A Phase II Trial of Sutent (Sunitinib; SU011248) for Recurrent Anaplastic Astrocytoma and Glioblastoma

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00606008
• Collaborator: Pfizer (Industry)
• Enrollment: 30
• Location: 1
• Arm: 1
• Duration (Months): 65.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

We are asked patients to take part in this study because they had recurrent (returned) (1st or 2nd) anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM).

The purposes of this study are:

• To see if Sutent has any change on the patient and their cancer.

• To see if Sutent will slow or stop the growth of their tumor.

• To measure the safety of Sutent. Sutent is Food and Drug Administration (FDA) approved to treat patients with a gastrointestinal stromal tumor after the disease worsened while taking another medicine called imatinib mesylate or when imatinib mesylate cannot be taken. Sutent is also FDA approved to treat patients with advanced renal cell carcinoma. At this time, it is not known whether Sutent will improve symptoms, or help patients with this disease live longer.

Condition or Disease	Intervention/Treatment	Phase
Anaplastic Astrocytoma; Glioblastoma	Drug: Sunitinib Malate	Phase 2

Detailed Description

Trial patients received sunitinib 50 mg daily for 4 weeks without regard to meals, followed by a 2-week rest period. This 6-week regimen constituted 1 cycle. Patients were treated for up to 9 cycles [~ year) or until disease progression or death or if persistent toxicities occurred. Complete blood count with differential, complete metabolic profile, neurologic exam, and brain magnetic resonance imaging (MRI) with contrast were obtained after each cycle. Toxicity assessments were obtained after each cycle. Toxicity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0.

SCHEDULE OF EVENTS - PROTOCOL ACTIVITIES

<14 Days Prior to Initial Study Treatment:

• Neurological/Oncological History

• Neurological Examination

• Height/Weight/Body Surface Area

• Performance Status

• Quality of Life (QOL) FACT-L

• Laboratory Studies; complete blood count (CBC), Differential, Platelets, prothrombin time/partial thromboplastin time (PT/PTT), international normalized ratio (INR), Serum Creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), Total Bilirubin, alkaline phosphatase (AlkPHs), Pregnancy Test, electrocardiogram (EKG)

• Cranial MRI or CT with and without contrast

• Multiple uptake gated acquisition (MUGA) Scan

Day 1, At the Beginning of Each Treatment Cycle:

• Adverse Event Assessment

• Laboratory Studies; CBC, Differential, Platelets

Every Cycle, Days 42-45 (within 3 days of next scheduled Sutent treatment):

• Neurological/Oncological History

• Neurological Examination

• Height/Weight/Body Surface Area

• Performance Status

• QOL FACT-L

• Laboratory Studies; Serum Creatinine, BUN, ALT, AST, LDH, Total Bilirubin, AlkPHs

• Cranial MRI or CT with and without contrast

• Survival

At Off Study:

• Performance Status

• Cranial MRI or CT with and without contrast

• Survival

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Sutent (Sunitinib; SU011248) for Recurrent Anaplastic Astrocytoma and Glioblastoma Multiforme
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sutent Treatment Sutent was administered daily for 4 weeks at a dose of 50 mg followed by a 2 week study drug free break.	Drug: Sunitinib Malate; Initially, patients were started on sunitinib at a dose of 50 mg daily. If 50 mg daily resulted in unacceptable toxicity, 2 dose modifications were allowed (to 37.5 and to 25 mg daily, if necessary). Study patients who could not tolerate 25 mg daily of sunitinib were taken off study.; Other Names: Sutent SU011248

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Progression Free Survival (PFS) at 6 Months Utilizing McDonald Criteria for Response, Progression and Relapse [6 Months]

   Complete Response: Disappearance of all lesions, disease signs and symptoms related to the tumor. Partial Response (PR): When compared with pretreatment measurements, a reduction of 50% decrease in the sum of the longest diameters of all target enhancing lesions, taking as reference the baseline sum of the longest diameter. Stable Disease: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since treatment started. Objective Progression or Relapse: Relative to pretreatment measurements, an increase in the sum of the diameters of any measured enhancing lesion by at least 25% increase in the sum of the longest diameters since the treatment started or the appearance of new enhancing lesions.

Secondary Outcome Measures

1. Best Overall Response [12 Months]

   To estimate best response rates (proportion of patients who ever had a radiographic response equal to or better than stable disease during course assessment).

2. Number of Participants With Related Grade 3 and Greater Adverse Events [12 Months]

   To evaluate toxicities associated with sunitinib treatment (grade 3 and greater toxicities).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Resolution of all acute toxic effects of prior chemotherapy or radiotherapy or surgical procedures to NCI CTCAE Version 3.0 grade ≤1.

• Adequate organ function as defined by the following criteria:

• Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤3 x local laboratory upper limit of normal (ULN), or AST and ALT ≤3 x ULN if liver function abnormalities are due to underlying malignancy

• Total serum bilirubin ≤1.5 x ULN

• Absolute neutrophil count (ANC) ≥1500/µL

• Platelets ≥100,000/µL

• Hemoglobin ≥9.0 g/dL

• Serum calcium ≤12.0 mg/dL

• Serum creatinine ≤1.5 x ULN

• Patients must have histologically or neuroradiographically recurrent anaplastic astrocytoma (AA) or glioblastoma (GBM). Must have had prior pathologic confirmation of primary tumor histology.

• Must be ≥ 18 years old.

• Must have a Karnofsky performance status (KPS) ≥ 60%

• Measurable disease per MacDonald criteria required using contrast enhanced cranial MRI.

• Life expectancy ≥ 12 weeks.

• Must sign and date an Institutional Review Board (IRB) approved informed consent stating that he or she is aware of the neoplastic nature of the disease. Must willingly provide written consent after being informed of procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.

• Willing and able to comply with scheduled visits, treatment plan, laboratory tests and accessible for follow-up.

• Have undergone surgery documenting tumor histology though repeat surgery at time of tumor recurrence is not mandatory.

• Have received prior external beam radiotherapy.

• Patients may have received one or two prior salvage chemotherapy and may have received adjuvant chemotherapy following initial surgery.

• May not have received prior stereotactic radiotherapy.

• May have been treated with Gliadel at initial surgery only.

Exclusion Criteria:

• Major surgery or radiation therapy within 4 weeks of starting study treatment.

• NCI CTCAE grade 3 hemorrhage within 4 weeks of starting study treatment.

• History of or known spinal cord compression or carcinomatous meningitis, or evidence of leptomeningeal disease on screening CT or MRI scan.

• Any of the following within 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.

• Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2.

• Prolonged QTc interval on baseline EKG.

• Hypertension that cannot be controlled by medications (>150/100 mm Hg despite optimal medical therapy).

• Pre-existing thyroid abnormality with thyroid function that cannot be maintained in normal range with medication.

• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection.

• Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g. QOL, are allowed.

• Concomitant use of ketoconazole and other agents known to inhibit Cytochrome P450 3A4 (CYP3A4).

• Concomitant use of theophylline and phenobarbital and/or other agents metabolized by the cytochrome P450 system.

• Ongoing treatment with therapeutic doses of Coumadin (low dose up to 2 mg po daily for thrombo-prophylaxis is allowed).

• Pregnancy or breastfeeding. Female subjects must be surgically sterile, postmenopausal, or must agree to use effective contraception during the period of therapy. Female subjects with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment. Male subjects must be surgically sterile or must agree to use effective contraception during the period of therapy.

• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with interpretation of study results, and in the judgment of investigator would make patient inappropriate for entry into this study.

• Patients having been treated with 3 or more salvage regimens.

• Patients with a second active malignancy or diagnosis of other cancer within 3 years of enrollment, except for surgically cured basal cell carcinoma, or in situ carcinoma of the cervix.

• Mentally incapacitated patients or psychiatric illness that would prevent them from giving informed consent.

• Poorly controlled diabetes, hepatitis infection, uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, and myocardial infarction within previous 6 months, or serious uncontrolled cardiac arrhythmia.

• Known to be HIV positive or to have an AIDS-related illness.

• Patients with an active infection that is not adequately controlled with antibiotics.

• Patients with other severe concurrent disease, which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

• Known sensitivity to any of the products to be administered during treatment.

• Currently enrolled in another clinical trial or patients who have participated in a trial of an investigational device or drug within the last 30 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Pfizer

Investigators

• Principal Investigator: Edward Pan, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT00606008
• Other Study ID Numbers: MCC-14916
• First Posted: Feb 1, 2008
• Last Update Posted: Nov 19, 2012
• Last Verified: Sep 1, 2012

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Sutent
• Additional relevant MeSH terms: Glioblastoma; Astrocytoma; Sunitinib

Study Results

Participant Flow

Recruitment Details	Patients must have had pathologically or neuroradiographically recurrent AA or GB and prior pathologic confirmation of primary tumor histology. Patients with prior low-grade glioma were eligible if histological transformation to malignant astrocytic gliomas (MAG) was confirmed before enrollment.
Pre-assignment Detail	Study patients were stratified by tumor histology (AAor GB).

Arm/Group Title	Sutent Treatment
Arm/Group Description	Sutent was administered daily for 4 weeks at a dose of 50 mg followed by a 2 week study drug free break. Sunitinib Malate : Initially, patients were started on sunitinib at a dose of 50 mg daily. If 50 mg daily resulted in unacceptable toxicity, 2 dose modifications were allowed (to 37.5 and to 25 mg daily, if necessary). Study patients who could not tolerate 25 mg daily of sunitinib were taken off study.
Period Title: Overall Study
STARTED	30
COMPLETED	25
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Sutent Treatment
Arm/Group Description	Sutent was administered daily for 4 weeks at a dose of 50 mg followed by a 2 week study drug free break. Sunitinib Malate : Initially, patients were started on sunitinib at a dose of 50 mg daily. If 50 mg daily resulted in unacceptable toxicity, 2 dose modifications were allowed (to 37.5 and to 25 mg daily, if necessary). Study patients who could not tolerate 25 mg daily of sunitinib were taken off study.
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	26 86.7%
>=65 years	4 13.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52
Sex: Female, Male (Count of Participants)
Female	8 26.7%
Male	22 73.3%
Region of Enrollment (participants) [Number]
United States	30 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Progression Free Survival (PFS) at 6 Months Utilizing McDonald Criteria for Response, Progression and Relapse
Description	Complete Response: Disappearance of all lesions, disease signs and symptoms related to the tumor. Partial Response (PR): When compared with pretreatment measurements, a reduction of 50% decrease in the sum of the longest diameters of all target enhancing lesions, taking as reference the baseline sum of the longest diameter. Stable Disease: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since treatment started. Objective Progression or Relapse: Relative to pretreatment measurements, an increase in the sum of the diameters of any measured enhancing lesion by at least 25% increase in the sum of the longest diameters since the treatment started or the appearance of new enhancing lesions.
Time Frame	6 Months

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Sutent Treatment	AA Cohort Patients	GB Cohort Patients
Arm/Group Description	Sutent was administered daily for 4 weeks at a dose of 50 mg followed by a 2 week study drug free break. Sunitinib Malate : Initially, patients were started on sunitinib at a dose of 50 mg daily. If 50 mg daily resulted in unacceptable toxicity, 2 dose modifications were allowed (to 37.5 and to 25 mg daily, if necessary). Study patients who could not tolerate 25 mg daily of sunitinib were taken off study.	Recurrent glioblastoma (GB) patients	Anaplastic astrocytoma (AA)patients
Measure Participants	30	14	16
Number [Participants]	4 13.3%	2 NaN	2 NaN

2. Secondary Outcome

Title	Best Overall Response
Description	To estimate best response rates (proportion of patients who ever had a radiographic response equal to or better than stable disease during course assessment).
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Sutent Treatment	AA Cohort Patients	GB Cohort Patients
Arm/Group Description	Sutent was administered daily for 4 weeks at a dose of 50 mg followed by a 2 week study drug free break. Sunitinib Malate : Initially, patients were started on sunitinib at a dose of 50 mg daily. If 50 mg daily resulted in unacceptable toxicity, 2 dose modifications were allowed (to 37.5 and to 25 mg daily, if necessary). Study patients who could not tolerate 25 mg daily of sunitinib were taken off study.	Recurrent glioblastoma (GB) patients	Anaplastic astrocytoma (AA)patients
Measure Participants	30	14	16
Number [Participants]	13 43.3%	8 NaN	5 NaN

3. Secondary Outcome

Title	Number of Participants With Related Grade 3 and Greater Adverse Events
Description	To evaluate toxicities associated with sunitinib treatment (grade 3 and greater toxicities).
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Sutent Treatment	AA Cohort Patients	GB Cohort Patients
Arm/Group Description	Sutent was administered daily for 4 weeks at a dose of 50 mg followed by a 2 week study drug free break. Sunitinib Malate : Initially, patients were started on sunitinib at a dose of 50 mg daily. If 50 mg daily resulted in unacceptable toxicity, 2 dose modifications were allowed (to 37.5 and to 25 mg daily, if necessary). Study patients who could not tolerate 25 mg daily of sunitinib were taken off study.	Recurrent glioblastoma (GB) patients	Anaplastic astrocytoma (AA)patients
Measure Participants	30	14	16
Number [Participants]	11 36.7%	6 NaN	5 NaN

Adverse Events

Time Frame	4 years, 8 months
Adverse Event Reporting Description	Toxicity assessments were obtained after each cycle. Toxicity was graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Response evaluations were performed using modified Macdonald criteria. Serious Adverse Events: =/> Grade 3 toxicities associated with sunitinib.
Arm/Group Title	Sutent Treatment		AA Cohort Patients		GB Cohort Patients
Arm/Group Description	Sutent was administered daily for 4 weeks at a dose of 50 mg followed by a 2 week study drug free break. Sunitinib Malate : Initially, patients were started on sunitinib at a dose of 50 mg daily. If 50 mg daily resulted in unacceptable toxicity, 2 dose modifications were allowed (to 37.5 and to 25 mg daily, if necessary). Study patients who could not tolerate 25 mg daily of sunitinib were taken off study.		Recurrent glioblastoma (GB) patients		Anaplastic astrocytoma (AA)patients
All Cause Mortality
	Sutent Treatment		AA Cohort Patients		GB Cohort Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sutent Treatment		AA Cohort Patients		GB Cohort Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/30 (36.7%)		6/14 (42.9%)		5/16 (31.3%)
Blood and lymphatic system disorders
Leukocytes (total WBC)	3/30 (10%)		3/14 (21.4%)		0/16 (0%)
Lymphopenia	1/30 (3.3%)		1/14 (7.1%)		0/16 (0%)
Platelets	4/30 (13.3%)		2/14 (14.3%)		2/16 (12.5%)
Neutrophils/granulocytes (ANC/AGC)	1/30 (3.3%)		0/14 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Mucositis/stomatitis (functional/symptomatic) - anus	1/30 (3.3%)		0/14 (0%)		1/16 (6.3%)
General disorders
Fatigue (asthenia, lethargy, malaise)	3/30 (10%)		1/14 (7.1%)		2/16 (12.5%)
Death not associated with CTCAE term - disease progression NOS	1/30 (3.3%)		1/14 (7.1%)		0/16 (0%)
Hemorrhage/bleeding-other	1/30 (3.3%)		1/14 (7.1%)		0/16 (0%)
Metabolism and nutrition disorders
ALT, SGPT	1/30 (3.3%)		0/14 (0%)		1/16 (6.3%)
AST, SGOT	1/30 (3.3%)		0/14 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Dermatology/skin-other	1/30 (3.3%)		1/14 (7.1%)		0/16 (0%)
Rash: hand-foot skin reaction	2/30 (6.7%)		2/14 (14.3%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Sutent Treatment		AA Cohort Patients		GB Cohort Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/30 (93.3%)		14/14 (100%)		14/16 (87.5%)
Blood and lymphatic system disorders
Lymphatics - other	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Leukocytes (total WBC)	5/30 (16.7%)	7	3/14 (21.4%)	5	2/16 (12.5%)	2
Neutrophils/granulocytes (ANC/AGC)	7/30 (23.3%)	13	4/14 (28.6%)	6	3/16 (18.8%)	7
Platelets	6/30 (20%)	6	3/14 (21.4%)	3	3/16 (18.8%)	3
Lymphopenia	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Hemoglobin	3/30 (10%)	5	2/14 (14.3%)	2	1/16 (6.3%)	3
Edema: limb	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Blood/Bone Marrow - Other	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Cardiac disorders
Hypertension	3/30 (10%)	3	1/14 (7.1%)	1	2/16 (12.5%)	2
Ear and labyrinth disorders
Hearing: patients without baseline audiogram and not enrolled n a monitoring program	2/30 (6.7%)	2	0/14 (0%)	0	2/16 (12.5%)	2
Endocrine disorders
Hot flashes/flushes	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Eye disorders
Vision - Blurred vision	3/30 (10%)	3	2/14 (14.3%)	2	1/16 (6.3%)	1
Ocular/Visual - Other	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Pain - Eye	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Gastrointestinal disorders
Constipation	7/30 (23.3%)	8	2/14 (14.3%)	2	5/16 (31.3%)	6
Anorexia	4/30 (13.3%)	4	3/14 (21.4%)	3	1/16 (6.3%)	1
Gastrointestinal - other	3/30 (10%)	3	1/14 (7.1%)	1	2/16 (12.5%)	2
Heartburn/dyspepsia	3/30 (10%)	4	1/14 (7.1%)	1	2/16 (12.5%)	3
Nausea	7/30 (23.3%)	8	5/14 (35.7%)	6	2/16 (12.5%)	2
Vomiting	7/30 (23.3%)	7	4/14 (28.6%)	4	3/16 (18.8%)	3
Diarrhea	15/30 (50%)	16	7/14 (50%)	8	8/16 (50%)	8
Mucositis/stomatitis (clinical exam) - Oral cavity	5/30 (16.7%)	6	2/14 (14.3%)	2	3/16 (18.8%)	4
Flatulence	2/30 (6.7%)	2	0/14 (0%)	0	2/16 (12.5%)	2
Perforation, GI - Rectum	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Dysphagia (difficulty swallowing)	2/30 (6.7%)	2	1/14 (7.1%)	1	1/16 (6.3%)	1
Mucositis/stomatitis (functional/symptomatic) - Stomach	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
General disorders
Fatigue (asthenia, lethargy, malaise)	21/30 (70%)	27	11/14 (78.6%)	12	10/16 (62.5%)	15
Confusion	4/30 (13.3%)	5	3/14 (21.4%)	3	1/16 (6.3%)	2
Mood alteration - Depression	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Pain - Back	3/30 (10%)	3	2/14 (14.3%)	2	1/16 (6.3%)	1
Weight loss	4/30 (13.3%)	4	2/14 (14.3%)	2	0/16 (0%)	0
Cognitive disturbance	3/30 (10%)	3	2/14 (14.3%)	2	1/16 (6.3%)	2
Insomnia	2/30 (6.7%)	2	2/14 (14.3%)	2	0/16 (0%)	0
Pain - Abdomen NOS	2/30 (6.7%)	2	0/14 (0%)	0	2/16 (12.5%)	2
Pain - Other	3/30 (10%)	3	1/14 (7.1%)	1	2/16 (12.5%)	2
Pain - Stomach	2/30 (6.7%)	2	0/14 (0%)	0	2/16 (12.5%)	2
Sweating (diaphoresis)	4/30 (13.3%)	5	2/14 (14.3%)	2	2/16 (12.5%)	3
Rigors/chills	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Pain - Extremity-limb	2/30 (6.7%)	3	1/14 (7.1%)	1	1/16 (6.3%)	2
Petechiae/purpura (hemorrhage/bleeding into skin or mucosa)	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Pain - Chest wall	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Mood alteration - Agitation	5/30 (16.7%)	5	3/14 (21.4%)	3	2/16 (12.5%)	2
Hemorrhage/Bleeding - Other	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	3/30 (10%)	5	1/14 (7.1%)	3	2/16 (12.5%)	2
Allergy/Immunology - Other	3/30 (10%)	3	2/14 (14.3%)	2	1/16 (6.3%)	1
Allergic reaction/hypersensitivity (including drug fever)	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils - Mucosa	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils - Upper airway NOS	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Infection with unknown ANC - Oral cavity-gums (gingivitis)	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Metabolism and nutrition disorders
Glucose, serum-high (hyperglycemia)	3/30 (10%)	3	2/14 (14.3%)	2	1/16 (6.3%)	1
ALT, SGPT (serum glutamic pyruvic transaminase)	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
AST, SGOT (serum glutamic oxaloacetic transaminase)	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Sodium, serum-low (hyponatremia)	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy) - Whole body/generalized	2/30 (6.7%)	2	1/14 (7.1%)	1	1/16 (6.3%)	1
Muscle weakness, generalized or specific area (not due to neuropathy) - Extremity - lower	2/30 (6.7%)	2	1/14 (7.1%)	1	1/16 (6.3%)	1
Muscle weakness, generalized or specific area (not due to neuropathy) - Extremity - upper	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Pain - Joint	5/30 (16.7%)	6	3/14 (21.4%)	4	2/16 (12.5%)	2
Muscoleoskeletal/Soft Tissue - Other	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Pain - Muscle	2/30 (6.7%)	2	1/14 (7.1%)	1	1/16 (6.3%)	1
Nervous system disorders
Ataxia (incoordination)	3/30 (10%)	3	3/14 (21.4%)	3	0/16 (0%)	0
Neuropathy: cranial - CN IV Downward, inward movement of eye	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Neuropathy: cranial - CN II Vision	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Neuropathy: motor	11/30 (36.7%)	13	5/14 (35.7%)	6	6/16 (37.5%)	7
Neuropathy: sensory	8/30 (26.7%)	10	5/14 (35.7%)	6	3/16 (18.8%)	4
Speech impairment (e.g., dysphasia or aphasia)	5/30 (16.7%)	5	2/14 (14.3%)	2	3/16 (18.8%)	3
Pain - Head/headache	8/30 (26.7%)	10	2/14 (14.3%)	3	6/16 (37.5%)	7
Seizure	3/30 (10%)	4	2/14 (14.3%)	3	1/16 (6.3%)	1
Dizziness	2/30 (6.7%)	2	1/14 (7.1%)	1	1/16 (6.3%)	1
Neuropathy: cranial - CN VII Motor-face; Sensory-taste	2/30 (6.7%)	2	0/14 (0%)	0	2/16 (12.5%)	2
Somnolence/depressed level of consciousness	2/30 (6.7%)	2	1/14 (7.1%)	1	1/16 (6.3%)	1
Neuropathy: cranial - CN I Smell	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Neuropathy: cranial - CN V Motor-jaw muscles; Sensory-facial	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Hemorrhage, CNS	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Tremor	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Neurology - Other	2/30 (6.7%)	2	1/14 (7.1%)	1	1/16 (6.3%)	1
Renal and urinary disorders
Urinary frequency/urgency	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Renal/Genitourinary - Other	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Hiccoughs (hiccups, singultus)	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Cough	3/30 (10%)	3	1/14 (7.1%)	1	2/16 (12.5%)	2
Infection with unknown ANC - Lung pneumonia)	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Dermatology/Skin - other	7/30 (23.3%)	9	4/14 (28.6%)	5	3/16 (18.8%)	4
Hair loss/alopecia (scalp or body)	3/30 (10%)	3	2/14 (14.3%)	2	1/16 (6.3%)	1
Rash: hand-foot skin reaction	4/30 (13.3%)	5	3/14 (21.4%)	3	1/16 (6.3%)	2
Urticaria (hives, welts, wheals)	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0
Dry skin	2/30 (6.7%)	2	0/14 (0%)	0	2/16 (12.5%)	2
Pruritus/itching	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Hypopigmentation	3/30 (10%)	3	3/14 (21.4%)	3	0/16 (0%)	0
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	2/30 (6.7%)	2	1/14 (7.1%)	1	1/16 (6.3%)	1
Rash: acne/acneiform	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Photosensitivity	1/30 (3.3%)	1	0/14 (0%)	0	1/16 (6.3%)	1
Rash/desquamation	4/30 (13.3%)	6	2/14 (14.3%)	4	2/16 (12.5%)	2
Flushing	1/30 (3.3%)	1	1/14 (7.1%)	1	0/16 (0%)	0

Limitations/Caveats

No definitive conclusions can be made regarding outcome differences between bevacizumab vs. bevacizumab-naive study patients, due to not enough patients who received bevacizumab prior to study enrollment (2 AA, 3 GB).

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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.