FALCON: A Safety and Efficacy Study of Carboplatin, Paclitaxel, Bevacizumab and CA4P in Non-Small Cell Lung Cancer

• Sponsor: Mateon Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00653939
• Collaborator: (none)
• Enrollment: 63
• Locations: 15
• Arms: 2
• Duration (Months): 43
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety, tolerability and efficacy of combretastatin A4 phosphate (CA4P), also known as fosbretabulin, in combination with bevacizumab (Avastin), carboplatin and paclitaxel in patients with chemotherapy naïve non-small cell lung cancer (NSCLC). This is a randomized parallel arm study. All participants will receive carboplatin, paclitaxel and bevacizumab, and half will additionally receive CA4P. Patients who complete the first 6 cycles of therapy and have not experienced disease progression will receive maintenance therapy with bevacizumab alone or with bevacizumab plus CA4P.

The rationale for this study is the potential additive or synergistic actions of vascular disrupting agents like CA4P with anti-angiogenic agents like bevacizumab.

Condition or Disease	Intervention/Treatment	Phase
Tumors	Drug: Fosbretabulin; Drug: Carboplatin; Drug: Paclitaxel; Drug: Bevacizumab	Phase 2

Detailed Description

Lung cancer has become the leading cause of cancer death in both men and women in the US and Europe, accounting for 29% of all cancer deaths. Non-Small Cell Lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases. Currently, no curative treatment is available for advanced stages of the disease (stages III and IV), which comprise the majority of cases. Treatment with the combination of carboplatin and paclitaxel has been shown to be effective and well tolerated in advanced stage NSCLC. Targeted therapies, such as bevacizumab, often act synergistically with chemotherapy. Bevacizumab inhibits vascular endothelial growth factor (VEGF), necessary for endothelial cell proliferation and new blood vessel formation. CA4P targets existing abnormal vasculature of tumors, impeding tumor blood flow and leading to extensive tumor cell death as a consequence of oxygen and nutrient deprivation.

This study will compare the effect of CA4P when combined with chemotherapy and bevacizumab on progression free survival (PFS) to PFS after chemotherapy and bevacizumab alone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study to Assess the Safety and Efficacy of the Combination of Carboplatin, Paclitaxel, and Bevacizumab ± Combretastatin A4 Phosphate (CA4P) Followed by Bevacizumab ± CA4P in Subjects With Chemotherapy Naïve Stage IIIB/IV Non-Squamous Cell Histology Non-Small Cell Lung Cancer (NSCLC)
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1: Chemotherapy+Bevacizumab Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization.	Drug: Carboplatin; Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles.; Other Names: Paraplatin ; Drug: Paclitaxel; Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles.; Other Names: Taxol ; Drug: Bevacizumab; Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.; Other Names: Avastin
Experimental: Arm 2: Active Comparator+Fosbretabulin Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization.	Drug: Fosbretabulin; Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles.; Other Names: Combretastatin A4 Phosphate Zybrestat CA4P ; Drug: Carboplatin; Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles.; Other Names: Paraplatin ; Drug: Paclitaxel; Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles.; Other Names: Taxol ; Drug: Bevacizumab; Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) in the Intent-to-Treat Population [Six 21-day cycles]

   Progression was defined using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0. Based on 20% increase of the longest diameter of target lesions or appearance of one or more new non-target lesions or/and progression of non-target lesions since the treatment started.

Secondary Outcome Measures

1. Best Overall Tumor Response Rate (RR) in the Intent-to-Treat Population [Six 21-day cycles]

   Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 for target lesions (assessed by MRI or CT scan): Complete Response (CR) is defined as the disappearance of all target lesions, Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, Progressive Disease is defined as at least 20% increase in the sum of the longest diameter of target lesions, Stable Disease (SD) is defined as neither shrinkage to qualify for a PR or increase to qualify for a PD.

2. Overall Survival (OS) Using a Multivariate Cox Regression Model in the Intent-to-Treat Population [Until death or lost to follow-up, up to 12 months since randomization]

3. Chemistry NCI-CTCAE Toxicity Grade of 3 or 4 (Safety Population) [Days 1 (pretreatment) per 21-day Cycle (6 Cycles)]

4. Hematology NCI-CTCAE Grade 3 or 4 (Safety Population) [Days 1 (pretreatment), 7, 14, and 21 per 21-day Cycle (6 Cycles)]

5. Coagulation NCI-CTCAE Grade 3 or 4 (Safety Population) [Day 1 (pretreatment) per 21-day Cycle (6 Cycles)]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Pathologically confirmed Stage IIIB NSCLC with malignant pleural effusion, or Stage IV disease

• Measurable disease on CT scan (by the Response Evaluation Criteria in Solid Tumors [RECIST] criteria)

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 (which means able to independently care for self and to perform light work) .

• Adequate blood counts

• Adequate liver and kidney function

• Subjects or their legal representatives must be able to read, understand and provide written informed consent to participate in the trial.

Exclusion Criteria:

• Predominant Squamous Cell NSCLC histology.

• History of treatment for NSCLC with chemotherapy, biological therapy, immunotherapy (surgery or radiation therapy are accepted)

• Brain (CNS) metastasis by head CT scan or MRI

• Subjects with history of prior malignancy except for curatively treated basal cell carcinoma of the skin; cervical intra-epithelial neoplasia; or localized prostate cancer with a current prostate specific antigen (PSA) of < 4.0 mg/dL. Subjects with other curatively treated malignancies who have no evidence of metastatic disease and

2 year disease free interval may be entered after discussion with the Medical Monitor.

• History of bleeding disorders, particularly coughing up ≥ ½ teaspoon bright red blood during the last 3 months

• Certain cardiac disorders such as recent myocardial infarction (MI), severe congestive heart failure, certain types of abnormal cardiac rhythm

• Uncontrolled high blood pressure despite medications

• Uncontrolled, clinically significant active infection.

• Known HIV

• Known hypersensitivity to any of the components of CA4P, paclitaxel, carboplatin, bevacizumab, or radiologic contrast dyes.

Details of the above and additional inclusion and exclusion criteria can be discussed with an investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southbay Oncology Hematology	Campbell	California	United States	95008
2	Pacific Coast Hematology and Oncology Medical Group	Fountain Valley	California	United States	92708
3	UCLA Division of Hematology and Oncology	Los Angeles	California	United States	90095
4	Bay Area Cancer Research Group, LLC	Pleasant Hill	California	United States	94523
5	Boca Raton Comprehensive Cancer Center	Boca Raton	Florida	United States	21020
6	Kentuckiana Cancer Institute	Louisville	Kentucky	United States	40202
7	Lahey Clinic Medical Center	Burlington	Massachusetts	United States	01805
8	The Center for Cancer and Hematologic Disease	Cherry Hill	New Jersey	United States	08003
9	San Juan Oncology Associates	Farmington	New Mexico	United States	87401
10	Gabrail Cancer Center	Canton	Ohio	United States	44718
11	The Mark H. Zangmeister Center	Columbus	Ohio	United States	43219
12	Signal Point Clinical Research	Middletown	Ohio	United States	45042
13	Blueridge Cancer Care	Salem	Virginia	United States	24153
14	Northwest Medical Specialties	Tacoma	Washington	United States	98405
15	Mary Babb Randolph Cancer Center-Clinical Trials Unit	Morgantown	West Virginia	United States	26506

Sponsors and Collaborators

• Mateon Therapeutics

Investigators

• Study Director: Jai Balkissoon, MD, FACS, Mateon Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Publications

• Chaplin DJ, Pettit GR, Hill SA. Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Res. 1999 Jan-Feb;19(1A):189-95.
• Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4-25. Review.
• Lin CM, Singh SB, Chu PS, Dempcy RO, Schmidt JM, Pettit GR, Hamel E. Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: a structure-activity study. Mol Pharmacol. 1988 Aug;34(2):200-8.
• Monestiroli S, Mancuso P, Burlini A, Pruneri G, Dell'Agnola C, Gobbi A, Martinelli G, Bertolini F. Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma. Cancer Res. 2001 Jun 1;61(11):4341-4.
• Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. Erratum in: N Engl J Med. 2007 Jan 18;356(3):318.
• Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006 Sep 22;313(5794):1785-7.
• Siemann DW, Mercer E, Lepler S, Rojiani AM. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy. Int J Cancer. 2002 May 1;99(1):1-6.

• Responsible Party: Mateon Therapeutics
• ClinicalTrials.gov Identifier: NCT00653939
• Other Study ID Numbers: OXC401-216
• First Posted: Apr 7, 2008
• Last Update Posted: Feb 9, 2015
• Last Verified: Jan 1, 2015

• Keywords provided by Mateon Therapeutics: non-small cell lung cancer; non-small cell lung carcinoma; neoplasms, lung; lung cancer; tumors; NSCLC
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Paclitaxel; Fosbretabulin; Combretastatin; Bevacizumab; Carboplatin

Study Results

Participant Flow

Arm/Group Title	Arm 1: Chemotherapy+Bevacizumab	Arm 2: Active Comparator+Fosbretabulin
Arm/Group Description	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. Fosbretabulin: Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.
Period Title: Overall Study
STARTED	31	32
COMPLETED	19	17
NOT COMPLETED	12	15

Baseline Characteristics

Arm/Group Title	Arm 1: Chemotherapy+Bevacizumab	Arm 2: Active Comparator+Fosbretabulin	Total
Arm/Group Description	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg) administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. Fosbretabulin: Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7, 14 and 21 for 6 cycles. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.	Total of all reporting groups
Overall Participants	29	31	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.5 (9.5)	61.0 (9.4)	62.2 (9.5)
Sex: Female, Male (Count of Participants)
Female	17 58.6%	12 38.7%	29 48.3%
Male	12 41.4%	19 61.3%	31 51.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	23 79.3%	27 87.1%	50 83.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	6 20.7%	4 12.9%	10 16.7%
Region of Enrollment (participants) [Number]
United States	29 100%	31 100%	60 100%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (participants) [Number]
0 - Fully active	16 55.2%	16 51.6%	32 53.3%
1 - Restricted in physically strenuous activity	13 44.8%	15 48.4%	28 46.7%
Surgery Performed (participants) [Number]
Yes	5 17.2%	4 12.9%	9 15%
No	24 82.8%	27 87.1%	51 85%
Prior Surgery Due to NSCLC (participants) [Number]
Yes	3 10.3%	2 6.5%	5 8.3%
No	26 89.7%	29 93.5%	55 91.7%
Subject Given Radiation Therapy (participants) [Number]
Yes	5 17.2%	4 12.9%	9 15%
No	23 79.3%	27 87.1%	50 83.3%
Information Missing	1 3.4%	0 0%	1 1.7%
Prior Radiation Due to NSCLC (participants) [Number]
Yes	4 13.8%	4 12.9%	8 13.3%
No	25 86.2%	27 87.1%	52 86.7%
Stage of Disease at Study Entry (participants) [Number]
IIIB	4 13.8%	2 6.5%	6 10%
IV	25 86.2%	29 93.5%	54 90%

Outcome Measures

1. Secondary Outcome

Title	Best Overall Tumor Response Rate (RR) in the Intent-to-Treat Population
Description	Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 for target lesions (assessed by MRI or CT scan): Complete Response (CR) is defined as the disappearance of all target lesions, Partial Response (PR) is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, Progressive Disease is defined as at least 20% increase in the sum of the longest diameter of target lesions, Stable Disease (SD) is defined as neither shrinkage to qualify for a PR or increase to qualify for a PD.
Time Frame	Six 21-day cycles

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Arm 1: Chemotherapy+Bevacizumab	Arm 2: Active Comparator+Fosbretabulin
Arm/Group Description	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. Fosbretabulin: Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.
Measure Participants	31	32
Complete Response	0 0%	0 0%
Partial Response	11 37.9%	18 58.1%
Stable Disease	13 44.8%	8 25.8%
Progressive Disease	3 10.3%	1 3.2%
Unknown	4 13.8%	5 16.1%

2. Secondary Outcome

Title	Overall Survival (OS) Using a Multivariate Cox Regression Model in the Intent-to-Treat Population
Time Frame	Until death or lost to follow-up, up to 12 months since randomization

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Arm 1: Chemotherapy+Bevacizumab	Arm 2: Active Comparator+Fosbretabulin
Arm/Group Description	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg) administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. Fosbretabulin: Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7, 14 and 21 for 6 cycles. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.
Measure Participants	31	32
Median (95% Confidence Interval) [Months]	16.2	13.6

3. Primary Outcome

Title	Progression Free Survival (PFS) in the Intent-to-Treat Population
Description	Progression was defined using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0. Based on 20% increase of the longest diameter of target lesions or appearance of one or more new non-target lesions or/and progression of non-target lesions since the treatment started.
Time Frame	Six 21-day cycles

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	Arm 1: Chemotherapy+Bevacizumab	Arm 2: Active Comparator+Fosbretabulin
Arm/Group Description	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. Fosbretabulin: Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.
Measure Participants	31	32
Median (95% Confidence Interval) [months]	9.3	8.6

4. Secondary Outcome

Title	Chemistry NCI-CTCAE Toxicity Grade of 3 or 4 (Safety Population)
Time Frame	Days 1 (pretreatment) per 21-day Cycle (6 Cycles)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Arm 1: Chemotherapy+Bevacizumab	Arm 2: Active Comparator+Fosbretabulin
Arm/Group Description	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. Fosbretabulin: Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.
Measure Participants	29	31
ALT - Grade 3	1 3.4%	1 3.2%
ALT - Grade 4	0 0%	0 0%
AST - Grade 3	0 0%	1 3.2%
AST - Grade 4	0 0%	0 0%
ALP - Grade 3	0 0%	0 0%
ALP - Grade 4	0 0%	0 0%
Total Bilirubin - Grade 3	0 0%	0 0%
Total Bilirubin - Grade 4	0 0%	0 0%
Glucose - Grade 3	0 0%	0 0%
Glucose - Grade 4	1 3.4%	0 0%
Creatinine - Grade 3	0 0%	0 0%
Creatinine - Grade 4	1 3.4%	1 3.2%
Calcium - Grade 3	3 10.3%	0 0%
Calcium - Grade 4	1 3.4%	1 3.2%
Magnesium - Grade 3	2 6.9%	1 3.2%
Magnesium - Grade 4	2 6.9%	1 3.2%
Phosphorus - Grade 3	0 0%	1 3.2%
Phosphorus - Grade 4	0 0%	0 0%
Potassium - Grade 3	5 17.2%	0 0%
Potassium - Grade 4	1 3.4%	0 0%
Sodium - Grade 3	5 17.2%	2 6.5%
Sodium - Grade 4	0 0%	0 0%

5. Secondary Outcome

Title	Hematology NCI-CTCAE Grade 3 or 4 (Safety Population)
Time Frame	Days 1 (pretreatment), 7, 14, and 21 per 21-day Cycle (6 Cycles)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Arm 1: Chemotherapy+Bevacizumab	Arm 2: Active Comparator+Fosbretabulin
Arm/Group Description	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. Fosbretabulin: Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.
Measure Participants	29	31
Hemoglobin - Grade 3	7 24.1%	0 0%
Hemoglobin - Grade 4	4 13.8%	1 3.2%
White Blood Cell - Grade 3	14 48.3%	12 38.7%
White Blood Cell - Grade 4	2 6.9%	1 3.2%
Absolute Neutrophils - Grade 3	4 13.8%	5 16.1%
Absolute Neutrophils - Grade 4	20 69%	20 64.5%
Platelets - Grade 3	3 10.3%	5 16.1%
Platelets - Grade 4	6 20.7%	3 9.7%

6. Secondary Outcome

Title	Coagulation NCI-CTCAE Grade 3 or 4 (Safety Population)
Time Frame	Day 1 (pretreatment) per 21-day Cycle (6 Cycles)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Arm 1: Chemotherapy+Bevacizumab	Arm 2: Active Comparator+Fosbretabulin
Arm/Group Description	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. Fosbretabulin: Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.
Measure Participants	29	31
INR - Grade 3	2 6.9%	3 9.7%
INR - Grade 4	0 0%	0 0%
PTT - Grade 3	3 10.3%	5 16.1%
PTT - Grade 4	0 0%	0 0%

Adverse Events

Arm/Group Title	Arm 1: Chemotherapy+Bevacizumab		Arm 2: Active Comparator+Fosbretabulin
Arm/Group Description	Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg)administered intravenously on Day 1 of a 21-day cycle for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) alone on Day 1 every 3 weeks until progression or until 12 months from randomization. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.		Carboplatin (AUC 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg), administered intravenously Day 1 of a 21-day cycle and fosbretabulin (60 mg/m2) on Days 7, 14, and 21 for up to six treatment cycles. After 6 cycles, subjects who have not progressed may continue to receive bevacizumab (15 mg/kg) on Day 1 and fosbretabulin on Days 1, 7 and 14 every 3 weeks until progression or until 12 months from randomization. Fosbretabulin: Arm 2 only: Fosbretabulin (60 mg/m2) on Days 7,14 and 21 for 6 cycles. Carboplatin: Chemotherapy: Carboplatin (AUC 6) on Day 1 of each 21 day cycle for 6 cycles. Paclitaxel: Chemotherapy: Paclitaxel (20 mg/m2) on Day 1 of each 21-day cycle for 6 cycles. Bevacizumab: Bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for 6 cycles.
All Cause Mortality
	Arm 1: Chemotherapy+Bevacizumab		Arm 2: Active Comparator+Fosbretabulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1: Chemotherapy+Bevacizumab		Arm 2: Active Comparator+Fosbretabulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/29 (55.2%)		16/31 (51.6%)
Blood and lymphatic system disorders
Anaemia	1/29 (3.4%)		0/31 (0%)
Febrile Neutropenia	0/29 (0%)		2/31 (6.5%)
Neutropenia	1/29 (3.4%)		1/31 (3.2%)
Thrombocytopenia	1/29 (3.4%)		0/31 (0%)
Cardiac disorders
Cardiac Failure Congestive	1/29 (3.4%)		0/31 (0%)
Myocardial Infarction	1/29 (3.4%)		0/31 (0%)
Myocardial Ischaemia	0/29 (0%)		2/31 (6.5%)
Gastrointestinal disorders
Colitis Ischaemic	1/29 (3.4%)		0/31 (0%)
Constipation	0/29 (0%)		1/31 (3.2%)
Diarrhoea	0/29 (0%)		1/31 (3.2%)
General disorders
Asthenia	0/29 (0%)		1/31 (3.2%)
Disease Progression	1/29 (3.4%)		0/31 (0%)
Fatigue	1/29 (3.4%)		0/31 (0%)
Infusion Site Thrombosis	0/29 (0%)		1/31 (3.2%)
Non-cardiac Chest Pain	1/29 (3.4%)		0/31 (0%)
Pyrexia	0/29 (0%)		1/31 (3.2%)
Hepatobiliary disorders
Cholelithiasis	1/29 (3.4%)		0/31 (0%)
Infections and infestations
Arthritis Infective	1/29 (3.4%)		0/31 (0%)
Bronchitis	0/29 (0%)		1/31 (3.2%)
Lung Abscess	1/29 (3.4%)		0/31 (0%)
Pneumonia	2/29 (6.9%)		0/31 (0%)
Pseudomonal Bacteraemia	1/29 (3.4%)		0/31 (0%)
Sepsis	1/29 (3.4%)		0/31 (0%)
Metabolism and nutrition disorders
Dehydration	1/29 (3.4%)		0/31 (0%)
Failure to Thrive	1/29 (3.4%)		0/31 (0%)
Hypoglycaemia	0/29 (0%)		1/31 (3.2%)
Musculoskeletal and connective tissue disorders
Back Pain	1/29 (3.4%)		1/31 (3.2%)
Bone Pain	0/29 (0%)		1/31 (3.2%)
Musculoskeletal Chest Pain	1/29 (3.4%)		0/31 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to Meninges	0/29 (0%)		2/31 (6.5%)
Nervous system disorders
Cerbral Infarction	1/29 (3.4%)		0/31 (0%)
Cerebrovascular Accident	1/29 (3.4%)		0/31 (0%)
Spinal Cord Compression	0/29 (0%)		1/31 (3.2%)
Psychiatric disorders
Delirium	2/29 (6.9%)		0/31 (0%)
Mental Status Changes	1/29 (3.4%)		0/31 (0%)
Renal and urinary disorders
Hydronephrosis	0/29 (0%)		1/31 (3.2%)
Renal Failure	0/29 (0%)		1/31 (3.2%)
Urinary Retention	1/29 (3.4%)		0/31 (0%)
Reproductive system and breast disorders
Pelvic Pain	1/29 (3.4%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	0/29 (0%)		1/31 (3.2%)
Dyspnoea	0/29 (0%)		1/31 (3.2%)
Epixtaxis	1/29 (3.4%)		0/31 (0%)
Haemoptysis	1/29 (3.4%)		1/31 (3.2%)
Hypoxia	1/29 (3.4%)		0/31 (0%)
Interstitial Lung Disease	0/29 (0%)		1/31 (3.2%)
Pulmonary Embolism	1/29 (3.4%)		3/31 (9.7%)
Repiratory Failure	0/29 (0%)		1/31 (3.2%)
Vascular disorders
Deep Vein Thrombosis	0/29 (0%)		1/31 (3.2%)
Hypertension	1/29 (3.4%)		0/31 (0%)
Hypotension	0/29 (0%)		1/31 (3.2%)
Thrombophlebitis	0/29 (0%)		1/31 (3.2%)
Other (Not Including Serious) Adverse Events
	Arm 1: Chemotherapy+Bevacizumab		Arm 2: Active Comparator+Fosbretabulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/29 (100%)		31/31 (100%)
Blood and lymphatic system disorders
Neutropenia	14/29 (48.3%)		25/31 (80.6%)
Anaemia	20/29 (69%)		13/31 (41.9%)
Thrombocytopenia	18/29 (62.1%)		13/31 (41.9%)
Leukopenia	7/29 (24.1%)		14/31 (45.2%)
Leukocytosis	3/29 (10.3%)		1/31 (3.2%)
Febrile Neutropenia	0/29 (0%)		3/31 (9.7%)
Lymphopenia	0/29 (0%)		2/31 (6.5%)
Cardiac disorders
Tachycardia	3/29 (10.3%)		8/31 (25.8%)
Bradycardia	0/29 (0%)		4/31 (12.9%)
Angina Pectoris	2/29 (6.9%)		1/31 (3.2%)
Coronary Artery Disease	1/29 (3.4%)		2/31 (6.5%)
Myocardial Ischaemia	0/29 (0%)		3/31 (9.7%)
Cardiac Failure Congestive	2/29 (6.9%)		0/31 (0%)
Ventricular Extrasystoles	0/29 (0%)		2/31 (6.5%)
Ear and labyrinth disorders
Ear Pain	2/29 (6.9%)		2/31 (6.5%)
Hypoacusis	0/29 (0%)		2/31 (6.5%)
Endocrine disorders
Endocrine Disorders	2/29 (6.9%)		1/31 (3.2%)
Eye disorders
Vision Blurred	2/29 (6.9%)		2/31 (6.5%)
Gastrointestinal disorders
Nausea	20/29 (69%)		13/31 (41.9%)
Diarrhoea	17/29 (58.6%)		11/31 (35.5%)
Constipation	11/29 (37.9%)		11/31 (35.5%)
Vomiting	11/29 (37.9%)		7/31 (22.6%)
Abdominal Pain	5/29 (17.2%)		5/31 (16.1%)
Stomatitis	3/29 (10.3%)		5/31 (16.1%)
Gastrooesophageal Reflux Disease	5/29 (17.2%)		1/31 (3.2%)
Gingival Bleeding	3/29 (10.3%)		2/31 (6.5%)
Toothache	4/29 (13.8%)		0/31 (0%)
Abdominal Discomfort	0/29 (0%)		3/31 (9.7%)
Dyspepsia	1/29 (3.4%)		2/31 (6.5%)
Oral Pain	1/29 (3.4%)		2/31 (6.5%)
Cheilitis	0/29 (0%)		2/31 (6.5%)
Gastritis	2/29 (6.9%)		0/31 (0%)
Haemorrhoids	2/29 (6.9%)		0/31 (0%)
General disorders
Fatigue	25/29 (86.2%)		18/31 (58.1%)
Pyrexia	10/29 (34.5%)		6/31 (19.4%)
Oedema peripheral	6/29 (20.7%)		8/31 (25.8%)
Asthenia	6/29 (20.7%)		4/31 (12.9%)
Chest Discomfort	2/29 (6.9%)		5/31 (16.1%)
Chills	3/29 (10.3%)		2/31 (6.5%)
Gait Disturbance	2/29 (6.9%)		3/31 (9.7%)
Non-cardiac Chest Pain	2/29 (6.9%)		3/31 (9.7%)
Mucosal Inflammation	1/29 (3.4%)		3/31 (9.7%)
Pain	3/29 (10.3%)		1/31 (3.2%)
Chest Pain	1/29 (3.4%)		2/31 (6.5%)
Infusion Site Pain	0/29 (0%)		3/31 (9.7%)
Adverse Drug Reaction	0/29 (0%)		2/31 (6.5%)
Hepatobiliary disorders
Hepatobiliary Disorders	1/29 (3.4%)		2/31 (6.5%)
Immune system disorders
Drug Hypersensitivity	1/29 (3.4%)		2/31 (6.5%)
Infections and infestations
Upper Respiratory Tract Infections	4/29 (13.8%)		5/31 (16.1%)
Urinary Tract Infection	6/29 (20.7%)		3/31 (9.7%)
Bronchitis	4/29 (13.8%)		1/31 (3.2%)
Nasopharyngitis	4/29 (13.8%)		1/31 (3.2%)
Pneumonia	4/29 (13.8%)		0/31 (0%)
Catheter Site Infection	2/29 (6.9%)		1/31 (3.2%)
Cellulitis	2/29 (6.9%)		1/31 (3.2%)
Fungal Infection	3/29 (10.3%)		0/31 (0%)
Sinusitis	1/29 (3.4%)		2/31 (6.5%)
Oral Candidiasis	2/29 (6.9%)		0/31 (0%)
Tooth Infection	0/29 (0%)		2/31 (6.5%)
Injury, poisoning and procedural complications
Fall	2/29 (6.9%)		1/31 (3.2%)
Investigations
Weight Decreased	8/29 (27.6%)		3/31 (9.7%)
Alanine Aminotransferase Increased	3/29 (10.3%)		1/31 (3.2%)
Breath Sounds Abnormal	1/29 (3.4%)		3/31 (9.7%)
Gamma-glutamyltransferase Increased	2/29 (6.9%)		2/31 (6.5%)
Blood Chloride Decreased	0/29 (0%)		2/31 (6.5%)
Blood Lactate Dehydrogenase Increased	0/29 (0%)		2/31 (6.5%)
Blood Urea Increased	2/29 (6.9%)		0/31 (0%)
Electrocardiogram T Wave Abnormal	0/29 (0%)		2/31 (6.5%)
Oxygen Saturation Decreased	2/29 (6.9%)		0/31 (0%)
Prothrombin Time Prolonged	0/29 (0%)		2/31 (6.5%)
Metabolism and nutrition disorders
Hypomagnesaemia	10/29 (34.5%)		3/31 (9.7%)
Anorexia	9/29 (31%)		3/31 (9.7%)
Decreased Appetite	5/29 (17.2%)		6/31 (19.4%)
Dehydration	8/29 (27.6%)		3/31 (9.7%)
Hypokalaemia	5/29 (17.2%)		2/31 (6.5%)
Hyponatraemia	2/29 (6.9%)		5/31 (16.1%)
Hyperglycaemia	2/29 (6.9%)		4/31 (12.9%)
Hyperlipidaemia	2/29 (6.9%)		1/31 (3.2%)
Hypoalbuminaemia	2/29 (6.9%)		0/31 (0%)
Musculoskeletal and connective tissue disorders
Pain in Extremity	10/29 (34.5%)		7/31 (22.6%)
Arthralgia	7/29 (24.1%)		7/31 (22.6%)
Back Pain	4/29 (13.8%)		9/31 (29%)
Bone Pain	6/29 (20.7%)		6/31 (19.4%)
Musculoskeletal Chest Pain	6/29 (20.7%)		5/31 (16.1%)
Myalgia	5/29 (17.2%)		6/31 (19.4%)
Musculoskeletal Pain	4/29 (13.8%)		4/31 (12.9%)
Muscular Weakness	3/29 (10.3%)		2/31 (6.5%)
Flank Pain	2/29 (6.9%)		2/31 (6.5%)
Neck Pain	1/29 (3.4%)		3/31 (9.7%)
Muscle Spasms	2/29 (6.9%)		1/31 (3.2%)
Musculoskeletal Discomfort	0/29 (0%)		2/31 (6.5%)
Musculoskeletal Stiffness	0/29 (0%)		2/31 (6.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to Meninges	0/29 (0%)		2/31 (6.5%)
Nervous system disorders
Neuropathy	19/29 (65.5%)		15/31 (48.4%)
Headache	12/29 (41.4%)		4/31 (12.9%)
Dizziness	9/29 (31%)		3/31 (9.7%)
Hypoaesthesia	3/29 (10.3%)		6/31 (19.4%)
Dysgeusia	3/29 (10.3%)		3/31 (9.7%)
Burning Sensation	1/29 (3.4%)		3/31 (9.7%)
Syncope	2/29 (6.9%)		2/31 (6.5%)
Amnesia	0/29 (0%)		2/31 (6.5%)
Balance Disorder	0/29 (0%)		2/31 (6.5%)
Memory Impairment	0/29 (0%)		2/31 (6.5%)
Paraesthesia	0/29 (0%)		2/31 (6.5%)
Psychiatric disorders
Insomnia	5/29 (17.2%)		7/31 (22.6%)
Depression	4/29 (13.8%)		6/31 (19.4%)
Anxiety	3/29 (10.3%)		2/31 (6.5%)
Confusional State	2/29 (6.9%)		1/31 (3.2%)
Delirium	2/29 (6.9%)		0/31 (0%)
Renal and urinary disorders
Proteinuria	5/29 (17.2%)		3/31 (9.7%)
Haematuria	2/29 (6.9%)		1/31 (3.2%)
Urinary Retention	2/29 (6.9%)		1/31 (3.2%)
Reproductive system and breast disorders
Prostatitis	2/29 (6.9%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	16/29 (55.2%)		11/31 (35.5%)
Dyspnoea	11/29 (37.9%)		9/31 (29%)
Cough	7/29 (24.1%)		8/31 (25.8%)
Pharyngolarygeal Pain	9/29 (31%)		4/31 (12.9%)
Haemoptysis	5/29 (17.2%)		3/31 (9.7%)
Dysphonia	2/29 (6.9%)		5/31 (16.1%)
Rhinorrhoea	3/29 (10.3%)		2/31 (6.5%)
Chronic Obstructive Pulmonary Disease	2/29 (6.9%)		2/31 (6.5%)
Hypoxia	4/29 (13.8%)		0/31 (0%)
Pulmonary Embolism	1/29 (3.4%)		3/31 (9.7%)
Nasal Congestion	2/29 (6.9%)		1/31 (3.2%)
Sinus Congestion	3/29 (10.3%)		0/31 (0%)
Wheezing	2/29 (6.9%)		1/31 (3.2%)
Hiccups	0/29 (0%)		2/31 (6.5%)
Productive Cough	0/29 (0%)		2/31 (6.5%)
Skin and subcutaneous tissue disorders
Alopecia	16/29 (55.2%)		13/31 (41.9%)
Rash	7/29 (24.1%)		7/31 (22.6%)
Pruritus	2/29 (6.9%)		4/31 (12.9%)
Dry Skin	3/29 (10.3%)		1/31 (3.2%)
Hyperhidrosis	2/29 (6.9%)		2/31 (6.5%)
Night Sweats	2/29 (6.9%)		0/31 (0%)
Pain of Skin	0/29 (0%)		2/31 (6.5%)
Vascular disorders
Hypertension	13/29 (44.8%)		17/31 (54.8%)
Hypotension	7/29 (24.1%)		1/31 (3.2%)
Flushing	1/29 (3.4%)		4/31 (12.9%)
Orthostatic Hypotension	5/29 (17.2%)		0/31 (0%)
Deep Vein Thrombosis	0/29 (0%)		3/31 (9.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.