Pazopanib Hydrochloride in Treating Patients With Advanced Neuroendocrine Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00454363
• Collaborator: (none)
• Enrollment: 52
• Locations: 3
• Arm: 1
• Duration (Months): 93
• Patients Per Site: 17.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial studies how well pazopanib hydrochloride works in treating patients with advanced neuroendocrine cancer. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Condition or Disease	Intervention/Treatment	Phase
Gastrin-Producing Neuroendocrine Tumor; Lung Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Multiple Endocrine Neoplasia Type 1; Pancreatic Glucagonoma; Pancreatic Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Pancreatic Neuroendocrine Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Somatostatin-Producing Neuroendocrine Tumor	Other: Laboratory Biomarker Analysis; Drug: Pazopanib Hydrochloride; Other: Pharmacological Study	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. To determine the objective response rate (ORR) (complete and partial response) of GW786034 (pazopanib hydrochloride) 800 mg administered orally once daily in patients with advanced low or intermediate grade carcinoid tumors (in carcinoid cohort).

2. To determine the objective response rate (ORR) (complete response and partial response) of GW786034 800mg administered orally once daily in patients with advanced low or intermediate grade pancreatic islet cell carcinoma (in islet cell cohort).

SECONDARY OBJECTIVES:

1. To determine the progression free survival (PFS) duration of GW786034 800mg administered orally once daily in patients with low grade neuroendocrine carcinoma.

2. To determine the safety and tolerability of GW786034 800mg administered orally once daily in patients with low grade neuroendocrine carcinoma.

3. To explore the effect on tumor blood flow as determined by functional computed tomography (CT) of GW786034 800 mg orally once daily in patients with low grade neuroendocrine carcinoma.

4. To assess the trough level of GW786034 800 mg orally once daily in patients with low grade neuroendocrine carcinoma.

OUTLINE:

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 90 days for up to 18 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of GW786034 (Pazopanib) in Advanced Low-Grade or Intermediate-Grade Neuroendocrine Carcinoma
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (pazopanib hydrochloride) Patients receive pazopanib hydrochloride PO QD on days 1-28. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Pazopanib Hydrochloride; Given PO; Other Names: GW786034B Votrient ; Other: Pharmacological Study; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (Complete and Partial Response) for Each Cohort Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) [Up to 18 months]

   RECIST Criteria: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): 30% decrease in sum of longest diameter (LD) of target lesions, reference baseline sum LD; Progressive Disease (PD): 20% increase in sum of LD of target lesions, reference smallest sum LD recorded since treatment started or appearance 1/> new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum LD since treatment started.

Secondary Outcome Measures

1. Percent Change in Tumor Blood Flow Assessed by Functional CT [Baseline and week 12]

   Explore the effect on tumor blood flow as determined by functional CT of GW786034 (Pazopanib) 800 mg orally once daily on both arms, carcinoid and pNET.

Other Outcome Measures

1. Progression Free Survival (PFS) [Baseline to 18 months.]

   PFS is defined as the duration of time from start of treatment to time of progression or death.

2. Plasma Trough Level of GW786034 [assessed at Baseline and day 28, day 28 reported]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed low or intermediate grade carcinoid or islet cell carcinoma; patients with carcinoid or islet cell carcinoma associated with multiple endocrine neoplasia (MEN)1 syndrome will be eligible and entered in the islet cell cohort

• Patients must have 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

• Patients may have received 0 or 1 prior cytotoxic therapy; chemotherapy used as a radiosensitizer will be considered one prior chemotherapy regimen; patient must not have received prior bevacizumab or any other therapy targeting vascular endothelial growth factor (VEGF) or VEGF receptors (i.e., SU11248, PTK787/ZK222584, Sorafenib, GW786034)

• Patients must be on a stable dose of somatostatin analogue for 2 months prior to start of protocol; octreotide dose not count toward prior therapy

• Prior radiation therapy is permitted; a recovery period of at least 4 weeks after completion of radiotherapy is required prior to enrollment

• Patients may have received prior interferon (not counted toward prior cytotoxic chemotherapy)

• Patients may have received prior therapy targeting v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (c-kit), c-abl oncogene 1, non-receptor tyrosine kinase (abl), platelet-derived growth factor receptor (PDGFR), or epidermal growth factor receptor (EGFR) (imatinib, gefitinib, erlotinib, cetuximab; not counted toward prior cytotoxic chemotherapy)

• Patients must have unresectable or metastatic disease

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1 (Karnofsky >= 70%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 120,000/mcL

• Total bilirubin within normal institutional limits

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X institutional upper limit of normal

• Creatinine =< 2.0 OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (calculated by Cockcroft Gault formula)

• Patients must have prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) within 1.2 X the upper limit of normal

• Patients must have resting blood pressure (BP) no greater than 140 mmHg (systolic) or 90 mmHg (diastolic) for eligibility; initiation or adjustment of BP medication is permitted prior to study entry

• Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation; women of child-bearing potential must have a negative blood pregnancy test prior to study entry; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows:

• An intrauterine device with a documented failure rate of less than 1% per year

• Vasectomized partner who is sterile prior to the female patient's entry and is the sole sexual partner for that female

• Complete abstinence from sexual intercourse for 14 days before exposure to investigation product, through the clinical trial, and for at least 21 days after the last dose of investigational product

• Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide)

• Note: Oral contraceptives are not reliable due to potential drug-drug interaction

• Ability to understand and the willingness to sign a written informed consent document

• Ability to swallow and retain oral medication

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to study enrollment; at least 4 weeks must have elapsed since any major surgery prior to study enrollment

• Patients may not be receiving any other investigational agents

• Patients with corrected QT (QTc) > 480 msecs

• Patients with greater than 1+ (>= 100 mg/dl) proteinuria on two consecutive routine urinalysis taken at least 1 week apart are ineligible

• Certain medications that act through the cytochrome P450 (CYP450) system are specifically prohibited in patients receiving GW786034 (pazopanib) because in vitro data indicate that the agent has the potential to interact with the cytochrome P450 isoenzymes; certain other agents should be used with caution

• Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous [IV] alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain GW786034 (pazopanib) tablets are excluded

• Patients with any of the following conditions are excluded:

• Serious or non-healing wound, ulcer, or bone fracture

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of treatment

• History of known active diverticulitis within the past 3 months

• Any history of cerebrovascular accident (CVA) within the last 6 months

• Current use of therapeutic warfarin; Note: Low molecular weight heparin and prophylactic low-dose warfarin are permitted; PT/PTT must meet the inclusion criteria

• History of myocardial infarction, cardiac arrhythmia, admission for unstable angina, cardiac angioplasty or stenting within the last 12 weeks

• History of venous thrombosis in last 12 weeks

• Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; a patient who has a history of class II heart failure and is asymptomatic on treatment may be considered eligible

• Patients with known brain metastases should be excluded from this clinical trial

• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for five years

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with GW786034 (pazopanib); these potential risks may also apply to other agents used in this study

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

• Uncontrolled diarrhea (8 or more bowel movements per day)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: James Yao, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00454363
• Other Study ID Numbers: NCI-2009-00201; NCI-2009-00201; CDR0000537034; MDACC 2006-0077; MDACC 2006-0077; 7650; N01CM62202; P30CA016672; U01CA062490
• First Posted: Mar 30, 2007
• Last Update Posted: Apr 3, 2020
• Last Verified: Mar 1, 2020

• Additional relevant MeSH terms: Carcinoma; Neuroendocrine Tumors; Carcinoid Tumor; Carcinoma, Neuroendocrine; Insulinoma; Endocrine Gland Neoplasms; Multiple Endocrine Neoplasia; Glucagonoma; Intestinal Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms; Carcinoma, Islet Cell; Multiple Endocrine Neoplasia Type 1; Malignant Carcinoid Syndrome; Gastrointestinal Neoplasms; Somatostatinoma; Gastrinoma; Recurrence

Study Results

Participant Flow

Recruitment Details	Open recruitment period: March 2007 to December 2009. All recruitment done at University of Texas (UT) and Dana Farber Cancer Institute.
Pre-assignment Detail	Of the 52 enrolled, one participant was excluded from the study prior to study treatment.

Arm/Group Title	Pazopanib + Carcinoid	Pazopanib + pNET
Arm/Group Description	Carcinoid Tumor Type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.	Pancreatic Neuroendocrine (pNET) tumor type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.
Period Title: Overall Study
STARTED	20	31
COMPLETED	15	29
NOT COMPLETED	5	2

Baseline Characteristics

Arm/Group Title	Pazopanib + Carcinoid	Pazopanib + pNET	Total
Arm/Group Description	Carcinoid Tumor Type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.	Pancreatic Neuroendocrine (pNET) tumor type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.	Total of all reporting groups
Overall Participants	20	31	51
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63	55	60
Sex: Female, Male (Count of Participants)
Female	7 35%	10 32.3%	17 33.3%
Male	13 65%	21 67.7%	34 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 10%	3 9.7%	5 9.8%
Not Hispanic or Latino	18 90%	28 90.3%	46 90.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 3.2%	1 2%
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%	2 6.5%	2 3.9%
White	20 100%	28 90.3%	48 94.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%	31 100%	51 100%
Participant from Enrolling Institutions (participants) [Number]
Dana Farber Cancer Institute	6 30%	11 35.5%	17 33.3%
MD Anderson Cancer Center	14 70%	20 64.5%	34 66.7%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (Complete and Partial Response) for Each Cohort Assessed by Response Evaluation Criteria in Solid Tumors (RECIST)
Description	RECIST Criteria: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): 30% decrease in sum of longest diameter (LD) of target lesions, reference baseline sum LD; Progressive Disease (PD): 20% increase in sum of LD of target lesions, reference smallest sum LD recorded since treatment started or appearance 1/> new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum LD since treatment started.
Time Frame	Up to 18 months

Outcome Measure Data

Analysis Population Description

RECIST best protocol response by intention to treat. Four participants were not evaluable for response.

Arm/Group Title	Pazopanib + Carcinoid	Pazopanib + pNET
Arm/Group Description	Carcinoid Tumor Type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.	Pancreatic Neuroendocrine (pNET) tumor type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.
Measure Participants	20	31
PR	0 0%	6 19.4%
SD	14 70%	21 67.7%
PD	3 15%	3 9.7%
Not Evaluable	3 15%	1 3.2%

2. Secondary Outcome

Title	Percent Change in Tumor Blood Flow Assessed by Functional CT
Description	Explore the effect on tumor blood flow as determined by functional CT of GW786034 (Pazopanib) 800 mg orally once daily on both arms, carcinoid and pNET.
Time Frame	Baseline and week 12

Outcome Measure Data

Analysis Population Description

Data were not collected from any participant in the Pazopanib + Carcinoid Arm Group

Arm/Group Title	Pazopanib + Carcinoid	Pazopanib + pNET
Arm/Group Description	Carcinoid Tumor Type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.	Pancreatic Neuroendocrine (pNET) tumor type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.
Measure Participants	0	11
Median (Full Range) [percentage of change in tumor blood flow]	139

3. Other Pre-specified Outcome

Title	Progression Free Survival (PFS)
Description	PFS is defined as the duration of time from start of treatment to time of progression or death.
Time Frame	Baseline to 18 months.

Outcome Measure Data

Analysis Population Description

Analysis calculated according to intent to treat.

Arm/Group Title	Pazopanib + Carcinoid	Pazopanib + pNET
Arm/Group Description	Carcinoid Tumor Type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.	Pancreatic Neuroendocrine (pNET) tumor type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.
Measure Participants	20	31
Median (95% Confidence Interval) [months]	12	14.2

4. Other Pre-specified Outcome

Title	Plasma Trough Level of GW786034
Time Frame	assessed at Baseline and day 28, day 28 reported

Outcome Measure Data

Analysis Population Description

Plasma trough level in blood was below the level of detection.

Arm/Group Title	Pazopanib + Carcinoid	Pazopanib + pNET
Arm/Group Description	Carcinoid Tumor Type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.	Pancreatic Neuroendocrine (pNET) tumor type: Oral Pazopanib hydrochloride 800 mg once daily on days 1-28.
Measure Participants	20	31
Count of Participants [Participants]	NA NaN	NA NaN

Adverse Events

Time Frame	Adverse events occurring within 30 days of last dose investigational drug, with each cycle 28 days for up to 12 cycles. Overall participation period April 2007 to March 2013.
Arm/Group Title	Pazopanib
Arm/Group Description	Oral pazopanib hydrochloride once daily on days 1-28.
All Cause Mortality
	Pazopanib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Pazopanib
	Affected / at Risk (%)	# Events
Total	16/51 (31.4%)
General disorders
Death NOS	11/51 (21.6%)
Metabolism and nutrition disorders
Hyperglycemia	1/51 (2%)
Hypertriglyceridemia	1/51 (2%)
Hyponatremia	1/51 (2%)
Nervous system disorders
Peripheral sensory neuropathy	1/51 (2%)
Respiratory, thoracic and mediastinal disorders
Thromboembolic event	1/51 (2%)
Other (Not Including Serious) Adverse Events
	Pazopanib
	Affected / at Risk (%)	# Events
Total	51/51 (100%)
Blood and lymphatic system disorders
Activated partial thromboplastin time prolonged	5/51 (9.8%)	10
Anemia	23/51 (45.1%)	45
INR increased	8/51 (15.7%)	16
Lymphocyte count decreased	1/51 (2%)	1
Neutrophil count decreased	11/51 (21.6%)	29
Platelet count decreased	12/51 (23.5%)	19
White blood cell decreased	10/51 (19.6%)	19
Cardiac disorders
Cardiac disorders	1/51 (2%)	1
Heart failure	1/51 (2%)	1
Hypertension	35/51 (68.6%)	45
Hypotension	2/51 (3.9%)	2
Sinus bradycardia	3/51 (5.9%)	3
Vasovagal reaction	1/51 (2%)	1
Ear and labyrinth disorders
External ear pain	1/51 (2%)	1
Hearing impaired	1/51 (2%)	1
Tinnitus	1/51 (2%)	1
Endocrine disorders
Hot flashes	3/51 (5.9%)	4
Hyperthyroidism	1/51 (2%)	1
Hypothyroidism	3/51 (5.9%)	3
Eye disorders
Blurred vision	3/51 (5.9%)	3
Cataract	1/51 (2%)	1
Eye infection/pain	2/51 (3.9%)	2
Gastrointestinal disorders
Abdominal distension	2/51 (3.9%)	4
Abdominal pain	36/51 (70.6%)	78
Anorexia	12/51 (23.5%)	14
Ascites	3/51 (5.9%)	3
Colitis	1/51 (2%)	1
Constipation	15/51 (29.4%)	20
Dental caries	1/51 (2%)	1
Diarrhea	41/51 (80.4%)	150
Dyspepsia	3/51 (5.9%)	3
Fecal incontinence	1/51 (2%)	1
Flatulence	3/51 (5.9%)	3
Gastritis	14/51 (27.5%)	17
Hemorrhoidal hemorrhage	3/51 (5.9%)	6
Malabsorption	1/51 (2%)	1
Mucositis oral	10/51 (19.6%)	21
Nausea	37/51 (72.5%)	104
Oral pain	4/51 (7.8%)	4
Rectal hemorrhage	1/51 (2%)	1
Rectal pain	1/51 (2%)	1
Stomach pain	1/51 (2%)	2
Vomiting	20/51 (39.2%)	37
General disorders
Chills	1/51 (2%)	1
Edema, Face	1/51 (2%)	1
Edema, Limbs	8/51 (15.7%)	10
Fatigue	43/51 (84.3%)	155
Fever	10/51 (19.6%)	13
Insomnia	11/51 (21.6%)	12
Myalgia	3/51 (5.9%)	4
Pain	20/51 (39.2%)	24
Weight gain	2/51 (3.9%)	2
Weight loss	8/51 (15.7%)	10
Hepatobiliary disorders
Pancreatitis	1/51 (2%)	1
Immune system disorders
Allergic rhinitis	3/51 (5.9%)	3
Infections and infestations
Infections	5/51 (9.8%)	5
Soft tissue infection	1/51 (2%)	1
Injury, poisoning and procedural complications
Administration site issue	1/51 (2%)	2
Investigations
Investigations	2/51 (3.9%)	3
Metabolism and nutrition disorders
Acidosis	2/51 (3.9%)	4
Alanine aminotransferase increased	19/51 (37.3%)	58
Alkaline phosphatase increased	9/51 (17.6%)	28
Aspartate aminotransferase increased	27/51 (52.9%)	83
Blood bilirubin increased	17/51 (33.3%)	33
Cholesterol high	3/51 (5.9%)	3
Creatinine increased	5/51 (9.8%)	7
Dehydration	2/51 (3.9%)	2
Hypercalcemia	2/51 (3.9%)	2
Hyperglycemia	23/51 (45.1%)	73
Hyperkalemia	1/51 (2%)	1
Hypernatremia	3/51 (5.9%)	5
Hypertriglyceridemia	2/51 (3.9%)	5
Hypoalbuminemia	6/51 (11.8%)	8
Hypocalcemia	10/51 (19.6%)	15
Hypoglycemia	4/51 (7.8%)	11
Hypokalemia	4/51 (7.8%)	8
Hypomagnesemia	10/51 (19.6%)	15
Hyponatremia	6/51 (11.8%)	11
Hypophosphatemia	7/51 (13.7%)	9
Proteinuria	7/51 (13.7%)	9
Musculoskeletal and connective tissue disorders
Arthralgia	6/51 (11.8%)	7
Back Pain	12/51 (23.5%)	15
Muscle Weakness	4/51 (7.8%)	5
Muscle Weakness, Trunk	1/51 (2%)	1
Osteoporosis	1/51 (2%)	1
Pain in extremity	7/51 (13.7%)	7
Nervous system disorders
Anxiety	4/51 (7.8%)	7
Cognitive disturbance	1/51 (2%)	1
Confusion	2/51 (3.9%)	2
Depression	5/51 (9.8%)	6
Dizziness	11/51 (21.6%)	15
Headache	14/51 (27.5%)	26
Nervous system disorders	3/51 (5.9%)	3
Neuralgia	1/51 (2%)	1
Peripheral sensory neuropathy	1/51 (2%)	1
Syncope	3/51 (5.9%)	3
Vertigo	1/51 (2%)	2
Psychiatric disorders
Agitation	1/51 (2%)	1
Renal and urinary disorders
Bladder Spasm	1/51 (2%)	1
Increased Urinary Frequency	6/51 (11.8%)	7
Urinary Incontinence	1/51 (2%)	1
Urine Retention	1/51 (2%)	1
Urinary tract infection	2/51 (3.9%)	2
Reproductive system and breast disorders
Erectile dysfunction	1/51 (2%)	1
Libido decreased	1/51 (2%)	1
Vaginal hemorrhage	1/51 (2%)	1
Vaginal infection	2/51 (3.9%)	2
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/51 (2%)	1
Chest wall pain	1/51 (2%)	1
Cough	7/51 (13.7%)	8
Dyspnea	10/51 (19.6%)	11
Epistaxis	2/51 (3.9%)	2
Non-cardiac chest pain	5/51 (9.8%)	6
Respiratory, thoracic and mediastinal	3/51 (5.9%)	3
Sinusitis	1/51 (2%)	1
Upper respiratory infection	3/51 (5.9%)	4
Voice alteration	1/51 (2%)	3
Skin and subcutaneous tissue disorders
Alopecia	3/51 (5.9%)	3
Dry skin	1/51 (2%)	1
Flushing	7/51 (13.7%)	11
Hyperhidrosis	4/51 (7.8%)	4
Nail Loss	1/51 (2%)	1
Palmar-plantar erythrodysesthesia	3/51 (5.9%)	5
Pruritus	1/51 (2%)	1
Rash acneiform	4/51 (7.8%)	6
Skin disorders	8/51 (15.7%)	10
Skin hypopigmentation	7/51 (13.7%)	7
Skin infection	1/51 (2%)	1
Wound dehiscence	1/51 (2%)	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.