Bevacizumab and Low-Dose Cyclophosphamide in Treating Patients With Recurrent Ovarian Epithelial or Primary Peritoneal Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00072566
• Collaborator: (none)
• Enrollment: 70
• Location: 1
• Arm: 1
• Duration (Months): 59
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This phase II trial is to see if combining bevacizumab with low-dose cyclophosphamide works in treating patients with ovarian epithelial or primary peritoneal cancer that has come back or spread to other parts of the body. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining bevacizumab with cyclophosphamide may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Primary Peritoneal Carcinoma; Recurrent Ovarian Carcinoma; Stage IV Ovarian Cancer	Biological: Bevacizumab; Drug: Cyclophosphamide; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

OBJECTIVES: Primary I. Determine the time to progression in patients with recurrent ovarian epithelial or primary peritoneal cancer treated with bevacizumab and low-dose cyclophosphamide.

Secondary I. Determine the response rate in patients treated with this regimen. II. Determine the toxicity of this regimen in these patients. III. Determine molecular correlates for response and outcomes in patients treated with this regimen.

OUTLINE: This is a nonrandomized, multicenter study.

Patients receive bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 23-55 patients will be accrued for this study within 1-2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Clinical Trial of Bevacizumab (NSC 704865) and Low Dose Oral Cyclophosphamide in Recurrent Ovarian Cancer, Primary Peritoneal Carcinoma
• Study Start Date: Dec 1, 2003
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (bevacizumab, cyclophosphamide) Patients receive bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Biological: Bevacizumab; Given IV; Other Names: Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF rhuMAb Avastin Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF ; Drug: Cyclophosphamide; Given PO; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Median Time to Progression [Up to 3 years]

   Time from treatment initiation to disease progresion calculated using the method of Kaplan-Meier. RECIST v1.0 was used to evaluate response. Progression was defined as a 20% or greater increase in the sums of the longest dimensions of target lesions, or the appearance of new lesions within 8 weeks of study entry.

Secondary Outcome Measures

1. Response Rate Based on the RECIST [Up to 3 years]

   Percentage of patients with a confirmed partial or complete response using RECIST v1.0 criteria. Complete response was defined as the disapperance of all target and nontarget lesions, no evidence of new lesions and normalization of CA-125; Partial response was defined as a 30% or greater reduction in the sum of the longest dimensions of all target lesions and no unequivocal progression of nontarget lesions, lasting at least 4 weeks.

2. Median Overall Survival [Time from first day of treatment to time of death due to any cause, assessed up to 3 years]

   Calculated using the method of Kaplan-Meier.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed recurrent or metastatic ovarian epithelial or primary peritoneal cancer

• Unidimensionally measurable disease

• Previously irradiated indicator lesions must have progressed after radiotherapy

• Received a platinum-containing regimen for primary disease

• No more than 2 prior chemotherapy regimens for recurrent disease

• Must have received prior platinum-based chemotherapy for recurrent disease if it has been > 12 months since treatment for primary disease (except if hypersensitivity to platinum has developed)

• Rechallenge with the same platinum-based regimen is considered 1 prior regimen

• No history or clinical evidence of CNS disease, including primary brain tumor

• No brain metastases

• Performance status - SWOG 0-2

• At least 3 months

• Absolute neutrophil count at least 1,500/mm^3

• Platelet count at least 100,000/mm^3

• No bleeding diathesis

• No coagulopathy

• Bilirubin no greater than 1.5 times normal

• ALT or AST no greater than 3 times upper limit of normal

• INR less than 1.5 (for patients receiving warfarin)

• Creatinine no greater than 1.5 times normal

• No proteinuria (less than 1+)

• Proteinuria less than 500 mg/24-hour urine collection

• No prior deep vein thrombosis

• No prior stroke

• No clinically significant cardiovascular disease

• None of the following within the past year:

• Uncontrolled hypertension

• New York Heart Association class II-IV congestive heart failure

• Serious cardiac arrhythmia requiring medication

• Grade II or greater peripheral vascular disease

• None of the following within the past 6 months:

• Unstable angina

• Myocardial infarction

• Transient ischemic attack

• Cerebrovascular accident

• Other arterial thromboembolic event

• No clinically significant peripheral artery disease

• No active infection requiring parenteral antibiotics

• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

• Not pregnant or nursing

• Fertile patients must use effective contraception

• No serious, non-healing wound, ulcer, or bone fracture

• No significant traumatic injury within the past 28 days

• No seizures not controlled with standard medical therapy

• No other malignancy within the past 5 years except nonmelanoma skin cancer or carcinoma in situ of the cervix

• All prior invasive malignancies must be in complete remission

• No other concurrent medical, psychological, or social condition that would preclude study participation

• No prior antiangiogenesis agents

• See Disease Characteristics

• Recovered from prior chemotherapy

• See Disease Characteristics

• Recovered from prior radiotherapy

• More than 28 days since prior major surgical procedure or open biopsy and recovered

• At least 3 weeks since prior therapy directed at the malignancy

• No recent or concurrent full-dose anticoagulants or thrombolytic agents

• Anticoagulants to maintain patency of preexisting, permanent indwelling IV catheters allowed

• No concurrent chronic daily aspirin (greater than 325 mg/day) or nonsteroidal anti-inflammatory drugs known to inhibit platelet function

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Agustin Garcia, City of Hope Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00072566
• Other Study ID Numbers: NCI-2012-02562; NCI-2012-02562; NCI-5789; CHNMC-PHII-45; CDR0000340522; CCC-PHII-45; PHII-45; 5789; N01CM17101; P30CA033572
• First Posted: Nov 5, 2003
• Last Update Posted: May 12, 2015
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Carcinoma; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Recurrence; Cyclophosphamide; Bevacizumab; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Endothelial Growth Factors

Study Results

Participant Flow

Arm/Group Title	Treatment (Bevacizumab, Cyclophosphamide)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide 50 mg/d on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV cyclophosphamide: Given PO
Period Title: Overall Study
STARTED	70
COMPLETED	70
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Bevacizumab, Cyclophosphamide)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide 50 mg/d on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV cyclophosphamide: Given PO
Overall Participants	70
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	70 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	70 100%

Outcome Measures

1. Primary Outcome

Title	Median Time to Progression
Description	Time from treatment initiation to disease progresion calculated using the method of Kaplan-Meier. RECIST v1.0 was used to evaluate response. Progression was defined as a 20% or greater increase in the sums of the longest dimensions of target lesions, or the appearance of new lesions within 8 weeks of study entry.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab, Cyclophosphamide)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide 50 mg/d on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV cyclophosphamide: Given PO
Measure Participants	70
Median (95% Confidence Interval) [months]	7.2

2. Secondary Outcome

Title	Response Rate Based on the RECIST
Description	Percentage of patients with a confirmed partial or complete response using RECIST v1.0 criteria. Complete response was defined as the disapperance of all target and nontarget lesions, no evidence of new lesions and normalization of CA-125; Partial response was defined as a 30% or greater reduction in the sum of the longest dimensions of all target lesions and no unequivocal progression of nontarget lesions, lasting at least 4 weeks.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab, Cyclophosphamide)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide 50 mg/d on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV cyclophosphamide: Given PO
Measure Participants	70
Number [percentage of responding patients]	24

3. Secondary Outcome

Title	Median Overall Survival
Description	Calculated using the method of Kaplan-Meier.
Time Frame	Time from first day of treatment to time of death due to any cause, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Bevacizumab, Cyclophosphamide)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide 50 mg/d on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV cyclophosphamide: Given PO
Measure Participants	70
Median (95% Confidence Interval) [months]	16.9

Adverse Events

Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Treatment (Bevacizumab, Cyclophosphamide)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide 50 mg/d on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV cyclophosphamide: Given PO
All Cause Mortality
	Treatment (Bevacizumab, Cyclophosphamide)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Bevacizumab, Cyclophosphamide)
	Affected / at Risk (%)	# Events
Total	23/70 (32.9%)
Cardiac disorders
Sinus tachycardia	1/70 (1.4%)	1
Eye disorders
Eye pain	1/70 (1.4%)	1
Gastrointestinal disorders
Abdominal pain	3/70 (4.3%)	3
Cecal obstruction	1/70 (1.4%)	1
Constipation	3/70 (4.3%)	3
Jejunal perforation	1/70 (1.4%)	1
Small intestinal obstruction	5/70 (7.1%)	5
Small intestinal perforation	1/70 (1.4%)	1
General disorders
Death	2/70 (2.9%)	2
Disease progression	1/70 (1.4%)	1
Fatigue	2/70 (2.9%)	3
Injury, poisoning and procedural complications
Wound dehiscence	1/70 (1.4%)	1
Investigations
Alanine aminotransferase increased	2/70 (2.9%)	2
Alkaline phosphatase increased	2/70 (2.9%)	2
Aspartate aminotransferase increased	2/70 (2.9%)	2
Cardiac troponin T increased	1/70 (1.4%)	1
Lymphopenia	1/70 (1.4%)	1
Metabolism and nutrition disorders
Hyponatremia	1/70 (1.4%)	1
Musculoskeletal and connective tissue disorders
Arthritis	1/70 (1.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplasia	1/70 (1.4%)	1
Nervous system disorders
Dizziness	2/70 (2.9%)	2
Intracranial hemorrhage	1/70 (1.4%)	1
Ischemia cerebrovascular	2/70 (2.9%)	2
Speech disorder	1/70 (1.4%)	1
Psychiatric disorders
Confusion	1/70 (1.4%)	1
Renal and urinary disorders
Proteinuria	1/70 (1.4%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/70 (2.9%)	2
Hypoxia	1/70 (1.4%)	1
Pulmonary hypertension	2/70 (2.9%)	2
Skin and subcutaneous tissue disorders
Rash desquamating	1/70 (1.4%)	1
Sweating	1/70 (1.4%)	1
Vascular disorders
Hypertension	1/70 (1.4%)	1
Hypotension	1/70 (1.4%)	1
Thrombosis	2/70 (2.9%)	3
Other (Not Including Serious) Adverse Events
	Treatment (Bevacizumab, Cyclophosphamide)
	Affected / at Risk (%)	# Events
Total	70/70 (100%)
Blood and lymphatic system disorders
Blood disorder	1/70 (1.4%)	1
Hemoglobin decreased	32/70 (45.7%)	105
Lymphatic disorder	1/70 (1.4%)	3
Cardiac disorders
Myocardial ischemia	1/70 (1.4%)	1
Palpitations	2/70 (2.9%)	5
Pericardial effusion	1/70 (1.4%)	16
Sinus tachycardia	4/70 (5.7%)	6
Ear and labyrinth disorders
Ear pain	2/70 (2.9%)	3
External ear inflammation	1/70 (1.4%)	1
Hearing loss	2/70 (2.9%)	24
Hearing test abnormal	2/70 (2.9%)	18
Tinnitus	5/70 (7.1%)	58
Eye disorders
Cataract	1/70 (1.4%)	1
Dry eye syndrome	3/70 (4.3%)	4
Eye pain	1/70 (1.4%)	1
Flashing vision	2/70 (2.9%)	11
Vision blurred	5/70 (7.1%)	8
Gastrointestinal disorders
Abdominal distension	18/70 (25.7%)	47
Abdominal pain	43/70 (61.4%)	142
Ascites	1/70 (1.4%)	1
Colitis	1/70 (1.4%)	1
Colonic perforation	1/70 (1.4%)	1
Constipation	37/70 (52.9%)	129
Diarrhea	27/70 (38.6%)	99
Dry mouth	4/70 (5.7%)	16
Dyspepsia	17/70 (24.3%)	80
Dysphagia	1/70 (1.4%)	1
Ear, nose and throat examination abnormal	2/70 (2.9%)	2
Esophageal pain	2/70 (2.9%)	12
Esophagitis	1/70 (1.4%)	5
Fecal incontinence	1/70 (1.4%)	1
Flatulence	6/70 (8.6%)	12
Gastritis	2/70 (2.9%)	5
Gastrointestinal disorder	7/70 (10%)	31
Gastrointestinal pain	3/70 (4.3%)	3
Gingival pain	1/70 (1.4%)	1
Hemorrhoidal hemorrhage	1/70 (1.4%)	1
Hemorrhoids	9/70 (12.9%)	48
Ileus	1/70 (1.4%)	1
Lip pain	1/70 (1.4%)	1
Malabsorption	1/70 (1.4%)	4
Mucositis oral	16/70 (22.9%)	38
Nausea	44/70 (62.9%)	115
Oral hemorrhage	5/70 (7.1%)	21
Oral pain	1/70 (1.4%)	1
Periodontal disease	4/70 (5.7%)	13
Rectal fistula	1/70 (1.4%)	2
Rectal hemorrhage	3/70 (4.3%)	8
Small intestinal obstruction	2/70 (2.9%)	2
Stomach pain	1/70 (1.4%)	3
Tooth disorder	7/70 (10%)	26
Toothache	1/70 (1.4%)	2
Vomiting	29/70 (41.4%)	57
General disorders
Chest pain	5/70 (7.1%)	15
Chills	10/70 (14.3%)	11
Disease progression	41/70 (58.6%)	41
Edema limbs	8/70 (11.4%)	33
Fatigue	63/70 (90%)	408
Fever	9/70 (12.9%)	10
Flu-like symptoms	5/70 (7.1%)	6
General symptom	4/70 (5.7%)	5
Injection site reaction	1/70 (1.4%)	1
Localized edema	1/70 (1.4%)	1
Pain	13/70 (18.6%)	36
Immune system disorders
Hypersensitivity	3/70 (4.3%)	3
Infections and infestations
Bladder infection	3/70 (4.3%)	21
Conjunctivitis infective	1/70 (1.4%)	2
Infection	6/70 (8.6%)	9
Infectious colitis	1/70 (1.4%)	1
Lip infection	1/70 (1.4%)	1
Opportunistic infection	5/70 (7.1%)	8
Phlebitis infective	2/70 (2.9%)	4
Pneumonia	3/70 (4.3%)	7
Rhinitis infective	2/70 (2.9%)	4
Sinusitis	1/70 (1.4%)	1
Upper respiratory infection	3/70 (4.3%)	5
Urinary tract infection	4/70 (5.7%)	12
Vaginal infection	2/70 (2.9%)	2
Vulvitis	1/70 (1.4%)	2
Injury, poisoning and procedural complications
Bruising	3/70 (4.3%)	6
Fracture	4/70 (5.7%)	7
Radiation recall reaction (dermatologic)	1/70 (1.4%)	1
Vascular access complication	1/70 (1.4%)	1
Wound dehiscence	2/70 (2.9%)	3
Investigations
Activated partial thromboplastin time prolonged	14/70 (20%)	41
Alanine aminotransferase increased	25/70 (35.7%)	109
Alkaline phosphatase increased	31/70 (44.3%)	97
Amylase increased	3/70 (4.3%)	3
Aspartate aminotransferase increased	29/70 (41.4%)	62
Coagulopathy	1/70 (1.4%)	2
Creatine phosphokinase increased	1/70 (1.4%)	2
Creatinine increased	25/70 (35.7%)	162
Haptoglobin decreased	1/70 (1.4%)	1
Hyperbilirubinemia	3/70 (4.3%)	6
Hypercholesterolemia	1/70 (1.4%)	1
INR increased	5/70 (7.1%)	6
Laboratory test abnormal	1/70 (1.4%)	1
Leukopenia	29/70 (41.4%)	114
Lymphopenia	44/70 (62.9%)	351
Neutrophil count decreased	18/70 (25.7%)	40
Platelet count decreased	10/70 (14.3%)	65
Serum cholesterol increased	1/70 (1.4%)	2
Weight gain	1/70 (1.4%)	2
Weight loss	7/70 (10%)	44
Metabolism and nutrition disorders
Anorexia	28/70 (40%)	73
Blood bicarbonate decreased	3/70 (4.3%)	3
Dehydration	1/70 (1.4%)	1
Glucose intolerance	1/70 (1.4%)	19
Hypercalcemia	13/70 (18.6%)	27
Hyperglycemia	19/70 (27.1%)	53
Hyperkalemia	5/70 (7.1%)	16
Hypermagnesemia	3/70 (4.3%)	3
Hypernatremia	7/70 (10%)	10
Hypertriglyceridemia	1/70 (1.4%)	2
Hyperuricemia	4/70 (5.7%)	10
Hypoalbuminemia	17/70 (24.3%)	24
Hypocalcemia	10/70 (14.3%)	12
Hypoglycemia	2/70 (2.9%)	2
Hypokalemia	13/70 (18.6%)	27
Hypomagnesemia	26/70 (37.1%)	165
Hyponatremia	23/70 (32.9%)	62
Hypophosphatemia	6/70 (8.6%)	8
Serum calcium decreased	1/70 (1.4%)	4
Serum magnesium decreased	1/70 (1.4%)	3
Serum sodium decreased	1/70 (1.4%)	4
Serum triglycerides increased	1/70 (1.4%)	6
Musculoskeletal and connective tissue disorders
Arthritis	9/70 (12.9%)	74
Back pain	17/70 (24.3%)	82
Bone pain	4/70 (5.7%)	5
Chest wall pain	1/70 (1.4%)	1
Joint disorder	1/70 (1.4%)	1
Joint pain	26/70 (37.1%)	182
Muscle weakness lower limb	1/70 (1.4%)	1
Musculoskeletal disorder	1/70 (1.4%)	3
Myalgia	17/70 (24.3%)	73
Neck pain	4/70 (5.7%)	14
Pain in extremity	5/70 (7.1%)	17
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor flare	1/70 (1.4%)	15
Tumor pain	6/70 (8.6%)	27
Nervous system disorders
Dizziness	14/70 (20%)	38
Extrapyramidal disorder	3/70 (4.3%)	4
Headache	42/70 (60%)	234
Ischemia cerebrovascular	1/70 (1.4%)	1
Memory impairment	3/70 (4.3%)	5
Neurological disorder NOS	1/70 (1.4%)	2
Olfactory nerve disorder	1/70 (1.4%)	1
Peripheral sensory neuropathy	18/70 (25.7%)	127
Sinus pain	1/70 (1.4%)	6
Speech disorder	1/70 (1.4%)	1
Taste alteration	6/70 (8.6%)	30
Tremor	1/70 (1.4%)	1
Psychiatric disorders
Anxiety	22/70 (31.4%)	124
Confusion	1/70 (1.4%)	6
Depression	13/70 (18.6%)	62
Insomnia	19/70 (27.1%)	145
Renal and urinary disorders
Bladder pain	2/70 (2.9%)	5
Cystitis	2/70 (2.9%)	5
Hemoglobinuria	1/70 (1.4%)	3
Hemorrhage urinary tract	10/70 (14.3%)	38
Kidney pain	2/70 (2.9%)	31
Protein urine positive	2/70 (2.9%)	13
Proteinuria	30/70 (42.9%)	137
Ureteric obstruction	1/70 (1.4%)	6
Urethral hemorrhage	2/70 (2.9%)	2
Urethral pain	2/70 (2.9%)	14
Urinary frequency	5/70 (7.1%)	9
Urinary incontinence	2/70 (2.9%)	12
Urine discoloration	1/70 (1.4%)	1
Urogenital disorder	1/70 (1.4%)	1
Reproductive system and breast disorders
Breast pain	2/70 (2.9%)	2
Pelvic pain	2/70 (2.9%)	8
Vaginal discharge	1/70 (1.4%)	2
Vaginal dryness	2/70 (2.9%)	4
Vaginal hemorrhage	2/70 (2.9%)	2
Vaginal inflammation	1/70 (1.4%)	2
Vaginal pain	2/70 (2.9%)	3
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	18/70 (25.7%)	57
Bronchial fistula	1/70 (1.4%)	1
Cough	23/70 (32.9%)	45
Dyspnea	28/70 (40%)	112
Hemorrhage nasal	11/70 (15.7%)	23
Laryngeal mucositis	1/70 (1.4%)	2
Pharyngeal hemorrhage	1/70 (1.4%)	1
Pharyngeal mucositis	1/70 (1.4%)	1
Pharyngolaryngeal pain	9/70 (12.9%)	13
Pleural effusion	2/70 (2.9%)	3
Respiratory disorder	1/70 (1.4%)	1
Respiratory tract hemorrhage	3/70 (4.3%)	3
Voice alteration	9/70 (12.9%)	22
Skin and subcutaneous tissue disorders
Alopecia	12/70 (17.1%)	115
Decubitus ulcer	1/70 (1.4%)	1
Dry skin	6/70 (8.6%)	23
Erythema multiforme	1/70 (1.4%)	1
Nail disorder	5/70 (7.1%)	17
Pain of skin	3/70 (4.3%)	13
Petechiae	2/70 (2.9%)	12
Photosensitivity	1/70 (1.4%)	1
Pruritus	4/70 (5.7%)	30
Rash desquamating	12/70 (17.1%)	25
Skin disorder	6/70 (8.6%)	20
Skin hypopigmentation	2/70 (2.9%)	2
Sweating	7/70 (10%)	17
Urticaria	2/70 (2.9%)	2
Vascular disorders
Flushing	2/70 (2.9%)	2
Hemorrhage	3/70 (4.3%)	6
Hot flashes	10/70 (14.3%)	68
Hypertension	27/70 (38.6%)	185
Hypotension	1/70 (1.4%)	1
Vascular disorder	1/70 (1.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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