Trial of Dasatinib Plus Ixabepilone in 2nd or 3rd Line Metastatic Breast Cancer

• Sponsor: Accelerated Community Oncology Research Network (Other)
• Overall Status: Completed
• CT.gov ID: NCT00924352
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 56
• Locations: 13
• Arm: 1
• Duration (Months): 52
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective for the Phase I portion of the study is to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) and for the Phase II portion of the study is to evaluate progression free survival (PFS). Secondary objectives are response rate, clinical benefit rate, and overall toxicity.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Dasatinib; Drug: Ixabepilone	Phase 1/Phase 2

Detailed Description

In the Phase I portion of the study, patients will receive study treatment according to the assigned dose level. Ixabepilone will be administered over 1 hour on Days 1, 8, and 15 of a 28-day cycle. Dasatinib will be administered continuously starting on Day 1, Cycle 1 once daily (QD).

Three patients will be enrolled at dose level 0 and observed for dose-limiting toxicity (DLT) for 1 course of treatment.

Dose escalation or reduction will depend on the number of patients experiencing DLT as follows:

• If 0 of 3 patients experiences a DLT, then 3 additional patients will be enrolled at the next higher dose level.

• If 1 of 3 patients experiences a DLT, then 3 additional patients will be enrolled at that dose level.

• If 2 of 3 or 3 of 3 patients experience a DLT, then 3 patients will be enrolled at the next lower dose unless 6 patients have already been treated at that dose.

• If ≥2 of 6 patients experience a DLT at that dose level, then the MTD is considered to have been exceeded. At that point, 3 patients are treated at the next lower dose.

• If no more than 1 of the 6 patients experiences a DLT, then the dose level will be escalated 1 level.

Maximum-tolerated dose (MTD) is defined as the dose at which ≤1 of 6 patients experience DLT, and above which ≥2 of 6 patients experience DLT.

In the Phase II portion of the study, dasatinib and ixabepilone will be administered at the MTD determined during Phase I. Dasatinib will be started on Day 1, Cycle 1 and will be administered continuously once daily. Ixabepilone will be administered over 1 hour on Days 1, 8, and 15 of a 28-day cycle. Patients will be treated with both agents for up to 8 cycles, after which stable or responding patients are eligible for monotherapy with dasatinib at the investigator's discretion in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of Dasatinib Plus Ixabepilone in 2nd or 3rd Line Metastatic Breast Cancer
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Ixabepilone + Dasatinib Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD.

Drug: Dasatinib; Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD.; Other Names: SPRYCEL ; Drug: Ixabepilone; Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.; Other Names: IXEMPRA

Outcome Measures

Primary Outcome Measures

1. Determination of the Maximum Tolerated Dose (MTD) of Dasatinib When Given in Combination With Ixabepilone (Phase I) [MTD was assessed during the first cycle of combination therapy (days 1-28).]

   The MTD of dasatinib (taken daily, continuously) when given in combination with ixabepilone (administered on Days 1, 8, and 15 of a 28-day cycle) was determined using a standard 3 + 3 dose escalation cohort design. The total sample and the number of patients who receive each dose in this design depends on the frequency of dose limiting toxicities (DLT) at each dosage. The MTD was defined as the dose at which ≤ 1 of 6 patients experienced DLT, and above which ≥ 2 of 6 patients experienced DLT.

2. Determination of the Maximum Tolerated Dose (MTD) of Ixabepilone When Given in Combination With Dasatinib (Phase I) [MTD was assessed during the first cycle of combination therapy (days 1-28).]

   The MTD of ixabepilone (administered on Days 1, 8, and 15 of a 28-day cycle) when given in combination with dasatinib (taken daily, continuously) was determined using a standard 3 + 3 dose escalation cohort design. The total sample and the number of patients who receive each dose in this design depends on the frequency of dose limiting toxicities (DLT) at each dosage. The MTD was defined as the dose at which ≤ 1 of 6 patients experienced DLT, and above which ≥ 2 of 6 patients experienced DLT.

3. Determination of the Dose Limiting Toxicities (DLTs) of the Combination of Dasatinib and Ixabepilone (Phase I) [DLTs were assessed during the first cycle of combination therapy (days 1-28).]

   DLTs were assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Dose limiting toxicity was defined as any grade 4 hematologic event or any grade 3 or 4 non-hematologic event occurring during cycle 1 that is attributable to dasatinib, ixabepilone, or the combination. The following events were excluded from this definition: grade 4 neutropenia lasting for 3 days or less; grade 3 nausea responsive to antiemetics; grade 3 infection with normal ANC or grade 1 or 2 neutrophils; grade 3 diarrhea responsive to optimal use of antidiarrheal therapy.

4. Evaluation of Progression-free Survival (PFS) of the Combination of Dasatinib and Ixabepilone (Phase II) [PFS was measured from day 1 of treatment until time of progression (assessed about every 8 weeks) or death, whichever came first, for up to 27.2 months.]

   Disease progression was determined through radiology imaging measurements and by clinical or symptomatic progression during or after treatment. Progression is defined per RECIST v1.0 guidelines as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions.

Secondary Outcome Measures

1. Best Overall Response of the Combination of Dasatinib and Ixabepilone (Phase II) [Response to treatment was assessed after about every 8 weeks of treatment, for up to 27.2 months.]

   Best overall response is defined as the best response across all time points. Response was evaluated via changes from baseline in radiological tumor measurements performed after every two treatment cycles and at the end of treatment or time of progression. Response was evaluated using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is >=30% decrease in the sum of the longest diameter (LD) of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of >=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions.

2. Clinical Benefit Rate of the Combination of Dasatinib and Ixabepilone (Phase II) [Response to treatment was assessed after about every 8 weeks of treatment, for up to 27.2 months.]

   Clinical benefit rate was defined as the percentage of participants experiencing stable disease (SD) of at least 24 weeks (from the start of treatment) plus complete response (CR) and partial response (PR). Response was evaluated via changes from baseline in radiological tumor measurements performed after every two treatment cycles and at the end of treatment or time of progression. Response was evaluated using RECIST version 1.0 guidelines, where CR is the disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter(LD) of target lesions; SD is neither sufficient shrinkage in sum of longest diameter of target lesions to be PR nor increase of >=20%.

3. Incidence of Grade 3 Adverse Events (AEs) With the Combination of Dasatinib and Ixabepilone (Phase II) [Adverse events were collected beginning on day 1 of treatment until one month after the end of study treatment.]

   All treatment emergent adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0

4. Incidence of Grade 4 Adverse Events (AEs) With the Combination of Dasatinib and Ixabepilone (Phase II) [Adverse events were collected beginning on day 1 of treatment until one month after the end of study treatment.]

   All treatment emergent adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0

Eligibility Criteria

Criteria

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

Inclusion Criteria:

A patient must meet each of the following criteria to be considered eligible for inclusion in this study:

1. Patient has the ability to understand and the willingness to sign a written informed consent including form according to institutional guidelines.

2. Patient has histologically-proven breast cancer.

3. Patient has locally recurrent or metastatic disease, measurable or non- measurable by RECIST criteria.

4. Patient has HER2-negative disease or disease that is refractory to HER2- directed therapy.

5. Patient is female or male ≥ 18 years of age.

6. Patient has(ECOG)performance status of ≤ 2.

7. Patient must have received at least 1 but no more than 2 prior chemotherapy regimens for locally recurrent or metastatic disease. Patients may have received neoadjuvant and/or adjuvant chemotherapy. These prior regimens can not have included ixabepilone or dasatinib. A line of chemotherapy will be defined as one or more agents used continuously or discontinuously (i.e., allowing a break or chemo holiday) without the addition of a new agent. Hormonal therapy will not be considered a line of therapy.

8. Prior chemotherapy must have been completed at least 3 weeks prior to study treatment start (6 weeks for nitrosoureas and mitomycin), and the patient must have recovered from all associated toxicities (except for alopecia and neuropathy grade 1 according to CTCAE, v3.0 classification).

9. Radiation therapy, immunotherapy, biologic therapy, and hormonal/endocrine therapy must have been completed at least 2 weeks prior to study treatment start. Any major surgery must have been completed at least 4 weeks prior to study treatment start.

10. Patient has adequate organ, metabolic and bone marrow function as follows:

11. Total bilirubin ≤ 1.0 × institutional ULN

12. AST, ALT ≤ 2.5 × institutional ULN

13. Serum sodium, potassium, calcium, magnesium, and phosphate ≥ institutional LLN. (Hypokalemia or hypomagnesemia must be corrected prior to dasatinib administration.)

14. Serum creatinine < 1.5 × institutional ULN

15. Hematologic function: - ANC ≥ 1500/mm3. -Platelet count ≥ 100,000/mm3. - Hemoglobin ≥ 10.0 g/dL

16. PT and PTT < 1.5 x institutional ULN

17. Ability to take oral medication (dasatinib must be swallowed whole).

18. Concomitant medications:

19. Patient agrees to discontinue St John's Wort at least 5 days prior to starting dasatinib therapy and while receiving dasatinib therapy.

20. Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia.

21. The use of CYP3A4 inducers, inhibitors, and substrates; medications that prolong QT interval; antacids; H2 blockers and proton pump inhibitors; and medications that inhibit platelet function and anticoagulation should be avoided during dasatinib therapy. These are restricted therapies that are permitted with caution when medically indicated.

22. Women of childbearing potential must have a negative serum or urine pregnancy test prior to the start of study treatment.

23. Patients of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 4 weeks after study treatment is stopped.

Exclusion Criteria:

A patient who meets any of the following criteria will be considered not eligible for inclusion in this study:

1. Patient has had prior treatment with ixabepilone, dasatinib, or both.

2. Patient has had more than 2 prior lines of chemotherapy for locally recurrent or metastatic breast cancer. A line of chemotherapy will be defined as one or more agents used continuously or discontinuously (i.e., allowing a break or chemo holiday) without the addition of a new agent. Hormonal therapy will not be considered a line of therapy.

3. Patient has received a cumulative dose of > 360 mg/m2 of doxorubicin or > 600 mg/m2 of epirubicin.

4. Prior radiation must not have included ≥ 30% of major bone marrow containing areas (pelvis, lumbar spine).

5. Patients with CTC grade 2 or greater neuropathy (motor or sensory) at study entry.

6. Patient has evidence CNS or brain metastases, unless CNS or brain metastases have been treated and stable for > 3 months.

7. Patient has psychiatric illness or social situation that would limit or prohibit compliance with study requirements.

8. Patient has an inability to take oral medication or inability to absorb oral medication.

9. Patient has had any invasive cancer other than the one being treated in this study within 3 years with the exception of surgically cured nonmelanoma skin cancer; in situ carcinoma of the cervix; in situ carcinoma of the breast.

10. Patient is receiving concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, or hormonal therapy for cancer).

11. Patient has other serious medical conditions as judged by the Principal Investigator.

12. Patient has a concurrent medical condition which may increase the risk of toxicity.

13. Patient has a pleural or pericardial effusion of any grade.

14. Patient has cardiac symptoms including any of the following:

15. Uncontrolled angina, congestive heart failure or myocardial infarction within 6 months of study entry.

16. Diagnosed congenital long QT syndrome.

17. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).

18. Prolonged QTc on pre-entry ECG (> 450 msec).

19. Hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration.

20. Patient has a history of significant bleeding disorder unrelated to cancer, including:

21. Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease).

22. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).

23. Ongoing or recent (≤ 3 months) significant GI bleeding.

24. Patient is taking any of the following concomitant medications at study entry:

1. Category I drugs that are generally accepted to have a risk of causing Torsades de pointes including (Patients must discontinue drug 7 days prior to starting dasatinib.):

• quinidine, procainamide, disopyramide.

• amiodarone, sotalol, ibutilide, dofetilide.

• erythromycin, clarithromycin.

• chlorpromazine,haloperidol,mesoridazine, thioridazine,pimozide .

• cisapride,bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,halofantrine, levomethadyl, pentamidine,sparfloxacin, lidoflazine.

1. Patient has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ixabepilone or dasatinib. Ixabepilone is contraindicated in patients who have a known, prior, severe (CTC grade 3 or 4) history of hypersensitivity reaction to a drug formulated in Cremophor® EL (polyoxyethylated castor oil).

2. Patient has received any investigational agent or therapy within 30 days prior to study treatment start.

3. Patient is unwilling or unable to comply with study requirements.

4. Women who:

5. are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after cessation of study treatment, or

6. have a positive pregnancy test at baseline, or

7. are pregnant or breastfeeding.

8. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hematology Oncology PC	Stamford	Connecticut	United States	06902
2	Central Georgia Cancer Care	Macon	Georgia	United States	31201
3	Northwest Georgia Oncology Centers	Marietta	Georgia	United States	30060
4	North Shore Cancer Research	Skokie	Illinois	United States	60076
5	Hematology Oncology Associates of the Quad Cities	Bettendorf	Iowa	United States	52722
6	Baystate Medical Center	Springfield	Massachusetts	United States	01107
7	Hematology Oncology Centers of the Northern Rockies	Billings	Montana	United States	59101
8	Oncology Hematology Specialists, P.A.	Denville	New Jersey	United States	07834
9	The Moses H. Cone Regional Cancer Center	Greensboro	North Carolina	United States	27403
10	North Coast Cancer Care	Sandusky	Ohio	United States	44870
11	Pennsylvania Oncology Hematology Associates	Philadelphia	Pennsylvania	United States	19106
12	University of Tennessee Cancer Institute	Memphis	Tennessee	United States	38104
13	The West Clinic	Memphis	Tennessee	United States	38120

Sponsors and Collaborators

• Accelerated Community Oncology Research Network
• Bristol-Myers Squibb

Investigators

• Study Chair: Lee S. Schwartzberg, MD, FACP, The West Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Accelerated Community Oncology Research Network
• ClinicalTrials.gov Identifier: NCT00924352
• Other Study ID Numbers: ALSSMBC0804
• First Posted: Jun 18, 2009
• Last Update Posted: Oct 13, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Accelerated Community Oncology Research Network: Metastatic Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Dasatinib

Study Results

Participant Flow

Recruitment Details	The Phase I portion of this study was conducted at 4 oncology clinics located in the United States. The Phase II portion of the study was conducted at the 4 Phase I sites, plus 10 additional oncology clinics located in the United States. Enrollment started in July 2009 and was completed in June 2012.
Pre-assignment Detail	Informed consent was obtained from all subjects. All subjects underwent screening procedures to verify eligibility.

Arm/Group Title	Phase I	Phase II
Arm/Group Description	The Phase I sample includes patients who were enrolled into the Phase I portion of this study. Patients received treatment according to the assigned dose level. Ixabepilone was administered over 1 hour on Days 1, 8, and 15 of a 28-day cycle. Dasatinib was administered continuously starting on Day 1, Cycle 1 once daily. Patients were treated with both agents for up to 8 cycles, after which stable or responding patients were eligible for dasatinib monotherapy at the investigator's discretion in the absence of disease progression or unacceptable toxicity.	The Phase II sample includes patients who were enrolled into the Phase II portion of this study. Dasatinib and ixabepilone were administered at the maximum tolerated dose determined during the Phase I portion: dasatinib 100 mg daily and ixabepilone 20 mg/m2. Ixabepilone was administered over 1 hour on Days 1, 8, and 15 of a 28-day cycle. Dasatinib was administered continuously starting on Day 1, Cycle 1 once daily. Patients were treated with both agents for up to 8 cycles, after which stable or responding patients were eligible for dasatinib monotherapy at the investigator's discretion in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	12	44
COMPLETED	12	44
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ixabepilone + Dasatinib
Arm/Group Description	Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Dasatinib: Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Ixabepilone: Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.
Overall Participants	56
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.7 (9.29)
Sex: Female, Male (Count of Participants)
Female	56 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.8%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	22 39.3%
White	33 58.9%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	56 100%

Outcome Measures

1. Primary Outcome

Title	Determination of the Maximum Tolerated Dose (MTD) of Dasatinib When Given in Combination With Ixabepilone (Phase I)
Description	The MTD of dasatinib (taken daily, continuously) when given in combination with ixabepilone (administered on Days 1, 8, and 15 of a 28-day cycle) was determined using a standard 3 + 3 dose escalation cohort design. The total sample and the number of patients who receive each dose in this design depends on the frequency of dose limiting toxicities (DLT) at each dosage. The MTD was defined as the dose at which ≤ 1 of 6 patients experienced DLT, and above which ≥ 2 of 6 patients experienced DLT.
Time Frame	MTD was assessed during the first cycle of combination therapy (days 1-28).

Outcome Measure Data

Analysis Population Description

The Phase I analysis sample includes the 12 patients who were enrolled into the Phase I portion of the study.

Arm/Group Title	Ixabepilone + Dasatinib
Arm/Group Description	Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Dasatinib: Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Ixabepilone: Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.
Measure Participants	12
Number [mg daily]	100

2. Primary Outcome

Title	Determination of the Maximum Tolerated Dose (MTD) of Ixabepilone When Given in Combination With Dasatinib (Phase I)
Description	The MTD of ixabepilone (administered on Days 1, 8, and 15 of a 28-day cycle) when given in combination with dasatinib (taken daily, continuously) was determined using a standard 3 + 3 dose escalation cohort design. The total sample and the number of patients who receive each dose in this design depends on the frequency of dose limiting toxicities (DLT) at each dosage. The MTD was defined as the dose at which ≤ 1 of 6 patients experienced DLT, and above which ≥ 2 of 6 patients experienced DLT.
Time Frame	MTD was assessed during the first cycle of combination therapy (days 1-28).

Outcome Measure Data

Analysis Population Description

The Phase I analysis sample includes the 12 patients who were enrolled into the Phase I portion of the study.

Arm/Group Title	Ixabepilone + Dasatinib
Arm/Group Description	Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Dasatinib: Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Ixabepilone: Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.
Measure Participants	12
Number [mg/m2]	20

3. Primary Outcome

Title	Determination of the Dose Limiting Toxicities (DLTs) of the Combination of Dasatinib and Ixabepilone (Phase I)
Description	DLTs were assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Dose limiting toxicity was defined as any grade 4 hematologic event or any grade 3 or 4 non-hematologic event occurring during cycle 1 that is attributable to dasatinib, ixabepilone, or the combination. The following events were excluded from this definition: grade 4 neutropenia lasting for 3 days or less; grade 3 nausea responsive to antiemetics; grade 3 infection with normal ANC or grade 1 or 2 neutrophils; grade 3 diarrhea responsive to optimal use of antidiarrheal therapy.
Time Frame	DLTs were assessed during the first cycle of combination therapy (days 1-28).

Outcome Measure Data

Analysis Population Description

The Phase I analysis sample includes the 12 patients who were enrolled into the Phase I portion of the study.

Arm/Group Title	Ixabepilone + Dasatinib (Dose Level 0)	Ixabepilone + Dasatinib (Dose Level 1)	Ixabepilone + Dasatinib (Dose Level 2)
Arm/Group Description	Dasatinib 100 mg daily and Ixabepilone 16 mg/m2 on Days 1, 8, and 15 of a 28-day cycle.	Dasatinib 100 mg daily and Ixabepilone 20 mg/m2 on Days 1, 8, and 15 of a 28-day cycle.	Dasatinib 140 mg daily and Ixabepilone 20 mg/m2 on Days 1, 8, and 15 of a 28-day cycle.
Measure Participants	3	6	3
DLT: Grade 4 Thrombocytopenia	0 0%	0 NaN	1 NaN
DLT: Grade 4 Leukopenia	0 0%	0 NaN	1 NaN

4. Secondary Outcome

Title	Best Overall Response of the Combination of Dasatinib and Ixabepilone (Phase II)
Description	Best overall response is defined as the best response across all time points. Response was evaluated via changes from baseline in radiological tumor measurements performed after every two treatment cycles and at the end of treatment or time of progression. Response was evaluated using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is >=30% decrease in the sum of the longest diameter (LD) of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of >=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions.
Time Frame	Response to treatment was assessed after about every 8 weeks of treatment, for up to 27.2 months.

Outcome Measure Data

Analysis Population Description

The Phase II analysis sample of 50 patients includes the 6 patients from the Phase I portion of the study who were treated at the MTD as well as the 44 patients who were enrolled into the Phase II portion of the study.

Arm/Group Title	Ixabepilone + Dasatinib
Arm/Group Description	Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Dasatinib: Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Ixabepilone: Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.
Measure Participants	50
Complete Response	0 0%
Partial Response	4 7.1%
Stable Disease	11 19.6%
Progressive Disease	23 41.1%
Not Evaluable	12 21.4%

5. Secondary Outcome

Title	Clinical Benefit Rate of the Combination of Dasatinib and Ixabepilone (Phase II)
Description	Clinical benefit rate was defined as the percentage of participants experiencing stable disease (SD) of at least 24 weeks (from the start of treatment) plus complete response (CR) and partial response (PR). Response was evaluated via changes from baseline in radiological tumor measurements performed after every two treatment cycles and at the end of treatment or time of progression. Response was evaluated using RECIST version 1.0 guidelines, where CR is the disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter(LD) of target lesions; SD is neither sufficient shrinkage in sum of longest diameter of target lesions to be PR nor increase of >=20%.
Time Frame	Response to treatment was assessed after about every 8 weeks of treatment, for up to 27.2 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixabepilone + Dasatinib
Arm/Group Description	Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Dasatinib: Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Ixabepilone: Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.
Measure Participants	50
Number [percentage of participants]	26.0 46.4%

6. Secondary Outcome

Title	Incidence of Grade 3 Adverse Events (AEs) With the Combination of Dasatinib and Ixabepilone (Phase II)
Description	All treatment emergent adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
Time Frame	Adverse events were collected beginning on day 1 of treatment until one month after the end of study treatment.

Outcome Measure Data

Analysis Population Description

The Phase II analysis sample of 50 patients includes the 6 patients from the Phase I portion of the study who were treated at the MTD as well as the 44 patients who were enrolled into the Phase II portion of the study.

Arm/Group Title	Ixabepilone + Dasatinib
Arm/Group Description	Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Dasatinib: Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Ixabepilone: Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.
Measure Participants	50
Number [participants]	31 55.4%

7. Secondary Outcome

Title	Incidence of Grade 4 Adverse Events (AEs) With the Combination of Dasatinib and Ixabepilone (Phase II)
Description	All treatment emergent adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
Time Frame	Adverse events were collected beginning on day 1 of treatment until one month after the end of study treatment.

Outcome Measure Data

Analysis Population Description

The Phase II analysis sample of 50 patients includes the 6 patients from the Phase I portion of the study who were treated at the MTD as well as the 44 patients who were enrolled into the Phase II portion of the study.

Arm/Group Title	Ixabepilone + Dasatinib
Arm/Group Description	Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Dasatinib: Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Ixabepilone: Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.
Measure Participants	50
Number [participants]	5 8.9%

8. Primary Outcome

Title	Evaluation of Progression-free Survival (PFS) of the Combination of Dasatinib and Ixabepilone (Phase II)
Description	Disease progression was determined through radiology imaging measurements and by clinical or symptomatic progression during or after treatment. Progression is defined per RECIST v1.0 guidelines as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time Frame	PFS was measured from day 1 of treatment until time of progression (assessed about every 8 weeks) or death, whichever came first, for up to 27.2 months.

Outcome Measure Data

Analysis Population Description

The Phase II analysis sample of 50 patients includes the 6 patients from the Phase I portion of the study who were treated at the MTD as well as the 44 patients who were enrolled into the Phase II portion of the study.

Arm/Group Title	Ixabepilone + Dasatinib
Arm/Group Description	Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Dasatinib: Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Ixabepilone: Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.
Measure Participants	50
Median (95% Confidence Interval) [months]	6.01

Adverse Events

Time Frame	Adverse events were collected on day 1 of treatment until one month after the end of study treatment.
Arm/Group Title	Ixabepilone + Dasatinib
Arm/Group Description	Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2. Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Dasatinib: Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level - 1;100 mg QD,Dose Level - 2;70 mg QD. Ixabepilone: Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level - 1;12 mg/m2,Dose Level - 2;12 mg/m2.
All Cause Mortality
	Ixabepilone + Dasatinib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ixabepilone + Dasatinib
	Affected / at Risk (%)	# Events
Total	11/56 (19.6%)
Blood and lymphatic system disorders
Febrile Neutropenia	3/56 (5.4%)
Neutropenia	1/56 (1.8%)
Pancytopenia	1/56 (1.8%)
Cardiac disorders
Atrial Fibrillation	1/56 (1.8%)
Coronary Artery Disease	1/56 (1.8%)
Gastrointestinal disorders
Constipation	1/56 (1.8%)
General disorders
Chest Pain	1/56 (1.8%)
Non-Cardiac Chest Pain	1/56 (1.8%)
Edema due to Cardiac Disease	1/56 (1.8%)
Infections and infestations
Cellulitis	1/56 (1.8%)
Pneumonia	1/56 (1.8%)
Skin Infection	1/56 (1.8%)
Urinary Tract Infection	1/56 (1.8%)
Investigations
Electrocardiogram QT Prolonged	1/56 (1.8%)
QT Prolonged	1/56 (1.8%)
Renal and urinary disorders
Renal Failure Acute	1/56 (1.8%)
Respiratory, thoracic and mediastinal disorders
Pleural Effusion	1/56 (1.8%)
Respiratory Failure	1/56 (1.8%)
Other (Not Including Serious) Adverse Events
	Ixabepilone + Dasatinib
	Affected / at Risk (%)	# Events
Total	56/56 (100%)
Blood and lymphatic system disorders
Anemia	29/56 (51.8%)
Leukopenia	5/56 (8.9%)
Neutropenia	20/56 (35.7%)
Thrombocytopenia	8/56 (14.3%)
White Blood Cell Disorder	1/56 (1.8%)
Cardiac disorders
Palpitations	3/56 (5.4%)
Sinus Tachycardia	1/56 (1.8%)
Ear and labyrinth disorders
Ear Pain	1/56 (1.8%)
Eye disorders
Eye Irritation	1/56 (1.8%)
Eyelid Edema	1/56 (1.8%)
Vision Blurred	2/56 (3.6%)
Gastrointestinal disorders
Abdominal Distension	1/56 (1.8%)
Abdominal Pain	7/56 (12.5%)
Abdominal Pain Lower	1/56 (1.8%)
Abdominal Pain Upper	1/56 (1.8%)
Constipation	10/56 (17.9%)
Diarrhea	31/56 (55.4%)
Dry Mouth	1/56 (1.8%)
Dyspepsia	4/56 (7.1%)
Dysphagia	2/56 (3.6%)
Gastritis	1/56 (1.8%)
Hematochezia	1/56 (1.8%)
Hemorrhoids	1/56 (1.8%)
Nausea	30/56 (53.6%)
Salivary Hypersecretion	1/56 (1.8%)
Stomatitis	5/56 (8.9%)
Vomiting	22/56 (39.3%)
General disorders
Asthenia	3/56 (5.4%)
Chest Pain	2/56 (3.6%)
Chills	3/56 (5.4%)
Fatigue	34/56 (60.7%)
Generalized Edema	1/56 (1.8%)
Influenza-like Illness	1/56 (1.8%)
Infusion-related Reaction	1/56 (1.8%)
Injection Site Pain	1/56 (1.8%)
Localized Edema	1/56 (1.8%)
Malaise	1/56 (1.8%)
Mucosal Inflammation	1/56 (1.8%)
Mucosal Ulceration	1/56 (1.8%)
Myalgia	1/56 (1.8%)
Nodule	1/56 (1.8%)
Edema	1/56 (1.8%)
Edema Peripheral	4/56 (7.1%)
Pain	2/56 (3.6%)
Pyrexia	8/56 (14.3%)
Hepatobiliary disorders
Hyperbilirubinemia	1/56 (1.8%)
Immune system disorders
Cytokine Release Syndrome	2/56 (3.6%)
Hypersensitivity	3/56 (5.4%)
Infections and infestations
Breast Infection	1/56 (1.8%)
Candidiasis	1/56 (1.8%)
Cellulitis	2/56 (3.6%)
Eye Infection	1/56 (1.8%)
Gastroenteritis	1/56 (1.8%)
Herpes Zoster	1/56 (1.8%)
Nail infection	1/56 (1.8%)
Oral Candidiasis	4/56 (7.1%)
Pneumonia	1/56 (1.8%)
Pyelonephritis	1/56 (1.8%)
Rhinitis	1/56 (1.8%)
Sinusitis	2/56 (3.6%)
Tooth Abscess	1/56 (1.8%)
Upper Respiratory Tract Infection	3/56 (5.4%)
Urinary Tract Infection	5/56 (8.9%)
Vulvovaginal Mycotic Infection	1/56 (1.8%)
Injury, poisoning and procedural complications
Arthropod Bite	1/56 (1.8%)
Contusion	1/56 (1.8%)
Infusion-related Reaction	4/56 (7.1%)
Muscle Strain	1/56 (1.8%)
Procedural Pain	1/56 (1.8%)
Wound Complication	1/56 (1.8%)
Investigations
Alanine Aminotransferase Increased	1/56 (1.8%)
Aspartate Aminotransferase Increased	5/56 (8.9%)
Blood Alkaline Phosphatase Increased	2/56 (3.6%)
Blood Creatinine Increased	1/56 (1.8%)
Blood Lactate Dehydrogenase Increased	1/56 (1.8%)
Electrocardiogram QT Prolonged	2/56 (3.6%)
Hemoglobin Decreased	6/56 (10.7%)
Neutrophil Count	1/56 (1.8%)
Neutrophil Count Decreased	3/56 (5.4%)
Platelet Count Decreased	1/56 (1.8%)
QT Prolonged	2/56 (3.6%)
Weight Decreased	4/56 (7.1%)
White Blood Cell Count	1/56 (1.8%)
White Blood Cell Count Decreased	3/56 (5.4%)
Metabolism and nutrition disorders
Decreased Appetite	17/56 (30.4%)
Dehydration	6/56 (10.7%)
Hypercalcemia	2/56 (3.6%)
Hypocalcemia	6/56 (10.7%)
Hypokalemia	13/56 (23.2%)
Hypomagnesemia	5/56 (8.9%)
Hyponatremia	2/56 (3.6%)
Hypophosphatemia	5/56 (8.9%)
Vitamin D Deficiency	1/56 (1.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/56 (7.1%)
Back Pain	5/56 (8.9%)
Bone Pain	3/56 (5.4%)
Muscle Spasms	5/56 (8.9%)
Muscular Weakness	3/56 (5.4%)
Musculoskeletal Chest Pain	3/56 (5.4%)
Musculoskeletal Pain	2/56 (3.6%)
Myalgia	8/56 (14.3%)
Pain in Extremity	5/56 (8.9%)
Pain in Jaw	1/56 (1.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ocular Neoplasm	1/56 (1.8%)
Nervous system disorders
Amnesia	1/56 (1.8%)
Dizziness	4/56 (7.1%)
Dysgeusia	18/56 (32.1%)
Headache	17/56 (30.4%)
Hypoesthesia	4/56 (7.1%)
Migraine	1/56 (1.8%)
Neuralgia	1/56 (1.8%)
Neuropathy Peripheral	20/56 (35.7%)
Paresthesia	1/56 (1.8%)
Peripheral Sensory Neuropathy	2/56 (3.6%)
Photophobia	1/56 (1.8%)
Somnolence	2/56 (3.6%)
Syncope	2/56 (3.6%)
Psychiatric disorders
Anxiety	7/56 (12.5%)
Confusional State	1/56 (1.8%)
Depression	3/56 (5.4%)
Insomnia	7/56 (12.5%)
Mood Altered	1/56 (1.8%)
Restlessness	2/56 (3.6%)
Renal and urinary disorders
Dysuria	1/56 (1.8%)
Hematuria	1/56 (1.8%)
Micturition Urgency	1/56 (1.8%)
Pollakiuria	2/56 (3.6%)
Reproductive system and breast disorders
Breast Pain	1/56 (1.8%)
Nipple Pain	1/56 (1.8%)
Vaginal Hemorrhage	1/56 (1.8%)
Vulvovaginal Pruritus	1/56 (1.8%)
Respiratory, thoracic and mediastinal disorders
Cough	18/56 (32.1%)
Dysphonia	3/56 (5.4%)
Dyspnea	9/56 (16.1%)
Dyspnea Exertional	3/56 (5.4%)
Epistaxis	4/56 (7.1%)
Hemoptysis	1/56 (1.8%)
Oropharyngeal Pain	3/56 (5.4%)
Paranasal Sinus Hypersecretion	2/56 (3.6%)
Pleural Effusion	3/56 (5.4%)
Productive Cough	2/56 (3.6%)
Pulmonary Embolism	1/56 (1.8%)
Rhinitis Allergic	1/56 (1.8%)
Sinus Congestion	4/56 (7.1%)
Skin and subcutaneous tissue disorders
Alopecia	12/56 (21.4%)
Dermatitis Acneiform	1/56 (1.8%)
Dry Skin	1/56 (1.8%)
Exfoliative Rash	1/56 (1.8%)
Hair Disorder	1/56 (1.8%)
Hair Growth Abnormal	1/56 (1.8%)
Nail Disorder	2/56 (3.6%)
Night Sweats	1/56 (1.8%)
Pruritus	3/56 (5.4%)
Rash	12/56 (21.4%)
Rash Generalized	1/56 (1.8%)
Rash Maculo-Papular	1/56 (1.8%)
Rash Papular	1/56 (1.8%)
Skin Burning Sensation	2/56 (3.6%)
Skin Disorder	1/56 (1.8%)
Skin Hypopigmentation	2/56 (3.6%)
Skin Lesion	2/56 (3.6%)
Swelling Face	1/56 (1.8%)
Vascular disorders
Deep Vein Thrombosis	1/56 (1.8%)
Epistaxis	1/56 (1.8%)
Hypertension	3/56 (5.4%)
Hypotension	1/56 (1.8%)
Lymphedema	2/56 (3.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The funder will be provided with a copy of the proposed publication at least 30 days prior to its submission or presentation. The funder may request the presentation/submission be delayed for an additional 90 days to allow the funder to seek patent protection. The funder can require the deletion of information deemed as confidential.