dodge City	Dodge City	Kansas	United States	67801
101	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas	United States	67801
102	Cancer Center of Kansas - El Dorado	El Dorado	Kansas	United States	67042
103	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas	United States	67042
104	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
105	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
106	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas	United States	67068
107	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
108	Cancer Center of Kansas, PA - Liberal	Liberal	Kansas	United States	67901
109	Cancer Center of Kansas - Newton	Newton	Kansas	United States	67114
110	Cancer Center of Kansas, PA - Newton	Newton	Kansas	United States	67114
111	Cancer Center of Kansas - Parsons	Parsons	Kansas	United States	67357
112	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas	United States	67357
113	Cancer Center of Kansas - Pratt	Pratt	Kansas	United States	67124
114	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas	United States	67124
115	Cancer Center of Kansas - Salina	Salina	Kansas	United States	67401
116	Cancer Center of Kansas, PA - Salina	Salina	Kansas	United States	67401
117	Cancer Center of Kansas - Wellington	Wellington	Kansas	United States	67152
118	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas	United States	67152
119	Associates in Women's Health - Wichita	Wichita	Kansas	United States	67208
120	Associates in Womens Health, PA - North Review	Wichita	Kansas	United States	67208
121	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas	United States	67208
122	Cancer Center of Kansas - Main Office	Wichita	Kansas	United States	67214
123	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas	United States	67214
124	CCOP - Wichita	Wichita	Kansas	United States	67214
125	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
126	Wesley Medical Center	Wichita	Kansas	United States	67214
127	Cancer Center of Kansas - Winfield	Winfield	Kansas	United States	67156
128	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas	United States	67156
129	Harold Alfond Center for Cancer Care	Augusta	Maine	United States	04330
130	CancerCare of Maine at Eastern Maine Medical Center	Bangor	Maine	United States	04401
131	Union Hospital of Cecil County	Elkton	Maryland	United States	21921
132	Bixby Medical Center	Adrian	Michigan	United States	49221
133	Hickman Cancer Center at Bixby Medical Center	Adrian	Michigan	United States	49221
134	Toledo Clinic Cancer Centers - Adrian	Adrian	Michigan	United States	49221
135	Toledo Clinic Cancer Centers-Adrian	Adrian	Michigan	United States	49221
136	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan	United States	48106-0995
137	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan	United States	48106
138	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48123-2500
139	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
140	Hurley Medical Center	Flint	Michigan	United States	48503
141	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
142	Foote Memorial Hospital	Jackson	Michigan	United States	49201
143	Sparrow Regional Cancer Center	Lansing	Michigan	United States	48912-1811
144	St. Mary Mercy Hospital	Livonia	Michigan	United States	48154
145	Community Cancer Center of Monroe	Monroe	Michigan	United States	48162
146	Mercy Memorial Hospital - Monroe	Monroe	Michigan	United States	48162
147	Toledo Clinic Cancer Centers-Monroe	Monroe	Michigan	United States	48162
148	St. Joseph Mercy Oakland	Pontiac	Michigan	United States	48341-2985
149	Mercy Regional Cancer Center at Mercy Hospital	Port Huron	Michigan	United States	48060
150	Saint Joseph Mercy Port Huron	Port Huron	Michigan	United States	48060
151	Seton Cancer Institute at Saint Mary's - Saginaw	Saginaw	Michigan	United States	48601
152	St. John Macomb Hospital	Warren	Michigan	United States	48093
153	MeritCare Bemidji	Bemidji	Minnesota	United States	56601
154	Sanford Clinic North-Bemidji	Bemidji	Minnesota	United States	56601
155	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
156	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
157	Essentia Health - Duluth Clinic	Duluth	Minnesota	United States	55805-1983
158	CCOP - Duluth	Duluth	Minnesota	United States	55805
159	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota	United States	55805
160	Miller - Dwan Medical Center	Duluth	Minnesota	United States	55805
161	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
162	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
163	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
164	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota	United States	55109
165	Minnesota Oncology - Maplewood	Maplewood	Minnesota	United States	55109
166	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
167	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55415
168	New Ulm Medical Center	New Ulm	Minnesota	United States	56073
169	Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
170	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
171	CentraCare Clinic - River Campus	Saint Cloud	Minnesota	United States	56303
172	Coborn Cancer Center	Saint Cloud	Minnesota	United States	56303
173	Saint Cloud Hospital	Saint Cloud	Minnesota	United States	56303
174	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
175	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
176	Regions Hospital Cancer Care Center	Saint Paul	Minnesota	United States	55101
177	United Hospital	Saint Paul	Minnesota	United States	55102
178	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota	United States	55379
179	Lakeview Hospital	Stillwater	Minnesota	United States	55082
180	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
181	Willmar Cancer Center at Rice Memorial Hospital	Willmar	Minnesota	United States	56201
182	Minnesota Oncology - Woodbury	Woodbury	Minnesota	United States	55125
183	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
184	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
185	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
186	St. Vincent Healthcare Cancer Care Services	Billings	Montana	United States	59101
187	Frontier Cancer Center and Blood Institutes-Billings	Billings	Montana	United States	59102
188	Hematology-Oncology Centers of the Northern Rockies - Billings	Billings	Montana	United States	59102
189	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
190	Billings Clinic	Billings	Montana	United States	59107-7000
191	Bozeman Deaconess Cancer Center	Bozeman	Montana	United States	59715
192	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
193	St. James Healthcare Cancer Care	Butte	Montana	United States	59701
194	Benefis Healthcare - Sletten Cancer Institute	Great Falls	Montana	United States	59405
195	Benefis Sletten Cancer Institute	Great Falls	Montana	United States	59405
196	St. Peter's Hospital	Helena	Montana	United States	59601
197	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
198	Montana Cancer Specialists at Montana Cancer Center	Missoula	Montana	United States	59807-7877
199	Montana Cancer Center at St. Patrick Hospital and Health Sciences Center	Missoula	Montana	United States	59807
200	Saint Francis Cancer Treatment Center at Saint Francis Memorial Health Center	Grand Island	Nebraska	United States	68803
201	Cancer Resource Center - Lincoln	Lincoln	Nebraska	United States	68510
202	Nebraska Cancer Research Center	Lincoln	Nebraska	United States	68510
203	Callahan Cancer Center at Great Plains Regional Medical Center	North Platte	Nebraska	United States	69103
204	CCOP - Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
205	Immanuel Medical Center	Omaha	Nebraska	United States	68122
206	Alegant Health Cancer Center at Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
207	Alegent Health Lakeside Hospital	Omaha	Nebraska	United States	68130
208	Lakeside Hospital	Omaha	Nebraska	United States	68130
209	Creighton University Medical Center	Omaha	Nebraska	United States	68131-2197
210	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-6805
211	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
212	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
213	New Hampshire Oncology - Hematology, PA at Payson Center for Cancer Care	Concord	New Hampshire	United States	03301
214	New Hampshire Oncology-Hematology PA	Concord	New Hampshire	United States	03301
215	New Hampshire Oncology - Hematology, PA - Hooksett	Hooksett	New Hampshire	United States	03106
216	Lakes Region General Hospital	Laconia	New Hampshire	United States	03246
217	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
218	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
219	Cooper Hospital University Medical Center	Camden	New Jersey	United States	08103
220	Valley Hospital - Ridgewood	Ridgewood	New Jersey	United States	07450
221	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey	United States	08043
222	Mount Kisco Medical Group at Northern Westchester Hospital	Mount Kisco	New York	United States	10549
223	Mount Sinai Medical Center	New York	New York	United States	10029
224	Wayne Memorial Hospital, Incorporated	Goldsboro	North Carolina	United States	27534
225	Kinston Medical Specialists	Kinston	North Carolina	United States	28501
226	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
227	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota	United States	58501
228	Mid Dakota Clinic, PC	Bismarck	North Dakota	United States	58501
229	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
230	St. Alexius Medical Center Cancer Center	Bismarck	North Dakota	United States	58502
231	MeritCare Broadway	Fargo	North Dakota	United States	58102
232	Sanford Clinic North-Fargo	Fargo	North Dakota	United States	58102
233	Dakota Cancer Institute at Dakota Clinic - South University	Fargo	North Dakota	United States	58103
234	Essentia Health Cancer Center-South University Clinic	Fargo	North Dakota	United States	58103
235	Sanford Medical Center-Fargo	Fargo	North Dakota	United States	58122
236	Sanford Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
237	Altru Cancer Center at Altru Hospital	Grand Forks	North Dakota	United States	58201
238	Wood County Oncology Center	Bowling Green	Ohio	United States	43402
239	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio	United States	45267
240	University of Cincinnati	Cincinnati	Ohio	United States	45267
241	Grandview Hospital	Dayton	Ohio	United States	45405
242	Good Samaritan Hospital	Dayton	Ohio	United States	45406
243	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio	United States	45409
244	Samaritan North Cancer Care Center	Dayton	Ohio	United States	45415
245	CCOP - Dayton	Dayton	Ohio	United States	45420
246	Community Cancer Center	Elyria	Ohio	United States	44035
247	Hematology Oncology Center	Elyria	Ohio	United States	44035
248	Blanchard Valley Medical Associates	Findlay	Ohio	United States	45840
249	Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
250	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio	United States	45005
251	Wayne Hospital	Greenville	Ohio	United States	45331
252	Charles F. Kettering Memorial Hospital	Kettering	Ohio	United States	45429
253	Lima Memorial Hospital	Lima	Ohio	United States	45804
254	Northwest Ohio Oncology Center	Maumee	Ohio	United States	43537-1839
255	St. Charles Mercy Hospital	Oregon	Ohio	United States	43616
256	Toledo Clinic - Oregon	Oregon	Ohio	United States	43616
257	Flower Hospital Cancer Center	Sylvania	Ohio	United States	43560
258	Mercy Hospital of Tiffin	Tiffin	Ohio	United States	44883
259	Toledo Hospital	Toledo	Ohio	United States	43606
260	St. Vincent Mercy Medical Center	Toledo	Ohio	United States	43608
261	Medical University of Ohio Cancer Center	Toledo	Ohio	United States	43614
262	University of Toledo	Toledo	Ohio	United States	43614
263	St. Anne Mercy Hospital	Toledo	Ohio	United States	43623
264	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio	United States	43623
265	Toledo Clinic, Incorporated - Main Clinic	Toledo	Ohio	United States	43623
266	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio	United States	45373-1300
267	Fulton County Health Center	Wauseon	Ohio	United States	43567
268	Precision Radiotherapy at University Pointe	West Chester	Ohio	United States	45069
269	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio	United States	45385
270	Cancer Care Associates - Norman	Norman	Oklahoma	United States	73071
271	Cancer Care Associates - Mercy Campus	Oklahoma City	Oklahoma	United States	73120
272	Legacy Mount Hood Medical Center	Gresham	Oregon	United States	97030
273	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon	United States	97210
274	Legacy Meridian Park Hospital	Tualatin	Oregon	United States	97062
275	Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest	Allentown	Pennsylvania	United States	18105
276	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
277	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
278	Geisinger Medical Center-Cancer Center Hazelton	Hazleton	Pennsylvania	United States	18201
279	Geisinger Medical Group	State College	Pennsylvania	United States	16801
280	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania	United States	18711
281	Rhode Island Hospital	Providence	Rhode Island	United States	02903
282	McLeod Regional Medical Center	Florence	South Carolina	United States	29501
283	Cancer Centers of the Carolinas - Faris Road	Greenville	South Carolina	United States	29605
284	Cancer Centers of the Carolinas - Grove Commons	Greenville	South Carolina	United States	29605
285	Greenville Health System Cancer Institute-Butternut	Greenville	South Carolina	United States	29605
286	Greenville Health System Cancer Institute-Faris	Greenville	South Carolina	United States	29605
287	Greenville Hospital Cancer Center	Greenville	South Carolina	United States	29605
288	CCOP - Greenville	Greenville	South Carolina	United States	29615
289	Cancer Centers of the Carolinas - Greer Medical Oncology	Greer	South Carolina	United States	29650
290	Cancer Centers of the Carolinas - Seneca	Seneca	South Carolina	United States	29672
291	Greenville Health System Cancer Institute-Seneca	Seneca	South Carolina	United States	29672
292	Cancer Centers of the Carolinas - Spartanburg	Spartanburg	South Carolina	United States	29307
293	Greenville Health System Cancer Institute-Spartanburg	Spartanburg	South Carolina	United States	29307
294	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
295	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
296	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
297	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota	United States	57117-5039
298	Fredericksburg Oncology, Incorporated	Fredericksburg	Virginia	United States	22401
299	Legacy Salmon Creek Hospital	Vancouver	Washington	United States	98686
300	Gundersen Lutheran Center for Cancer and Blood	La Crosse	Wisconsin	United States	54601
301	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
302	Westfields Hospital/Cancer Center of Western Wisconsin	New Richmond	Wisconsin	United States	54017
303	Oconomowoc Memorial Hospital-ProHealth Care Inc	Oconomowoc	Wisconsin	United States	53066
304	Regional Cancer Center at Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
305	Waukesha Memorial Hospital Regional Cancer Center	Waukesha	Wisconsin	United States	53188

Sponsors and Collaborators

• Alliance for Clinical Trials in Oncology
• National Cancer Institute (NCI)

Investigators

• Study Chair: Evanthia Galanis, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT00892177
• Other Study ID Numbers: NCCTG-N0872; NCI-2011-01921; CDR0000641746
• First Posted: May 4, 2009
• Last Update Posted: Oct 21, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Alliance for Clinical Trials in Oncology: adult giant cell glioblastoma; adult glioblastoma; adult gliosarcoma; adult mixed glioma; recurrent adult brain tumor; adult anaplastic oligodendroglioma; adult oligodendroglioma; adult anaplastic astrocytoma
• Additional relevant MeSH terms: Glioblastoma; Bevacizumab; Dasatinib

Study Results

Participant Flow

Arm/Group Title	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase I: Dose Level 2	Phase I: Dose Level 3	Phase II: Arm A (Bevacizumab + Dasatinib)	Phase II: Arm B (Bevacizumab + Placebo)
Arm/Group Description	Patients receive 5 mg/kg bevacizumab IV over 90 minutes on Day 1 and 50 mg oral dasatinib twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and 50 mg oral dasatinib twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and 70 mg oral dasatinib twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and 100 mg oral dasatinib twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Period Title: Phase I: Dose Level 0
STARTED	3	0	0	0	0	0
COMPLETED	3	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Phase I: Dose Level 0
STARTED	0	4	0	0	0	0
COMPLETED	0	4	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Phase I: Dose Level 0
STARTED	0	0	3	0	0	0
COMPLETED	0	0	3	0	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Phase I: Dose Level 0
STARTED	0	0	0	6	0	0
COMPLETED	0	0	0	6	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Phase I: Dose Level 0
STARTED	0	0	0	0	88	40
COMPLETED	0	0	0	0	83	38
NOT COMPLETED	0	0	0	0	5	2

Baseline Characteristics

Arm/Group Title	Phase I	Phase II: Arm A (Bevacizumab + Dasatinib)	Phase II: Arm B (Bevacizumab + Placebo)	Total
Arm/Group Description	Patients receive (either: 5 or 10 mg/kg) bevacizumab IV over 90 minutes on Day 1 and oral dasatinib (either: 50, 70, or 100 mg) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	16	83	38	137
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	46.5	58	56.5	57
Sex: Female, Male (Count of Participants)
Female	3 18.8%	28 33.7%	16 42.1%	47 34.3%
Male	13 81.3%	55 66.3%	22 57.9%	90 65.7%
Region of Enrollment (Count of Participants)
United States	16 100%	83 100%	38 100%	137 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Dasatinib in Combination With Bevacizumab (Phase I)
Description	The Maximum Tolerated Dose (MTD) will be based on the assessment of dose-limiting toxicities (DLT) during the first 4 weeks of treatment only (i.e., following the first 2 treatment cycles), and will be defined as the dose at which fewer than one-third of patients experience a DLT to study treatment. The MTD is the dose level at which 0/6 or 1/6 patients experience DLT with the next higher dose having at least 2 out of 3 or 2 out of 6 patients encountering DLT.> Three patients will be treated at each dose level, and can be enrolled simultaneously. If one DLT is encountered, an additional 3 patients will be added to that dose level. If at any point two DLTs are encountered within a given dose level, then the MTD has been exceeded and if only three patients have been treated at the next lower dose three more patients are treated at the next lower dose. The number of patients who developed DLTs are reported here by dose level, with the MTD reported in the statistical analysis section.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

Adverse event information is available for 4 patients on study 1 dose level 1 (with 1 being a MTD replacement due to disease progression prior to completing cycles 1 and 2).

Arm/Group Title	Phase I : Dose Level 0	Phase I : Dose Level 1	Phase I : Dose Level 2	Phase I : Dose Level 3 Cohort 1	Phase I: Dose Level 3 Cohort 2
Arm/Group Description	Patients receive 5 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 50 mg twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 50 mg twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 70 mg twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	3	4	3	3	3
Number [participants who developed DLTs]	0 0%	0 0%	0 0%	0 0%	1 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I : Dose Level 0, Phase I : Dose Level 1, Phase I : Dose Level 2, Phase I : Dose Level 3 Cohort 1, Phase I: Dose Level 3 Cohort 2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Maximum Tolerated Dose (mg)
	Estimated Value	100
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Progression-free Survival at 6 Months (PFS6) (Phase II)
Description	The primary endpoint is the proportion of patients alive and progression-free 6 months after study treatment initiation (PFS6). All eligible consented patients that received treatment will be considered evaluable. Those who die will be considered to have had disease progression unless documented evidence clearly indicates no progression has occurred. PFS6 is defined as the time from start of study therapy to the date of first observation of disease progression or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The PFS6 will be estimated as the number of evaluable patients progression free and still alive at 6 months divided by the total number of evaluable patients. The confidence interval will be calculated according to the Clopper-Pearson Method.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All patients that received treatment and were eligible for assessment were included in this analysis.

Arm/Group Title	Phase II: Arm A (Bevacizumab + Dasatinib)	Phase II: Arm B (Bevacizumab + Placebo)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	83	38
Number (90% Confidence Interval) [proportion of participants]	0.29 1.8%	0.18 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I : Dose Level 0, Phase I : Dose Level 1
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Chi-squared, Corrected
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.052 to 0.262
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference in proportion

3. Secondary Outcome

Title	Number of Participants With Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 (Phase II)
Description	Adverse events were collected systematically at the end of each cycle and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Events are scored as: 1="Mild symptoms", 2= "Moderate", 3="Severe", 4="Life-threatening", and 5="Death". The number of patients reporting a grade 3 or higher event regardless of attribution are summarized here. A complete list of all adverse events reported during treatment can be found in the Adverse Events Section.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All Phase II patients treated and evaluated for adverse events are included in this Phase II endpoint analysis.

Arm/Group Title	Phase II: Arm A (Bevacizumab + Dasatinib)	Phase II: Arm B (Bevacizumab + Placebo)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	83	38
Grade 3 Adverse Event	42 262.5%	23 27.7%
Grade 4 Adverse Event	8 50%	2 2.4%
Grade 5 Adverse Event	5 31.3%	3 3.6%

4. Secondary Outcome

Title	Overall Survival (Phase II)
Description	Survival time is defined to be the length of time from start of study therapy to death due to any cause. All patients meeting the eligibility criteria that have signed a consent form and begun treatment will be considered evaluable for estimation of the survival distribution. The distribution of overall survival for both arms of the study will be estimated using the Kaplan-Meier method, and be compared using log-rank tests.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All eligible Phase II patients are included in this Phase II endpoint analysis.

Arm/Group Title	Phase II: Arm A (Bevacizumab + Dasatinib)	Phase II: Arm B (Bevacizumab + Placebo)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	83	38
Median (95% Confidence Interval) [months]	7.3	7.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I : Dose Level 0, Phase I : Dose Level 1
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7
	Comments
	Method	Kaplan Meier
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Time-to-disease Progression (Phase II)
Description	Time-to-disease progression is defined as the time from start of study therapy to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death unless there is documented evidence that no progression occurred before death. Patients who fail to return for evaluation after beginning therapy will be censored for progression on the last day of therapy or date last known to be alive, whichever is later. Patients who are still alive and have not progressed will be censored for progression at the time of the last tumor assessment. Patients who experience major treatment violations will be censored for progression on the date the treatment violation occurred. The time-to-progression distribution will be estimated using the Kaplan-Meier method.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All eligible Phase II patients are included in this Phase II endpoint analysis.

Arm/Group Title	Phase II: Arm A (Bevacizumab + Dasatinib)	Phase II: Arm B (Bevacizumab + Placebo)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	83	38
Median (95% Confidence Interval) [months]	3.3	3.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I : Dose Level 0, Phase I : Dose Level 1
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	Kaplan Meier
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Patient-reported QOL, as Measure by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) (Phase II)
Description	FACT-Br questionnaires were used to assess QOL at every other cycle of treatment (prior to cycles 3, 5, 7, etc.). FACT-Br includes 50 questions used to assess patients' self-assessment in 4 broad categories: Physical, Social/Family, Emotional, and Function Well-being. Scores range from 0="Not at all", 1="A little bit", 2="Somewhat", 3="Quite a bit", 4="Very Much". Higher scores can be interpreted as having higher quality of life. The scores for all 50 questions were summed to give a total score per patient per cycle. Therefore the possible range is from 0 to 200. Below is the reported mean and standard deviation for patients at baseline and during cycles 2, 4, 6, 8, and 10.
Time Frame	Baseline to cycle 10 (20 weeks).

Outcome Measure Data

Analysis Population Description

All Phase II patients that began treatment and submitted at least one FACT-Br questionnaire were included in this analysis.

Arm/Group Title	Phase II: Arm A (Bevacizumab + Dasatinib)	Phase II: Arm B (Bevacizumab + Placebo)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	77	34
Cycle 0	139.5 (26.2)	138.3 (22.4)
Cycle 2	131.2 (27.9)	133.5 (23.5)
Cycle 4	137.6 (30.1)	137.4 (23.1)
Cycle 6	140.1 (29.0)	137.7 (25.7)
Cycle 8	142.3 (30.2)	142.8 (31.1)
Cycle10	142.1 (34.9)	149.3 (34.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I : Dose Level 0, Phase I : Dose Level 1
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.96
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.223
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimate is the net difference between Arm A and Arm B total score using information from all cycles. A negative value means that Arm A has a lower quality of life and a positive value means Arm A has a higher reported quality of life.

7. Secondary Outcome

Title	Objective Response (Phase II)
Description	Objective response to treatment will be determined by the results of neurological exam and the MRI and/or CT measurement of the tumor at each evaluation as is used for all NCCTG neuro-oncology trials. The percentage of patients in each response category will be summarized, 95% confidence intervals calculated, and rates between the 2 arms will be compared using a Fisher's Exact test. For bi-dimensionally measurable disease, CR: total disappearance of all tumor and that patients be on no corticosteroids or on only adrenal replacement maintenance; PR: ≥ 50% reduction in product of perpendicular diameters of contrast enhancement or mass with no new lesions, and stable or decreasing steroid dosing; PD: >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions; REGR: unequivocal reduction in extent of contrast-enhancement, or a decrease in mass effect, no new lesions (for evaluable disease); SD: failure to qualify for CR, PR,REGR or PD.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All eligible Phase II patients are included in this Phase II endpoint analysis.

Arm/Group Title	Phase II: Arm A (Bevacizumab + Dasatinib)	Phase II: Arm B (Bevacizumab + Placebo)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	83	38
CR	2.4 15%	2.6 3.1%
PR	2.4 15%	5.3 6.4%
REGR	10.8 67.5%	18.4 22.2%
SD	57.8 361.3%	57.9 69.8%
PD	12.0 75%	5.3 6.4%
Missing/Unknown	14.5 90.6%	10.5 12.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I : Dose Level 0, Phase I : Dose Level 1
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6325
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Adverse events are assessed 21 days prior to registration, prior to each new cycle, and at time of progression, withdrawal or removal from the study up to 3 years from registration.
Adverse Event Reporting Description	CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for expedited adverse event reporting only, beginning July 1, 2011.
Arm/Group Title	Phase I: Dose Level 0		Phase I: Dose Level 1		Phase I: Dose Level 2		Phase I: Dose Level 3		Phase II: Arm A (Bevacizumab + Dasatinib)		Phase II: Arm B (Bevacizumab + Placebo)
Arm/Group Description	Patients receive 5 mg/kg bevacizumab IV over 90 minutes on Day 1 and 50 mg oral dasatinib twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.		Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and 50 mg oral dasatinib twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.		Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and 70 mg oral dasatinib twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.		Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and 100 mg oral dasatinib twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.		Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral dasatinib 100 mg (2 tablets) twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.		Patients receive 10 mg/kg bevacizumab IV over 90 minutes on Day 1 and oral placebo twice daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Phase I: Dose Level 0		Phase I: Dose Level 1		Phase I: Dose Level 2		Phase I: Dose Level 3		Phase II: Arm A (Bevacizumab + Dasatinib)		Phase II: Arm B (Bevacizumab + Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I: Dose Level 0		Phase I: Dose Level 1		Phase I: Dose Level 2		Phase I: Dose Level 3		Phase II: Arm A (Bevacizumab + Dasatinib)		Phase II: Arm B (Bevacizumab + Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		1/4 (25%)		2/3 (66.7%)		1/6 (16.7%)		32/84 (38.1%)		18/39 (46.2%)
Blood and lymphatic system disorders
Hemoglobin decreased	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Leukocytosis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Cardiac disorders
Cardiac disorder	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Myocardial ischemia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Sinus arrhythmia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Sinus tachycardia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Eye disorders
Eye disorders - Other, specify	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Optic nerve disorder	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	2
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Anal hemorrhage	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Colitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Colonic perforation	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Diarrhea	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	3/84 (3.6%)	3	0/39 (0%)	0
Ear, nose and throat examination abnormal	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Ileal obstruction	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Jejunal perforation	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Nausea	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	3	1/39 (2.6%)	1
Rectal hemorrhage	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Retroperitoneal hemorrhage	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Vomiting	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
General disorders
Chest pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Death	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Disease progression	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Edema limbs	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Fatigue	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	3/84 (3.6%)	3	3/39 (7.7%)	4
Fever	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	3/39 (7.7%)	3
Gait abnormal	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Sudden death	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/84 (0%)	0	0/39 (0%)	0
Infections and infestations
Bladder infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Catheter related infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Lung infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Pneumonia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	3	1/39 (2.6%)	1
Sepsis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	2/39 (5.1%)	2
Soft tissue infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Urinary tract infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Wound infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Injury, poisoning and procedural complications
Fracture	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	2/39 (5.1%)	21
Intraoperative complications	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Wound dehiscence	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Investigations
Bilirubin increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Creatinine increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/84 (0%)	0	0/39 (0%)	0
Laboratory test abnormal	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/84 (0%)	0	0/39 (0%)	0
Neutrophil count decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Platelet count decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Weight loss	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	2/84 (2.4%)	2	0/39 (0%)	0
Blood glucose increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Dehydration	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	2/84 (2.4%)	2	1/39 (2.6%)	1
Serum phosphate decreased	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Generalized muscle weakness	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Muscle weakness	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	4/84 (4.8%)	5	0/39 (0%)	0
Muscle weakness left-sided	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Muscle weakness lower limb	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	2/39 (5.1%)	2
Muscle weakness right-sided	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Musculoskeletal disorder	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Pain in extremity	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Nervous system disorders
Ataxia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	1/39 (2.6%)	1
Cognitive disturbance	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Depressed level of consciousness	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	2/39 (5.1%)	2
Dysphasia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Extrapyramidal disorder	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Headache	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Ischemia cerebrovascular	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	2
Memory impairment	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Seizure	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	3	4/39 (10.3%)	4
Somnolence	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Syncope	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Psychiatric disorders
Confusion	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	2/39 (5.1%)	4
Renal and urinary disorders
Bladder hemorrhage	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Cystitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	2	0/39 (0%)	0
Respiratory, thoracic and mediastinal disorders
Aspiration	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Atelectasis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	2	0/39 (0%)	0
Dyspnea	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Epistaxis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Hypoxia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Pleural effusion	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	2	0/39 (0%)	0
Respiratory disorder	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	3	1/39 (2.6%)	1
Skin and subcutaneous tissue disorders
Rash desquamating	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Vascular disorders
Hematoma	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Hypertension	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Hypotension	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Thrombosis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	2	3/39 (7.7%)	4
Other (Not Including Serious) Adverse Events
	Phase I: Dose Level 0		Phase I: Dose Level 1		Phase I: Dose Level 2		Phase I: Dose Level 3		Phase II: Arm A (Bevacizumab + Dasatinib)		Phase II: Arm B (Bevacizumab + Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		4/4 (100%)		3/3 (100%)		6/6 (100%)		83/84 (98.8%)		39/39 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	3/3 (100%)	28	2/4 (50%)	24	2/3 (66.7%)	22	5/6 (83.3%)	20	67/84 (79.8%)	432	14/39 (35.9%)	38
Cardiac disorders
Atrial fibrillation	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Sinus tachycardia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Ear and labyrinth disorders
Hearing test abnormal	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	2
Tinnitus	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Endocrine disorders
Cushingoid	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/84 (0%)	0	0/39 (0%)	0
Eye disorders
Cataract	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	2
Eye disorder	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Gastrointestinal disorders
Abdominal distension	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Abdominal pain	0/3 (0%)	0	1/4 (25%)	2	0/3 (0%)	0	1/6 (16.7%)	1	10/84 (11.9%)	17	7/39 (17.9%)	14
Anal pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Constipation	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	6/84 (7.1%)	8	0/39 (0%)	0
Diarrhea	1/3 (33.3%)	6	1/4 (25%)	6	1/3 (33.3%)	2	3/6 (50%)	13	50/84 (59.5%)	186	12/39 (30.8%)	51
Dyspepsia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	3	3/84 (3.6%)	4	0/39 (0%)	0
Dysphagia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	2/39 (5.1%)	9
Ear, nose and throat examination abnormal	0/3 (0%)	0	1/4 (25%)	6	1/3 (33.3%)	2	0/6 (0%)	0	11/84 (13.1%)	17	2/39 (5.1%)	3
Gastrointestinal pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	3	0/39 (0%)	0
Hemorrhoids	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Ileus	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Mucositis oral	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/6 (0%)	0	8/84 (9.5%)	13	4/39 (10.3%)	9
Nausea	1/3 (33.3%)	1	1/4 (25%)	2	1/3 (33.3%)	1	2/6 (33.3%)	3	31/84 (36.9%)	82	11/39 (28.2%)	37
Tooth disorder	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Upper gastrointestinal hemorrhage	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/84 (0%)	0	0/39 (0%)	0
Vomiting	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	17/84 (20.2%)	35	4/39 (10.3%)	6
General disorders
Edema limbs	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	1/39 (2.6%)	1
Facial pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Fatigue	3/3 (100%)	50	4/4 (100%)	37	3/3 (100%)	29	6/6 (100%)	57	73/84 (86.9%)	478	35/39 (89.7%)	241
Fever	1/3 (33.3%)	1	1/4 (25%)	1	0/3 (0%)	0	1/6 (16.7%)	1	16/84 (19%)	18	2/39 (5.1%)	2
Flu-like symptoms	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	1/39 (2.6%)	1
Gait abnormal	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Infections and infestations
Abdominal infection	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Appendicitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Bladder infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/84 (1.2%)	1	0/39 (0%)	0
Bone infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Bronchitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	3	0/39 (0%)	0
Encephalitis infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Gingival infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	2	1/39 (2.6%)	1
Joint infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Mucosal infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	2	0/39 (0%)	0
Opportunistic infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Otitis externa	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Pneumonia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	2	0/39 (0%)	0
Sinusitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	2
Skin infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	3	1/39 (2.6%)	1
Tooth infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Upper respiratory infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Urinary tract infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	4/84 (4.8%)	6	0/39 (0%)	0
Wound infection	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Injury, poisoning and procedural complications
Fracture	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	4/84 (4.8%)	4	1/39 (2.6%)	1
Wound dehiscence	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/6 (16.7%)	1	1/84 (1.2%)	1	0/39 (0%)	0
Investigations
Alanine aminotransferase increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	5/84 (6%)	10	2/39 (5.1%)	2
Aspartate aminotransferase increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	4/84 (4.8%)	11	1/39 (2.6%)	1
Blood gonadotrophin abnormal	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Cardiac troponin I increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Creatinine increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	4	0/39 (0%)	0
Electrocardiogram QTc interval prolonged	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Investigations - Other, specify	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Leukocyte count decreased	2/3 (66.7%)	14	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	29/84 (34.5%)	97	6/39 (15.4%)	13
Lymphocyte count decreased	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	2/6 (33.3%)	3	13/84 (15.5%)	35	7/39 (17.9%)	19
Lymphocyte count increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/84 (0%)	0	0/39 (0%)	0
Neutrophil count decreased	2/3 (66.7%)	23	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	14/84 (16.7%)	51	1/39 (2.6%)	3
Platelet count decreased	2/3 (66.7%)	16	1/4 (25%)	1	2/3 (66.7%)	4	3/6 (50%)	5	47/84 (56%)	180	13/39 (33.3%)	29
Weight gain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	6	0/39 (0%)	0
Weight loss	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	27/84 (32.1%)	182	11/39 (28.2%)	105
Metabolism and nutrition disorders
Anorexia	0/3 (0%)	0	1/4 (25%)	30	0/3 (0%)	0	0/6 (0%)	0	34/84 (40.5%)	114	13/39 (33.3%)	70
Blood glucose increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	4/84 (4.8%)	8	1/39 (2.6%)	1
Dehydration	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Hypermagnesemia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Hypoalbuminemia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Hypocalcemia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	2	1/39 (2.6%)	1
Hypokalemia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/84 (0%)	0	1/39 (2.6%)	1
Hypophosphatemia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	3	1/39 (2.6%)	1
Serum albumin decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	8/84 (9.5%)	12	0/39 (0%)	0
Serum calcium decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	8/84 (9.5%)	14	0/39 (0%)	0
Serum phosphate decreased	1/3 (33.3%)	3	2/4 (50%)	3	0/3 (0%)	0	0/6 (0%)	0	21/84 (25%)	33	3/39 (7.7%)	3
Serum potassium decreased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	3	1/39 (2.6%)	1
Serum potassium increased	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Serum sodium decreased	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	6/84 (7.1%)	8	2/39 (5.1%)	4
Generalized muscle weakness	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Joint pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	2
Muscle weakness	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	5/84 (6%)	48	2/39 (5.1%)	7
Muscle weakness left-sided	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	5
Muscle weakness lower limb	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	6	3/39 (7.7%)	4
Muscle weakness right-sided	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	1
Muscle weakness upper limb	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	2/39 (5.1%)	2
Myalgia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Neck pain	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Pain in extremity	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	2/39 (5.1%)	19
Nervous system disorders
Acoustic nerve disorder NOS	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	2
Ataxia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Central nervous system necrosis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Cognitive disturbance	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	4/84 (4.8%)	6	1/39 (2.6%)	2
Depressed level of consciousness	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Dizziness	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	3/39 (7.7%)	3
Dysarthria	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Dysgeusia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Dysphasia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	3	0/39 (0%)	0
Headache	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	7/84 (8.3%)	12	4/39 (10.3%)	4
Memory impairment	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	2
Mini mental status examination abnormal	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Nervous system disorders - Other, specify	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Neurological disorder NOS	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	2/39 (5.1%)	3
Peripheral motor neuropathy	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Peripheral sensory neuropathy	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	3	0/39 (0%)	0
Seizure	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	5/84 (6%)	7	2/39 (5.1%)	2
Speech disorder	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	3	5/39 (12.8%)	22
Taste alteration	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	5	0/39 (0%)	0
Psychiatric disorders
Agitation	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	5	1/39 (2.6%)	3
Anxiety	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	5/84 (6%)	8	0/39 (0%)	0
Confusion	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	4/84 (4.8%)	7	4/39 (10.3%)	7
Depression	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	5/84 (6%)	14	3/39 (7.7%)	14
Insomnia	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	5/84 (6%)	5	2/39 (5.1%)	2
Personality change	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	10	0/39 (0%)	0
Renal and urinary disorders
Protein urine positive	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	2/84 (2.4%)	15	1/39 (2.6%)	5
Renal failure	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/84 (0%)	0	0/39 (0%)	0
Urinary incontinence	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	2	0/39 (0%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Apnea	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	2	0/39 (0%)	0
Aspiration	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Atelectasis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	3	0/39 (0%)	0
Cough	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	3	1/39 (2.6%)	2
Dyspnea	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	3/84 (3.6%)	5	0/39 (0%)	0
Hemorrhage nasal	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Pharyngeal examination abnormal	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Pharyngeal mucositis	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	2/39 (5.1%)	7
Pleural effusion	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	6/84 (7.1%)	14	0/39 (0%)	0
Pneumonitis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/84 (1.2%)	1	0/39 (0%)	0
Voice alteration	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Skin and subcutaneous tissue disorders
Decubitus ulcer	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	10	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Dry skin	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/84 (0%)	0	1/39 (2.6%)	1
Pruritus	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Rash acneiform	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/84 (2.4%)	4	0/39 (0%)	0
Rash desquamating	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	16	0/84 (0%)	0	0/39 (0%)	0
Skin ulceration	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	0/39 (0%)	0
Urticaria	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/84 (1.2%)	1	1/39 (2.6%)	2
Vascular disorders
Hemorrhage	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/84 (0%)	0	0/39 (0%)	0
Hypertension	0/3 (0%)	0	2/4 (50%)	11	2/3 (66.7%)	4	4/6 (66.7%)	14	28/84 (33.3%)	131	18/39 (46.2%)	92
Thrombosis	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	4/84 (4.8%)	6	2/39 (5.1%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.