Cabozantinib for Adults With Advanced Soft Tissue Sarcoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01755195
• Collaborator: (none)
• Enrollment: 55
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 117
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Background:

• Cabozantinib is a cancer treatment drug that blocks the growth of new blood vessels in tumors. It can also block a chemical on tumor cells that allows the cells to grow. A similar drug, pazopanib, is used to treat types of cancer known as sarcomas. Researchers want to see if cabozantinib can be an effective treatment for types of soft tissue sarcoma that have not responded to earlier treatments.

Objectives:

• To test the effectiveness of cabozantinib for soft tissue sarcomas that have not responded to standard treatments.

Eligibility:

• Individuals at least 18 years of age who have soft tissue sarcomas that have not responded to standard treatments.

Design:

• Participants will be screened with a physical exam and medical history. Blood samples will be collected. Imaging studies and other tests will be used to study the tumor before the start of treatment.

• Participants will take cabozantinib tablets daily for 28-day cycles of treatment. The tablets should be taken whole on an empty stomach.

• Treatment will be monitored with frequent blood tests and imaging studies.

• Participants will continue to take cabozantinib for as long as the tumor does not become worse and the side effects are not too severe.

Condition or Disease	Intervention/Treatment	Phase
Refractory Soft Tissue Sarcomas	Drug: Cabozantinib	Phase 2

Detailed Description

Background:

• Soft tissue sarcomas (STS) are a relatively rare heterogeneous group of tumors that constitute about 1% of adult cancers.

• The mainstay of treatment for advanced disease has been palliative chemotherapy with a median overall survival of approximately 12 months. This has not changed considerably in the past years and there is an unmet need for newer targeted therapies.

• Vascular endothelial growth factor (VEGF) levels are elevated in patients with STS and various sarcoma cell lines express high levels of activated c-Met receptor.

• We hypothesize that dual targeting of the VEGF and mesenchymal-epithelial transition factor (c-MET) pathways with cabozantinib would result in clinical benefit in patients with soft tissue sarcoma.

Objectives:

Primary:

• Assess the response rate (Complete Response (CR)+Partial Response (PR) of cabozantinib in patients with soft tissue sarcomas.

• Assess the 6 month progression free survival (PFS) of cabozantinib in soft tissue sarcomas.

Secondary:

-Determine and compare circulating levels of hepatocyte growth factor (HGF), soluble MET (sMET), VEGF-A, and soluble vascular endothelial growth factor receptor 2 (VEGFR2) (sVEGFR2) prior to and following administration of cabozantinib.

Eligibility:

• Patients must have had disease progression following one line of standard therapy

• Age greater than or equal to 18 years.

• Adequate organ function.

Design:

• All patients will receive cabozantinib at 60 mg by mouth (PO) daily in 4 week cycles.

• Tumor response evaluations by imaging will be done every 2 cycles (less frequently for patients on study more than one year).

• The study will be conducted as a dual-endpoint two-stage Phase II trial to target objective tumor response rate (CR+PR) of 30% against an unacceptably low rate of 10%, and 6-month PFS rate of 65% against an unacceptably low rate of 45% (corresponding to median PFS of 9.6 vs. 5.2 months).

• The trial will accrue up to 55 patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Cabozantinib (XL184), a Dual Inhibitor of MET and VEGFR, in Patients With Metastatic Refractory Soft Tissue Sarcoma
• Actual Study Start Date: Jan 15, 2013
• Actual Primary Completion Date: Sep 30, 2020
• Anticipated Study Completion Date: Oct 16, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cabozantinib 60 mg tablets orally once a day in a 28-day cycle.	Drug: Cabozantinib; Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).; Other Names: Cometriq

Outcome Measures

Primary Outcome Measures

1. Objective Response (Complete Response (CR)+Partial Response (PR) of Cabozantinib in Patients With Soft Tissue Sarcomas [Date treatment consent signed to date off study, approximately 86 months and 3 days.]

   Objective response was assessed by the Response Evaluation Criteria in Solid Tumors RECIST) v1.1. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

2. Percentage of Participants With 6 Month Progression Free Survival (PFS) [6 months]

   Progression in participants with soft tissue sarcomas treated with cabozantinib was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.

Secondary Outcome Measures

1. Mean Change From Baseline in Levels of Circulating Hepatocyte Growth Factor (HGF) [Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1]

   Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of HGF. HGF protein content (in picograms; pg) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome.

2. Mean Change From Baseline in Levels of Circulating Soluble Mesenchymal Epithelial Transition Factor (sMET) [Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1]

   Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of soluble MET (sMET). sMET protein content (in nanograms; ng) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome.

3. Mean Change From Baseline in Levels of Circulating Vascular Endothelial Growth Factor A (VEGF-A) [Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1]

   Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of VEGF-A. VEGF-A protein content (in picograms; pg) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome.

4. Mean Change From Baseline in Levels of Circulating Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR-2) [Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1]

   Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of soluble VEGFR2 (sVEGFR-2). sVEGFR-2 protein content (in nanograms; ng) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome..

Other Outcome Measures

1. Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) [Date treatment consent signed to date off study, approximately 86 months and 3 days.]

   Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

• Patients must have histologically or cytologically confirmed soft tissue sarcoma that is metastatic or unresectable and for which standard treatment that prolongs survival does not exist or is no longer effective.

• 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 for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam.

• Patients are allowed prior vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKI) therapy.

• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of cabozantinib in patients <18 years of age, children are excluded from this study.

• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky >70%).

• Life expectancy > 3 months.

• Patients must have normal organ and marrow function as defined below:

• leukocytes greater than or equal to 3,000/mcL

• absolute neutrophil count greater than or equal to 1,500/mcL

• platelets greater than or equal to 100,000/mcL

• total bilirubin less than or equal to 1.5 times ULN

• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase(SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase(SGPT) less than or equal to 2.5 times institutional upper limit of normal creatinine within normal institutional limits

• creatinine within normal institutional limits OR clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.

• hemoglobin greater than or equal to 9 g/dL

• serum albumin greater than or equal to 2.8g/dL

• lipase <2.0 times upper limit of normal (ULN) and no radiologic or clinical evidence of pancreatitis

• urine protein/creatinine ratio (UPCR) less than or equal to 1

• serum phosphorus calcium, magnesium and potassium greater than or equal to lower limit of normal (LLN)

• Subjects must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is permitted prior to study entry provided that the average of three BP readings at the time of enrollment is less than or equal to 140/90 mmHg

• Patients must be able to swallow whole tablets. Tablets must not be crushed or chewed.

• The effects of cabozantinib on the developing human fetus are unknown. For this reason and because receptor tyrosine kinases are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).

Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used.

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

EXCLUSION CRITERIA:

• Patients who have had anticancer therapy, including kinase inhibitors or any investigational agent within 4 weeks or 5 half-lives (whichever is shorter) (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered to baseline from adverse events (except alopecia and other non-clinically significant adverse events (AEs). Patients who have received prior cabozantinib or inhibitors of tyrosine-protein kinase mesenchymal epithelial transition factor (c-MET) or hepatocyte growth factor (HGF) are ineligible.

• The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment

• The subject has received radiation therapy within 4 weeks (greater than or equal to 2 weeks for palliative radiation therapy)

• Patients with active brain metastases or carcinomatous meningitis or epidural disease are excluded from this clinical trial. Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation who are asymptomatic and have remained stable for 4 weeks and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility.

• Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity of cabozantinib will be determined following review of their cases by the Principal Investigator. Patients who are taking enzyme-inducing anticonvulsant agents are not eligible.

• Patients with refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that could interfere with absorption.

• Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Pregnant women are excluded from this study because cabozantinib has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib, breastfeeding should be discontinued if the mother is treated with cabozantinib.

• Strong inhibitors and inducers of cytochrome P450 3A4 (CYP3A4) can affect levels of cabozantinib and should be avoided whenever possible or switched to alternatives. Subjects requiring chronic concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort) are not eligible for this study. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over the-counter medicine or herbal product.

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cabozantinib. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (less than or equal to 81 mg/day), low-dose warfarin (less than or equal to 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted. (Please note that there may be cases in which patients on study require anticoagulation for deep vein thrombosis (DVT)/pulmonary embolism (PE) management; this does not necessitate taking

the patient off study.)

• The subject has experienced any of the following

• clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment

• hemoptysis of greater than or equal to 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment

• any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment

• The subject has radiographic evidence of cavitating pulmonary lesion(s).

• The subject has tumor in contact with, invading, or encasing any major blood vessels

• The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib

• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

1. Cardiovascular disorders including:

2. Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening

3. Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment

4. Any history of congenital long QT syndrome

5. Any of the following within 6 months before the first dose of study treatment:

• unstable angina pectoris

• clinically-significant cardiac arrhythmias

• stroke (including transient ischemic attack (TIA), or other ischemic event)

• myocardial infarction

• thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)

1. Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

2. Any of the following within 28 days before the first dose of study treatment

• intra-abdominal tumor/metastases invading GI mucosa

• active peptic ulcer disease,

• inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis

• malabsorption syndrome

1. Any of the following within 6 months before the first dose of study treatment:

• abdominal fistula

• gastrointestinal perforation

• bowel obstruction or gastric outlet obstruction

• intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 6 months before the first dose of study treatment.

1. Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy

2. Other clinically significant disorders such as:

3. serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment

4. history of organ transplant, including allogeneic bone marrow transplant

5. concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment

6. history of major surgery as follows:

1. Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications

1. Minor surgery within 1 months of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications

In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery

• The subject is unable to swallow tablets

• The subject has a corrected QT interval calculated by the Fridericia formula (QTcF)

500 ms within 28 days before enrollment. Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is less than or equal to 500 ms, the subject meets eligibility in this regard.

• The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

• The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment.

• Patients should not have any clinical evidence of an active infection at the time of enrollment.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women of all races and ethnic groups are eligible for this trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Alice P Chen, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 18, 2021
• Informed Consent Form - Apr 6, 2021

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Coindre JM, Terrier P, Guillou L, Le Doussal V, Collin F, Ranchère D, Sastre X, Vilain MO, Bonichon F, N'Guyen Bui B. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001 May 15;91(10):1914-26.
• Edmonson JH, Ryan LM, Blum RH, Brooks JS, Shiraki M, Frytak S, Parkinson DR. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993 Jul;11(7):1269-75.
• Elias A, Ryan L, Sulkes A, Collins J, Aisner J, Antman KH. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989 Sep;7(9):1208-16.

• Responsible Party: Alice Chen, M.D., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01755195
• Other Study ID Numbers: 130044; 13-C-0044
• First Posted: Dec 24, 2012
• Last Update Posted: Nov 10, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Alice Chen, M.D., Principal Investigator, National Cancer Institute (NCI): Dual Inhibitor of MET and VEGFR; XL184; Metastatic Refractory; Soft Tissue Sarcoma; Rare Heterogeneous Tumor
• Additional relevant MeSH terms: Sarcoma

Study Results

Participant Flow

Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Period Title: Overall Study
STARTED	55
COMPLETED	42
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Overall Participants	55
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	50 90.9%
>=65 years	5 9.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.69 (12.21)
Sex: Female, Male (Count of Participants)
Female	31 56.4%
Male	24 43.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 20%
Not Hispanic or Latino	43 78.2%
Unknown or Not Reported	1 1.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.8%
Asian	10 18.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	9 16.4%
White	33 60%
More than one race	0 0%
Unknown or Not Reported	2 3.6%
Region of Enrollment (participants) [Number]
United States	55 100%

Outcome Measures

1. Primary Outcome

Title	Objective Response (Complete Response (CR)+Partial Response (PR) of Cabozantinib in Patients With Soft Tissue Sarcomas
Description	Objective response was assessed by the Response Evaluation Criteria in Solid Tumors RECIST) v1.1. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	Date treatment consent signed to date off study, approximately 86 months and 3 days.

Outcome Measure Data

Analysis Population Description

1/55 participants did not start therapy.

Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Measure Participants	54
Number (95% Confidence Interval) [percentage of particpants]	11.1

2. Primary Outcome

Title	Percentage of Participants With 6 Month Progression Free Survival (PFS)
Description	Progression in participants with soft tissue sarcomas treated with cabozantinib was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

1/55 participants did not start therapy.

Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Measure Participants	54
Number (95% Confidence Interval) [percentage of participants]	49.3 89.6%

3. Secondary Outcome

Title	Mean Change From Baseline in Levels of Circulating Hepatocyte Growth Factor (HGF)
Description	Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of HGF. HGF protein content (in picograms; pg) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome.
Time Frame	Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

42/54 participants were analyzed for this outcome measure. One participant did not start therapy, and twelve participants did not participate in the optional biomarker testing.

Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Measure Participants	42
Baseline to Cycle 1 Day 1	-51.3
Baseline to Cycle 2 Day 1	344.8

4. Secondary Outcome

Title	Mean Change From Baseline in Levels of Circulating Soluble Mesenchymal Epithelial Transition Factor (sMET)
Description	Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of soluble MET (sMET). sMET protein content (in nanograms; ng) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome.
Time Frame	Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

42/54 participants were analyzed for this outcome measure. One participant did not start therapy, and twelve participants did not participate in the optional biomarker testing.

Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Measure Participants	42
Baseline to Cycle 1 Day 1	-6.1
Baseline to Cycle 2 Day1	16.4

5. Secondary Outcome

Title	Mean Change From Baseline in Levels of Circulating Vascular Endothelial Growth Factor A (VEGF-A)
Description	Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of VEGF-A. VEGF-A protein content (in picograms; pg) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome.
Time Frame	Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

42/54 participants were analyzed for this outcome measure. One participant did not start therapy, and twelve participants did not participate in the optional biomarker testing.

Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Measure Participants	42
Baseline to Cycle 1 Day 1	5.6
Baseline to Cycle 2 Day 1	32.5

6. Secondary Outcome

Title	Mean Change From Baseline in Levels of Circulating Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR-2)
Description	Blood samples were collected before treatment on the first day of cycles 1 and 2 to determine circulating levels of soluble VEGFR2 (sVEGFR-2). sVEGFR-2 protein content (in nanograms; ng) in blood plasma (in milliliters; mL) was measured for each sample with a two-site immunoassay and the difference from before to after treatment for each patient was reported. A change in this biomarker from the baseline value has not been linked to clinical outcomes; that is, it is neither a good or a bad outcome..
Time Frame	Baseline to Cycle 1 Day 1 and baseline to Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

42/54 participants were analyzed for this outcome measure. One participant did not start therapy, and twelve participants did not participate in the optional biomarker testing.

Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Measure Participants	42
Baseline to Cycle 1 Day 1	-1.0
Baseline to Cycle 2 Day 1	-10.9

7. Other Pre-specified Outcome

Title	Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Description	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time Frame	Date treatment consent signed to date off study, approximately 86 months and 3 days.

Outcome Measure Data

Analysis Population Description

1/55 participants did not start therapy.

Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
Measure Participants	54
Count of Participants [Participants]	53 96.4%

Adverse Events

Time Frame	Date treatment consent signed to date off study, approximately 86 months and 3 days.
Adverse Event Reporting Description	1/55 participants did not start therapy.
Arm/Group Title	Cabozantinib
Arm/Group Description	60 mg tablets orally once a day in a 28-day cycle. Cabozantinib: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).
All Cause Mortality
	Cabozantinib
	Affected / at Risk (%)	# Events
Total	3/54 (5.6%)
Serious Adverse Events
	Cabozantinib
	Affected / at Risk (%)	# Events
Total	14/54 (25.9%)
Blood and lymphatic system disorders
Anemia	1/54 (1.9%)	1
Cardiac disorders
Supraventricular tachycardia	1/54 (1.9%)	1
Gastrointestinal disorders
Abdominal pain	2/54 (3.7%)	2
Diarrhea	1/54 (1.9%)	1
Nausea	3/54 (5.6%)	3
Small intestinal obstruction	2/54 (3.7%)	2
Vomiting	3/54 (5.6%)	3
General disorders
Fatigue	1/54 (1.9%)	1
General disorders and administration site conditions - Other, fever	1/54 (1.9%)	1
Infections and infestations
Tooth infection	1/54 (1.9%)	1
Upper respiratory infection	1/54 (1.9%)	1
Urinary tract infection	1/54 (1.9%)	1
Investigations
Serum amylase increased	1/54 (1.9%)	1
Metabolism and nutrition disorders
Dehydration	2/54 (3.7%)	3
Hypophosphatemia	1/54 (1.9%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness trunk	1/54 (1.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, neoplasm	1/54 (1.9%)	1
Nervous system disorders
Cerebrospinal fluid leakage	1/54 (1.9%)	1
Headache	1/54 (1.9%)	1
Stroke	1/54 (1.9%)	1
Syncope	1/54 (1.9%)	1
Transient ischemic attacks	1/54 (1.9%)	1
Renal and urinary disorders
Hematuria	1/54 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/54 (1.9%)	1
Pleural effusion	2/54 (3.7%)	2
Pleuritic pain	1/54 (1.9%)	1
Pneumothorax	1/54 (1.9%)	1
Respiratory failure	1/54 (1.9%)	1
Vascular disorders
Thromboembolic event	3/54 (5.6%)	4
Other (Not Including Serious) Adverse Events
	Cabozantinib
	Affected / at Risk (%)	# Events
Total	53/54 (98.1%)
Blood and lymphatic system disorders
Anemia	13/54 (24.1%)	32
Blood and lymphatic system disorders - Other, Blood in stool due to hemorrhoids	1/54 (1.9%)	1
Cardiac disorders
Chest pain - cardiac	3/54 (5.6%)	3
Electrocardiogram QT corrected interval prolonged	4/54 (7.4%)	4
Left ventricular systolic dysfunction	1/54 (1.9%)	1
Sinus bradycardia	3/54 (5.6%)	4
Sinus tachycardia	4/54 (7.4%)	5
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, Light headedness	1/54 (1.9%)	1
Ear pain	1/54 (1.9%)	1
Middle ear inflammation	1/54 (1.9%)	1
Tinnitus	1/54 (1.9%)	1
Vertigo	2/54 (3.7%)	2
Endocrine disorders
Endocrine disorders - Other, Lactate dehydrogenase increased	1/54 (1.9%)	1
Hyperthyroidism	4/54 (7.4%)	8
Hypothyroidism	18/54 (33.3%)	26
Eye disorders
Blurred vision	1/54 (1.9%)	1
Cataract	1/54 (1.9%)	1
Dry eye	1/54 (1.9%)	1
Eye disorders - Other, Eye disorders; erythrodysesthesia syndrome	1/54 (1.9%)	1
Eye disorders - Other, Eye disorders; loss of peripheral vision	1/54 (1.9%)	2
Eye disorders - Other, High Spatial Frequencies	1/54 (1.9%)	1
Eye disorders - Other, Vision change (black spots)	1/54 (1.9%)	1
Flashing lights	1/54 (1.9%)	1
Photophobia	1/54 (1.9%)	1
Gastrointestinal disorders
Abdominal pain	9/54 (16.7%)	25
Anal hemorrhage	1/54 (1.9%)	1
Bloating	2/54 (3.7%)	3
Constipation	16/54 (29.6%)	22
Dental caries	1/54 (1.9%)	2
Diarrhea	28/54 (51.9%)	72
Dry mouth	12/54 (22.2%)	17
Dyspepsia	9/54 (16.7%)	10
Esophageal pain	1/54 (1.9%)	1
Flatulence	7/54 (13%)	9
Gastroesophageal reflux disease	4/54 (7.4%)	5
Gastrointestinal disorders - Other, GI:Increased Salivation	1/54 (1.9%)	1
Gastrointestinal disorders - Other, Gastrointestinal disorders - Other, specify: Rectal discharge	1/54 (1.9%)	1
Gastrointestinal disorders - Other, blood in stool	1/54 (1.9%)	1
Gastrointestinal disorders - Other, intermittent decrease/loss of appetite	1/54 (1.9%)	1
Gastrointestinal disorders - Other, loose stool	1/54 (1.9%)	1
Gingival pain	2/54 (3.7%)	2
Mucositis oral	14/54 (25.9%)	33
Nausea	22/54 (40.7%)	50
Oral hemorrhage	1/54 (1.9%)	1
Oral pain	9/54 (16.7%)	11
Periodontal disease	1/54 (1.9%)	1
Rectal pain	2/54 (3.7%)	2
Stomach pain	2/54 (3.7%)	2
Tooth development disorder	1/54 (1.9%)	1
Toothache	4/54 (7.4%)	4
Vomiting	17/54 (31.5%)	42
General disorders
Chills	5/54 (9.3%)	5
Edema face	1/54 (1.9%)	1
Edema limbs	7/54 (13%)	9
Fatigue	23/54 (42.6%)	46
Fever	6/54 (11.1%)	6
Flu like symptoms	4/54 (7.4%)	4
Gait disturbance	1/54 (1.9%)	1
General disorders and administration site conditions - Other, Mouth Sores	1/54 (1.9%)	1
General disorders and administration site conditions - Other, Numbness of Tongue	1/54 (1.9%)	1
Malaise	1/54 (1.9%)	2
Pain	10/54 (18.5%)	16
Immune system disorders
Allergic reaction	1/54 (1.9%)	1
Immune system disorders - Other, Liver Function Enzymes	1/54 (1.9%)	1
Infections and infestations
Enterocolitis	1/54 (1.9%)	1
Gum infection	1/54 (1.9%)	2
Infections and infestations - Other, Facial infection	1/54 (1.9%)	1
Infections and infestations - Other, Infection - Tumor fungation	1/54 (1.9%)	1
Infections and infestations - Other, Malaria	1/54 (1.9%)	1
Infections and infestations - Other, Post-dental work	1/54 (1.9%)	1
Infections and infestations - Other, Urine	1/54 (1.9%)	1
Infections and infestations - Other, Viral Infection	1/54 (1.9%)	1
Mucosal infection	4/54 (7.4%)	4
Nail infection	1/54 (1.9%)	1
Pharyngitis	1/54 (1.9%)	1
Sinusitis	2/54 (3.7%)	2
Skin infection	1/54 (1.9%)	1
Tooth infection	1/54 (1.9%)	1
Upper respiratory infection	7/54 (13%)	10
Urinary tract infection	4/54 (7.4%)	6
Vaginal infection	1/54 (1.9%)	1
Injury, poisoning and procedural complications
Bruising	9/54 (16.7%)	10
Fall	1/54 (1.9%)	1
Injury, poisoning and procedural complications - Other, Urine PCR	1/54 (1.9%)	1
Investigations
Activated partial thromboplastin time prolonged	6/54 (11.1%)	14
Alanine aminotransferase increased	28/54 (51.9%)	61
Alkaline phosphatase increased	21/54 (38.9%)	27
Aspartate aminotransferase increased	24/54 (44.4%)	51
Blood bilirubin increased	3/54 (5.6%)	7
CPK increased	1/54 (1.9%)	1
Creatinine increased	5/54 (9.3%)	5
Investigations - Other, Hyperphosphatemia	1/54 (1.9%)	1
Investigations - Other, Lactate dehydrogenase increased	1/54 (1.9%)	1
Investigations - Other, Protein total decreased	3/54 (5.6%)	5
Lipase increased	10/54 (18.5%)	22
Lymphocyte count decreased	13/54 (24.1%)	46
Neutrophil count decreased	13/54 (24.1%)	66
Platelet count decreased	15/54 (27.8%)	22
Serum amylase increased	7/54 (13%)	57
Thyroid stimulating hormone increased	2/54 (3.7%)	2
Weight loss	16/54 (29.6%)	46
White blood cell decreased	19/54 (35.2%)	66
weight loss	1/54 (1.9%)	1
Metabolism and nutrition disorders
Anorexia	19/54 (35.2%)	30
Dehydration	6/54 (11.1%)	9
Hot flashes	5/54 (9.3%)	5
Hypercalcemia	1/54 (1.9%)	1
Hyperglycemia	6/54 (11.1%)	8
Hyperkalemia	5/54 (9.3%)	9
Hypermagnesemia	2/54 (3.7%)	4
Hypernatremia	2/54 (3.7%)	2
Hyperphosphatemia	1/54 (1.9%)	1
Hypoalbuminemia	17/54 (31.5%)	37
Hypocalcemia	4/54 (7.4%)	13
Hypoglycemia	3/54 (5.6%)	4
Hypokalemia	7/54 (13%)	10
Hypomagnesemia	6/54 (11.1%)	10
Hyponatremia	5/54 (9.3%)	16
Hypophosphatemia	14/54 (25.9%)	27
Metabolism and nutrition disorders - Other, Early Satiety	1/54 (1.9%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	3/54 (5.6%)	3
Arthritis	2/54 (3.7%)	2
Back pain	6/54 (11.1%)	7
Bone pain	2/54 (3.7%)	2
Chest wall pain	3/54 (5.6%)	3
Flank pain	3/54 (5.6%)	3
Muscle weakness lower limb	2/54 (3.7%)	2
Muscle weakness upper limb	1/54 (1.9%)	1
Musculoskeletal and connective tissue disorder - Other, intermittent muscle spasms	1/54 (1.9%)	1
Myalgia	10/54 (18.5%)	15
Neck pain	4/54 (7.4%)	9
Non-cardiac chest pain	3/54 (5.6%)	3
Pain in extremity	12/54 (22.2%)	15
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified	1/54 (1.9%)	1
Tumor pain	4/54 (7.4%)	9
Nervous system disorders
Brachial plexopathy	1/54 (1.9%)	1
Concentration impairment	1/54 (1.9%)	1
Dizziness	11/54 (20.4%)	16
Dysgeusia	17/54 (31.5%)	24
Dysphagia	6/54 (11.1%)	6
Headache	20/54 (37%)	42
Memory impairment	2/54 (3.7%)	2
Neuralgia	1/54 (1.9%)	1
Paresthesia	3/54 (5.6%)	3
Peripheral sensory neuropathy	2/54 (3.7%)	2
Presyncope	1/54 (1.9%)	1
Radiculitis	2/54 (3.7%)	2
Spasticity	4/54 (7.4%)	4
Syncope	1/54 (1.9%)	1
Psychiatric disorders
Anxiety	1/54 (1.9%)	1
Confusion	1/54 (1.9%)	1
Depression	2/54 (3.7%)	2
Insomnia	5/54 (9.3%)	5
Renal and urinary disorders
Bladder perforation	1/54 (1.9%)	1
Hematuria	7/54 (13%)	9
Hemoglobinuria	4/54 (7.4%)	5
Proteinuria	13/54 (24.1%)	27
Renal and urinary disorders - Other, Dysuria	1/54 (1.9%)	1
Renal and urinary disorders - Other, specify	1/54 (1.9%)	1
Renal and urinary disorders - Other, Protein Creatinine Ratio Increased	1/54 (1.9%)	2
Renal and urinary disorders - Other, Urine protein-Creatinine ratio increased	1/54 (1.9%)	1
Renal and urinary disorders - Other, elevated protein/creatinine ratio	1/54 (1.9%)	1
Renal and urinary disorders - Other, hesitancy	1/54 (1.9%)	1
Renal and urinary disorders - Other, proteinuria	1/54 (1.9%)	1
Urinary frequency	1/54 (1.9%)	1
Urinary retention	1/54 (1.9%)	1
Urinary tract pain	2/54 (3.7%)	2
Urinary urgency	1/54 (1.9%)	1
Urine discoloration	1/54 (1.9%)	1
Reproductive system and breast disorders
Irregular menstruation	4/54 (7.4%)	4
Vaginal hemorrhage	2/54 (3.7%)	2
Vaginal pain	1/54 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	3/54 (5.6%)	3
Cough	9/54 (16.7%)	14
Dyspnea	11/54 (20.4%)	15
Epistaxis	7/54 (13%)	10
Hiccups	1/54 (1.9%)	2
Hoarseness	9/54 (16.7%)	11
Nasal congestion	5/54 (9.3%)	6
Pleural effusion	1/54 (1.9%)	1
Pneumonitis	1/54 (1.9%)	1
Postnasal drip	3/54 (5.6%)	3
Respiratory, thoracic and mediastinal disorders - Other, URI with cold	1/54 (1.9%)	1
Respiratory, thoracic and mediastinal disorders - Other, bronchitis	1/54 (1.9%)	1
Rhinorrhea	1/54 (1.9%)	1
Sore throat	12/54 (22.2%)	13
Voice alteration	3/54 (5.6%)	3
Wheezing	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders
Alopecia	6/54 (11.1%)	9
Bullous dermatitis	1/54 (1.9%)	1
Dry skin	8/54 (14.8%)	10
Hair color changes	1/54 (1.9%)	1
Nail discoloration	1/54 (1.9%)	1
Nail ridging	2/54 (3.7%)	2
Pain of skin	2/54 (3.7%)	3
Palmar-plantar erythrodysesthesia syndrome	29/54 (53.7%)	53
Photosensitivity	1/54 (1.9%)	1
Pruritus	1/54 (1.9%)	1
Rash acneiform	4/54 (7.4%)	6
Rash maculo-papular	4/54 (7.4%)	4
Skin and subcutaneous tissue disorders - Other, B/L lower extremity lacerations;	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Cellulitis with fistula (supra-pubic area-LLQ)	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Cellulitis with fistula (supra-pubic area-LLQ);	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Chest Redness	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Erythema along port	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Graft dehiscence	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Hair hypopigmentation	7/54 (13%)	7
Skin and subcutaneous tissue disorders - Other, Hair thinning	2/54 (3.7%)	2
Skin and subcutaneous tissue disorders - Other, Lump on upper L chest wall	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Pruritus /Rash acneiform	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Seborrheic dermatitis	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, specify	2/54 (3.7%)	2
Skin and subcutaneous tissue disorders - Other, specify	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Skin and subcutaneous tissue disorders - Other: hair	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Skin discoloration (over R shoulder)	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, Skin lumps (face, ear, hairline)	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, fingernail splitting	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, hair lightening	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, hand purple/blue discoloration	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, intermittent petechiae bilateral breast	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, pin-size hole over port (no drainage)	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, sore on elbow	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, sunburn from swimming; chest, back, BUE	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other,	1/54 (1.9%)	1
Skin and subcutaneous tissue disorders - Other, specify	3/54 (5.6%)	3
Skin hyperpigmentation	2/54 (3.7%)	2
Skin hypopigmentation	10/54 (18.5%)	12
Skin ulceration	2/54 (3.7%)	2
Vascular disorders
Flushing	1/54 (1.9%)	1
Hypertension	43/54 (79.6%)	436
Hypotension	4/54 (7.4%)	8
Thromboembolic event	3/54 (5.6%)	3

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.