Bevacizumab in Treating Patients With Angiosarcoma

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00288015
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 32
• Locations: 5
• Arm: 1
• Duration (Months): 133.3
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: 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 stop the growth of tumor cells by blocking blood flow to the tumor.

PURPOSE: This phase II trial is studying how well bevacizumab works in treating patients with angiosarcoma.

Condition or Disease	Intervention/Treatment	Phase
Sarcoma	Biological: Bevacizumab	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the median progression-free survival, in terms of stable disease, of patients with newly diagnosed or recurrent/refractory angiosarcoma treated with bevacizumab.

Secondary

• Evaluate the treatment effect of bevacizumab on the objective response rate as assessed by modified RECIST criteria in patients with angiosarcoma.

• Evaluate the duration of response.

• Assess the treatment effect of bevacizumab on duration of overall survival.

• Explore the objective response by target tumor density changes on CT scan.

• Evaluate the safety and tolerability of bevacizumab in patients with angiosarcoma.

OUTLINE: This is an open-label, multicenter study.

Patients receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 to 4 months for 2 years.

PROJECTED ACCRUAL: A total of 31 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Multicenter Phase II Study of Bevacizumab for the Treatment of Angiosarcoma
• Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: Jun 6, 2013
• Actual Study Completion Date: Nov 10, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bevacizumab Bevacizumab treatment until disease progression or intolerance	Biological: Bevacizumab; Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).; Other Names: rhuMAb VEGF Avastin

Outcome Measures

Primary Outcome Measures

1. Median Progression-free Survival of Patients Treated With the Study Drug as Defined by RECIST Criteria. [After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years.]

   During treatment, tumor assessment was done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment, and then every 3 cycles of treatment thereafter. After Study drug completion, tumor assessment by MRI was done every 3 to 4 months (for up to 2 years after the last bevacizumab dosage). Responses were categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.0. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.

Secondary Outcome Measures

1. Objective Response Rate in Patients Treated With Bevacizumab. [After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years.]

   Objective response rate will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease, neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease, defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.

2. Duration of Response. [After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years.]

   During treatment, evaluation of response will be done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment, and then every 3 cycles of treatment. After Study drug completion, evaluation of response will be assessed by MRI every 3 to 4 months (for 2 years after the last bevacizumab dosage).

3. Assess the Treatment Effect of Bevacizumab on Duration of Overall Survival [After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years]

   After Study drug completion, assessment of treatment effect of bevacizumab on duration of overall survival will be assessed by MRI every 3 to 4 months (for 2 years after the last bevacizumab dosage).

4. Evaluate the Toxicity of Bevacizumab. [Day 1 of every cycle, on average every 21 days until end of treatment up to 2 years.]

   Toxicity data for bevacizumab will be collected on day 1 of every cycle (1 cycle = 21 days) during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically confirmed angiosarcoma

• Any stage disease

• Must be deemed not surgically resectable (complete resection) and/or no other therapeutic modality is known to be curative

• No angiosarcoma of a vessel wall

• Newly diagnosed or recurrent/refractory disease

• No prior tumor-related hemorrhage (any grade)

• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan

• No CNS disease, brain metastases, or primary brain tumors

PATIENT CHARACTERISTICS:

• ECOG performance status of 0 or 1

• Absolute granulocyte count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 9 gm/dL (transfusion and epoetin alfa allowed)

• Creatinine ≤ 1.5 times upper limit of normal (ULN)

• Urine protein:creatinine ratio ≤ 1.0

• Total bilirubin ≤ 1.5 mg/dL

• Aspartate aminotransferase < 5 times ULN

• Alkaline phosphatase < 5 times ULN

• PT/INR ≤ 1.5 times ULN

• PTT ≤ 1.5 times ULN

• Fertile patients must use effective contraception

• Ejection fraction > 49% for patients with prior anthracycline therapy, ischemic cardiac disease, or history of heart failure

• No uncontrolled active infection

• No uncontrolled high blood pressure (defined as > 150/100 mm Hg)

• No symptomatic congestive heart failure (New York Heart Association class II-IV), unstable angina, cardiac arrhythmia, or myocardial infarction within the past 6 months

• No psychiatric illness or social situation that would limit study compliance

• No serious, nonhealing wound, ulcer, or bone fracture

• No evidence of bleeding diathesis or coagulopathy

• No clinically significant peripheral vascular disease

• Not pregnant or nursing

• No seizures not controlled with standard medical therapy

• No embolic or hemorrhagic stroke or prior transient ischemic attack

• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months

• No significant traumatic injury within the past 6 weeks

PRIOR CONCURRENT THERAPY:

• No prior therapy with bevacizumab or other antiangiogenesis treatment

• No major surgical procedure or open biopsy within the past 6 weeks

• No more than 2 prior chemotherapy regimens

• No fine-needle aspiration or core-needle biopsy or other minor surgical procedure within the past 7 days

• No radiotherapy within the past 28 days

• No concurrent chronic daily treatment with aspirin > 325 mg/day or nonsteroidal anti-inflammatory medications

• No concurrent warfarin or any other anticoagulant (any dose)

• No concurrent radiotherapy

• No concurrent major surgery

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
2	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
3	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
4	Fox Chase Cancer Center CCOP Research Base	Philadelphia	Pennsylvania	United States	19140
5	M. D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009

Sponsors and Collaborators

• Northwestern University
• Genentech, Inc.

Investigators

• Principal Investigator: Mark Agulnik, MD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mark Agulnik, Principal Investigator, Northwestern University
• ClinicalTrials.gov Identifier: NCT00288015
• Other Study ID Numbers: NU 04S1; NU 04S1; STU00006784
• First Posted: Feb 7, 2006
• Last Update Posted: Jun 25, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Mark Agulnik, Principal Investigator, Northwestern University: adult angiosarcoma; recurrent adult soft tissue sarcoma; stage I adult soft tissue sarcoma; stage II adult soft tissue sarcoma; stage III adult soft tissue sarcoma; stage IV adult soft tissue sarcoma
• Additional relevant MeSH terms: Sarcoma; Hemangiosarcoma; Bevacizumab

Study Results

Participant Flow

Recruitment Details	The study opened for accrual on June 1, 2005 with an accrual goal of up to 31 patients. The study was designed to enroll 12 patients initially and do an interim efficacy assessment. Accrual was suspended on February 28, 2007 for this analysis and reopened on May 15, 2007. Study was closed to accrual permanently on April 19, 2010.

Arm/Group Title	Bevacizumab
Arm/Group Description	Bevacizumab treatment until disease progression or intolerance Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
Period Title: Registered to Study
STARTED	32
COMPLETED	32
NOT COMPLETED	0
Period Title: Registered to Study
STARTED	32
COMPLETED	30
NOT COMPLETED	2
Period Title: Registered to Study
STARTED	30
COMPLETED	26
NOT COMPLETED	4
Period Title: Registered to Study
STARTED	26
COMPLETED	19
NOT COMPLETED	7
Period Title: Registered to Study
STARTED	29
COMPLETED	3
NOT COMPLETED	26

Baseline Characteristics

Arm/Group Title	Bevacizumab
Arm/Group Description	Bevacizumab treatment until disease progression or intolerance Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
Overall Participants	32
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 50%
>=65 years	16 50%
Sex: Female, Male (Count of Participants)
Female	19 59.4%
Male	13 40.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	30 93.8%
Unknown or Not Reported	2 6.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 6.3%
White	30 93.8%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	32 100%
Type of Sarcoma (Count of Participants)
angiosarcoma	24 75%
epitheliod hemangioendothelioma	8 25%

Outcome Measures

1. Primary Outcome

Title	Median Progression-free Survival of Patients Treated With the Study Drug as Defined by RECIST Criteria.
Description	During treatment, tumor assessment was done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment, and then every 3 cycles of treatment thereafter. After Study drug completion, tumor assessment by MRI was done every 3 to 4 months (for up to 2 years after the last bevacizumab dosage). Responses were categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.0. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Time Frame	After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab
Arm/Group Description	Bevacizumab treatment until disease progression or intolerance Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
Measure Participants	30
Median (95% Confidence Interval) [Weeks]	12.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab
	Comments	This is a two stage optimal simon design testing the Null hypothesis: bevacizumab is not effective with P<=0.220 and the alternative hypothesis: bevacizumab is effective with P >=0.450 and has a sample size of 16.96 and a probability of early termination of 0.739. p=probability (progression free survival - PFS time>/=3 months).
	Type of Statistical Test	Other
	Comments	This is a two-stage optimal simon design. If bevacizumab is not effective, there is a 0.050 probability of concluding that it is. If bevacizumab is effective, there is a 0.2000 probability of concluding that it is not.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		P<=0.220 is the threshold value of significance that the null hypothesis is true or the alternative hypothesis is true. P Value was not calculated from the data. Median survival time was calculated using a 20% censored Kaplan-Meier table and graph.

2. Secondary Outcome

Title	Objective Response Rate in Patients Treated With Bevacizumab.
Description	Objective response rate will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease, neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease, defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Time Frame	After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab
Arm/Group Description	Bevacizumab treatment until disease progression or intolerance Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
Measure Participants	30
Partial response	4 12.5%
Stable disease	15 46.9%
Progressive disease	11 34.4%

3. Secondary Outcome

Title	Duration of Response.
Description	During treatment, evaluation of response will be done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment, and then every 3 cycles of treatment. After Study drug completion, evaluation of response will be assessed by MRI every 3 to 4 months (for 2 years after the last bevacizumab dosage).
Time Frame	After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years.

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was not collected. By the time the results of the study were being collected, this outcome measure was no longer relevant as Recist 1.0 was in use. As a result, data for this outcome measure was not collected or analysed. Time to progression was a more relevant data point.

Arm/Group Title	Bevacizumab
Arm/Group Description	Bevacizumab treatment until disease progression or intolerance Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
Measure Participants	0

4. Secondary Outcome

Title	Assess the Treatment Effect of Bevacizumab on Duration of Overall Survival
Description	After Study drug completion, assessment of treatment effect of bevacizumab on duration of overall survival will be assessed by MRI every 3 to 4 months (for 2 years after the last bevacizumab dosage).
Time Frame	After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); every 3-4 months after treatment up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab
Arm/Group Description	Bevacizumab treatment until disease progression or intolerance Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
Measure Participants	30
Median (95% Confidence Interval) [Weeks]	107

5. Secondary Outcome

Title	Evaluate the Toxicity of Bevacizumab.
Description	Toxicity data for bevacizumab will be collected on day 1 of every cycle (1 cycle = 21 days) during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
Time Frame	Day 1 of every cycle, on average every 21 days until end of treatment up to 2 years.

Outcome Measure Data

Analysis Population Description

Number of participants with either grade 1 (mild), 2 (moderate),3 (severe), 4 (life-threatening) adverse event related to treatment.

Arm/Group Title	Bevacizumab
Arm/Group Description	Bevacizumab treatment until disease progression or intolerance Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
Measure Participants	30
Participants with one bevacizumab related event	26 81.3%
Thromboyctopenia	4 12.5%
Shortness of breath	5 15.6%
Hypertension	7 21.9%
Pain	3 9.4%
Nausea	5 15.6%
Infection	2 6.3%
Headache	4 12.5%
Anemia	6 18.8%
Decline in FEV1	1 3.1%
Hyperglycemia	1 3.1%
Transient ischemic attack	1 3.1%
Neuromotor function	2 6.3%
Cardiac (congestive heart failure)	1 3.1%
Plural effusion	1 3.1%
Liver-clinical	1 3.1%
Anorexia	2 6.3%
Fatigue	9 28.1%
Alopecia	3 9.4%
Dizziness	2 6.3%
Edema	2 6.3%
Dementia	1 3.1%
Hemorrhage (epitasis)	1 3.1%

6. Post-Hoc Outcome

Title	Time to Progression
Description	During treatment, tumor assessment was done by MRI scan after the second cycle of study treatment, after the forth cycle of study treatment , and then every 3 cycles of treatment thereafter. After Study drug completion, tumor assessment by MRI was done every 3 to 4 months (for up to 2 years after the last bevacizumab dosage) Responses were categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.0. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Time Frame	After cycles 2 and 4, then every 3 cycles thereafter while on treatment (1 cycle = 21 days); ever 3-4 months after treatment up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab
Arm/Group Description	Bevacizumab treatment until disease progression or intolerance Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
Measure Participants	30
Mean (Standard Deviation) [Weeks]	26 (53)

Adverse Events

Time Frame	Adverse events were collected over a 5 year period.
Arm/Group Title	Bevacizumab
Arm/Group Description	Bevacizumab treatment until disease progression or intolerance Bevacizumab: Bevacizumab 15 mg/kg IV infusion given on day 1 every 21 days = (1 cycle).
All Cause Mortality
	Bevacizumab
	Affected / at Risk (%)	# Events
Total	14/30 (46.7%)
Serious Adverse Events
	Bevacizumab
	Affected / at Risk (%)	# Events
Total	8/30 (26.7%)
Cardiac disorders
Cardiac ( congestive heart failure)	1/30 (3.3%)	1
Infections and infestations
Pneumonia	1/30 (3.3%)	1
Sinus infection	1/30 (3.3%)	1
Bladder infection (urinary)	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Fracture	1/30 (3.3%)	1
Knee surgery	1/30 (3.3%)	1
Nervous system disorders
Dizziness	1/30 (3.3%)	1
Speech impairment	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	1/30 (3.3%)	1
Chest pain (non cardiac)	1/30 (3.3%)	1
Upper respiratory - bronchus	1/30 (3.3%)	1
Social circumstances
Shot in leg	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Bevacizumab
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Blood and lymphatic system disorders
Hemoglobin (anemia)	9/30 (30%)	16
Leukocytes (total white blood cells)	5/30 (16.7%)	10
Lymphopenia	2/30 (6.7%)	2
Platelet decrease	7/30 (23.3%)	16
Edema (limbs)	4/30 (13.3%)	5
Cardiac disorders
hypertension	15/30 (50%)	24
Palpitations	1/30 (3.3%)	1
Supraventricular and nodal arrhythmia- atrial fibrillation	2/30 (6.7%)	2
Endocrine disorders
Hot flashes	2/30 (6.7%)	2
Eye disorders
Blurred vision	2/30 (6.7%)	2
Watery eye	1/30 (3.3%)	3
Gastrointestinal disorders
Ascites (non malignant)	1/30 (3.3%)	1
Constipation	4/30 (13.3%)	7
Diarrhea	6/30 (20%)	6
Abdominal distension	1/30 (3.3%)	1
Hemorrhoids	1/30 (3.3%)	1
Mucositis/stomatitis	2/30 (6.7%)	2
Heartburn	2/30 (6.7%)	2
Nausea	9/30 (30%)	17
salivary gland changes (metallic taste)	1/30 (3.3%)	2
Stomach pain	1/30 (3.3%)	1
Vomiting	5/30 (16.7%)	9
difficulty swallowing (dysphagia)	1/30 (3.3%)	1
Abdominal pain	2/30 (6.7%)	5
anorexia	8/30 (26.7%)	9
General disorders
Fatigue	17/30 (56.7%)	23
Fever	4/30 (13.3%)	4
Insomnia	1/30 (3.3%)	1
Sweating	1/30 (3.3%)	1
Weight loss	5/30 (16.7%)	7
Nose bleed (Hemorrhage)	5/30 (16.7%)	7
Pain	4/30 (13.3%)	4
Chest pain	1/30 (3.3%)	1
Flu-like syndrome	3/30 (10%)	6
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	3/30 (10%)	4
Infections and infestations
upper respiratory infection	1/30 (3.3%)	1
Urinary tract infection	2/30 (6.7%)	3
Colon infection	1/30 (3.3%)	1
Eye infection	1/30 (3.3%)	1
Investigations
Partial Thromboplastin Time (PTT)	2/30 (6.7%)	2
Metabolism and nutrition disorders
High glucose (hyperglycemia)	4/30 (13.3%)	5
low glucose (hypoglycemia)	1/30 (3.3%)	1
High potassium (hyperkalemia)	1/30 (3.3%)	1
ALT, SGPT (serum glutamic pyruvic transaminase)	2/30 (6.7%)	2
AST, SGPT (serum glutamic oxaloacetic transaminase)	7/30 (23.3%)	11
Bilirubin (hyperbilirubinemia)	2/30 (6.7%)	2
Creatinine	7/30 (23.3%)	8
Alkaline phosphatase increase	8/30 (26.7%)	13
Musculoskeletal and connective tissue disorders
Back pain	2/30 (6.7%)	2
Limb pain	1/30 (3.3%)	2
Joint pain	5/30 (16.7%)	12
Muscle pain	3/30 (10%)	9
Neck pain	1/30 (3.3%)	1
Muscle weakness	1/30 (3.3%)	1
Nervous system disorders
Headache	10/30 (33.3%)	18
Sensory neuropathy	6/30 (20%)	7
Dizziness	2/30 (6.7%)	2
CNS cerebrovascularischemia - Transient ischemic attack	1/30 (3.3%)	1
Dementia	1/30 (3.3%)	1
Psychiatric disorders
Anxiety	3/30 (10%)	3
Renal and urinary disorders
Urine color change	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	4/30 (13.3%)	9
Shortness of breath (dyspnea)	6/30 (20%)	7
Pleural effusion	2/30 (6.7%)	2
Voice change/alteration	2/30 (6.7%)	5
Decline in FEV1 (forced expiratory volume)	1/30 (3.3%)	1
Skin and subcutaneous tissue disorders
Alopecia	3/30 (10%)	3
Pruritis	1/30 (3.3%)	1
Rash	5/30 (16.7%)	5
Flushing	1/30 (3.3%)	1
Vascular disorders
Phlebitis	1/30 (3.3%)	1

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.