Trial Outcomes & Findings for Randomized Phase II Trial of Letrozole With or Without Dasatinib as First and Second-line Treatment for Hormone Receptor-positive, HER2-negative Post-menopausal Breast Cancer That is Unresectable, Locally Recurrent or Metastatic (NCT NCT00696072)

Last Updated: 2016-06-13

Results Overview

CBR=participants with complete response (CR) + participants with partial response (PR) + participants with stable disease (SD) for a length of time greater than, equal to 6 months. CR= Disappearance of all target lesions. No new lesions. PR= At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. SD= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) taking as reference the smallest sum LD since the treatment started. Physical examination,radiological assessment, and bone scans (if applicable) were used to assess outcome.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

120 participants

Primary outcome timeframe

First dose of study drug to last dose plus 7 days, up to study completion (approximately 6 years)

Results posted on

2016-06-13

Participant Flow

Study started October 2008 and completed June 2014; 23 participants chose to remain on active treatment after the study completed.

120 participants were enrolled, randomized and treated.

Participant milestones

Participant milestones
Measure	Dasatinib Plus Letrozole Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg Tablets, once daily up to 2 years. If a participant experienced intolerable toxicity related to dasatinib, they had the option to crossover to letrozole arm.	Letrozole Participants received letrozole 2.5 mg tablets, once daily, up to 2 years. If the participant developed progressive disease while on the single agent, the participant had the option to add dasatinib to their treatment regimen.
Overall Study STARTED	57	63
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	57	63

Reasons for withdrawal

Reasons for withdrawal
Measure	Dasatinib Plus Letrozole Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg Tablets, once daily up to 2 years. If a participant experienced intolerable toxicity related to dasatinib, they had the option to crossover to letrozole arm.	Letrozole Participants received letrozole 2.5 mg tablets, once daily, up to 2 years. If the participant developed progressive disease while on the single agent, the participant had the option to add dasatinib to their treatment regimen.
Overall Study continuing active treatment	10	13
Overall Study Adverse Event	10	6
Overall Study Patient Request	3	7
Overall Study Investigator Request	1	4
Overall Study Sponsor Request	0	1
Overall Study Disease Progression	32	30
Overall Study Non-specified	1	2

Baseline Characteristics

Randomized Phase II Trial of Letrozole With or Without Dasatinib as First and Second-line Treatment for Hormone Receptor-positive, HER2-negative Post-menopausal Breast Cancer That is Unresectable, Locally Recurrent or Metastatic

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dasatinib Plus Letrozole n=57 Participants Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg	Letrozole n=63 Participants Letrozole: Tablets, Oral, 2.5 mg, once daily, up to 2 years	Total n=120 Participants Total of all reporting groups
Age, Customized Less than 65 years	33 participants n=5 Participants	34 participants n=7 Participants	67 participants n=5 Participants
Age, Customized Greater than or equal to 65 years	24 participants n=5 Participants	29 participants n=7 Participants	53 participants n=5 Participants
Sex: Female, Male Female	57 Participants n=5 Participants	63 Participants n=7 Participants	120 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	57 participants n=5 Participants	63 participants n=7 Participants	120 participants n=5 Participants

PRIMARY outcome

Timeframe: First dose of study drug to last dose plus 7 days, up to study completion (approximately 6 years)

Population: Evaluable Population was defined as all treated participants who met the protocol-specified efficacy analyses requirements and who received at least 1 dose of randomized study drug. Participants presented in the treatment arm to which they were originally randomized.

Outcome measures

Outcome measures
Measure	Dasatinib Plus Letrozole n=56 Participants Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg Patients on letrozole plus dasatinib received both drugs until progressive disease (PD) or intolerable toxicity. If the intolerable toxicity was determined to be related to dasatinib, dasatinib was discontinued and the patient continued on single-agent letrozole. Although drugs were taken daily, cycle length was 28-days	Letrozole n=61 Participants Letrozole: Tablets, Oral, 2.5 mg, once daily, up to 2 years Patients on letrozole who developed progressive disease continued letrozole, and dasatinib was added to their treatment regimen. Although drugs were taken daily, cycle length was 28-days
Number of Participants With Clinical Benefit (CBR) and Number of Participants With CBR Having a Disease Free Interval (DFI) Greater Than 2 Years - Evaluable Population CBR (CR+PR+SD)	40 participants	40 participants
Number of Participants With Clinical Benefit (CBR) and Number of Participants With CBR Having a Disease Free Interval (DFI) Greater Than 2 Years - Evaluable Population CBR, DFI <= 2 Years	20 participants	20 participants
Number of Participants With Clinical Benefit (CBR) and Number of Participants With CBR Having a Disease Free Interval (DFI) Greater Than 2 Years - Evaluable Population CBR, DFI > 2 Years	20 participants	20 participants

SECONDARY outcome

Timeframe: First dose of study drug to last dose plus 7 days, up to study completion (approximately 6 years)

Population: All treated participants who met the protocol-specified efficacy analyses requirements and who received at least 1 dose of study drug were analyzed. The participants are analyzed as per the treatment arm to which they were originally randomized.

CR= Disappearance of all target lesions. No new lesions. PR= At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. SD= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) taking as reference the smallest sum LD since the treatment started. Progression (PD): At least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Outcome measures

Outcome measures
Measure	Dasatinib Plus Letrozole n=56 Participants Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg Patients on letrozole plus dasatinib received both drugs until progressive disease (PD) or intolerable toxicity. If the intolerable toxicity was determined to be related to dasatinib, dasatinib was discontinued and the patient continued on single-agent letrozole. Although drugs were taken daily, cycle length was 28-days	Letrozole n=61 Participants Letrozole: Tablets, Oral, 2.5 mg, once daily, up to 2 years Patients on letrozole who developed progressive disease continued letrozole, and dasatinib was added to their treatment regimen. Although drugs were taken daily, cycle length was 28-days
Number of Participants With Complete Response, Partial Response, Stable Disease, and Disease Progression CR	1 participants	0 participants
Number of Participants With Complete Response, Partial Response, Stable Disease, and Disease Progression PR	12 participants	15 participants
Number of Participants With Complete Response, Partial Response, Stable Disease, and Disease Progression SD	32 participants	30 participants
Number of Participants With Complete Response, Partial Response, Stable Disease, and Disease Progression SD >=6 months	27 participants	25 participants
Number of Participants With Complete Response, Partial Response, Stable Disease, and Disease Progression PD	7 participants	16 participants
Number of Participants With Complete Response, Partial Response, Stable Disease, and Disease Progression Not Evaluable	4 participants	0 participants

SECONDARY outcome

Timeframe: Day 1 to Study Completion (approximately 6 years)

Population: ITT population includes all participants enrolled in the study. The participants were analyzed as per the treatment arm to which they were originally randomized.

PFS was measured in months. Progression=At least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Study initiated 2008 and completed 2014.

Outcome measures

Outcome measures
Measure	Dasatinib Plus Letrozole n=57 Participants Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg Patients on letrozole plus dasatinib received both drugs until progressive disease (PD) or intolerable toxicity. If the intolerable toxicity was determined to be related to dasatinib, dasatinib was discontinued and the patient continued on single-agent letrozole. Although drugs were taken daily, cycle length was 28-days	Letrozole n=63 Participants Letrozole: Tablets, Oral, 2.5 mg, once daily, up to 2 years Patients on letrozole who developed progressive disease continued letrozole, and dasatinib was added to their treatment regimen. Although drugs were taken daily, cycle length was 28-days
Median Progression Free Survival (PFS) - Intent to Treat (ITT) Population	20.1 months Interval 10.7 to 28.4	9.9 months Interval 7.4 to 19.8

SECONDARY outcome

Timeframe: First dose of study drug to last dose plus 7 days, up to study completion (approximately 6 years)

Population: Participants who changed their treatment regimen from single-agent letrozole to letrozole + dasatinib during the study.

Participants in single-agent letrozole treatment arm who developed progressive disease, could continue letrozole, and add dasatinib to their treatment regimen. CBR=participants with CR + participants with partial response (PR) + participants with SD for a length of time ≥6 months divided by the total number of participants (%). CR= Disappearance of all target lesions. No new lesions. PR= At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. SD= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) taking as reference the smallest sum LD since the treatment started. PD=At least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Outcome measures

Outcome measures
Measure	Dasatinib Plus Letrozole n=35 Participants Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg Patients on letrozole plus dasatinib received both drugs until progressive disease (PD) or intolerable toxicity. If the intolerable toxicity was determined to be related to dasatinib, dasatinib was discontinued and the patient continued on single-agent letrozole. Although drugs were taken daily, cycle length was 28-days	Letrozole Letrozole: Tablets, Oral, 2.5 mg, once daily, up to 2 years Patients on letrozole who developed progressive disease continued letrozole, and dasatinib was added to their treatment regimen. Although drugs were taken daily, cycle length was 28-days
Percentage of Participants Best Overall Response After Change From Letrozole to Letrozole Plus Dasatinib Best Response of SD	34.3 percentage of participants Interval 19.1 to 52.2	—
Percentage of Participants Best Overall Response After Change From Letrozole to Letrozole Plus Dasatinib Best Response of SD ≥6 months	22.9 percentage of participants Interval 10.4 to 40.1	—
Percentage of Participants Best Overall Response After Change From Letrozole to Letrozole Plus Dasatinib Best Response of CBR	22.9 percentage of participants Interval 10.4 to 40.1	—
Percentage of Participants Best Overall Response After Change From Letrozole to Letrozole Plus Dasatinib Best Response of PD	20.0 percentage of participants Interval 8.4 to 36.9	—
Percentage of Participants Best Overall Response After Change From Letrozole to Letrozole Plus Dasatinib Best Response Not Available	2.9 percentage of participants Interval 0.1 to 14.9	—
Percentage of Participants Best Overall Response After Change From Letrozole to Letrozole Plus Dasatinib Best Response Not Evaluable	2.9 percentage of participants Interval 0.1 to 14.9	—
Percentage of Participants Best Overall Response After Change From Letrozole to Letrozole Plus Dasatinib Best Response Pending	40.0 percentage of participants Interval 23.9 to 57.9	—

SECONDARY outcome

Timeframe: At 6 months and at 12 months

Population: ITT population=Includes all participants registered on the study. n= number at risk

Progression=At least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. ITT population: from time of first enrollment to first PD for all ITT participants.

Outcome measures

Outcome measures
Measure	Dasatinib Plus Letrozole n=57 Participants Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg Patients on letrozole plus dasatinib received both drugs until progressive disease (PD) or intolerable toxicity. If the intolerable toxicity was determined to be related to dasatinib, dasatinib was discontinued and the patient continued on single-agent letrozole. Although drugs were taken daily, cycle length was 28-days	Letrozole n=63 Participants Letrozole: Tablets, Oral, 2.5 mg, once daily, up to 2 years Patients on letrozole who developed progressive disease continued letrozole, and dasatinib was added to their treatment regimen. Although drugs were taken daily, cycle length was 28-days
Percentage of Participants With PFS At 6 Months and At 12 Months - ITT Population 6 Month (n=39, 39)	77.2 percentage of participants Interval 63.3 to 86.4	66.2 percentage of participants Interval 53.0 to 76.5
Percentage of Participants With PFS At 6 Months and At 12 Months - ITT Population 12 Month (n=29, 20)	64.6 percentage of participants Interval 49.8 to 76.1	42.9 percentage of participants Interval 29.77 to 55.5

SECONDARY outcome

Timeframe: First dose of study drug to last dose plus 7 days, up to study completion (approximately 6 years)

Population: ITT population: All participants enrolled in the study.

Time to TTF was measured in months. The number of participants with events (PD or off treatment due to any reason) was evaluated. The first PD was defined as the event for cross over participants in the single- agent letrozole treatment arm to add dasatinib to their regimen.

Outcome measures

Outcome measures
Measure	Dasatinib Plus Letrozole n=57 Participants Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg Patients on letrozole plus dasatinib received both drugs until progressive disease (PD) or intolerable toxicity. If the intolerable toxicity was determined to be related to dasatinib, dasatinib was discontinued and the patient continued on single-agent letrozole. Although drugs were taken daily, cycle length was 28-days	Letrozole n=63 Participants Letrozole: Tablets, Oral, 2.5 mg, once daily, up to 2 years Patients on letrozole who developed progressive disease continued letrozole, and dasatinib was added to their treatment regimen. Although drugs were taken daily, cycle length was 28-days
Median Time to Treatment Failure (TTF) - ITT Population	10.2 Months Interval 5.8 to 18.5	9.2 Months Interval 5.5 to 11.1

SECONDARY outcome

Timeframe: First dose of study drug to last dose plus 30 days, up to study completion (approximately 6 years)

Population: All participants who received at least one dose of study drug were summarized. The participants were analyzed as per the treatment arm to which they were originally randomized.

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

Outcome measures

Outcome measures
Measure	Dasatinib Plus Letrozole n=57 Participants Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg Patients on letrozole plus dasatinib received both drugs until progressive disease (PD) or intolerable toxicity. If the intolerable toxicity was determined to be related to dasatinib, dasatinib was discontinued and the patient continued on single-agent letrozole. Although drugs were taken daily, cycle length was 28-days	Letrozole n=63 Participants Letrozole: Tablets, Oral, 2.5 mg, once daily, up to 2 years Patients on letrozole who developed progressive disease continued letrozole, and dasatinib was added to their treatment regimen. Although drugs were taken daily, cycle length was 28-days
Number of Participants With Adverse Events (AEs) Leading to Discontinuation, Serious Adverse Events (SAEs), and Deaths Deaths	11 participants	16 participants
Number of Participants With Adverse Events (AEs) Leading to Discontinuation, Serious Adverse Events (SAEs), and Deaths SAEs	14 participants	2 participants
Number of Participants With Adverse Events (AEs) Leading to Discontinuation, Serious Adverse Events (SAEs), and Deaths AEs Leading to Discontinuation	10 participants	6 participants

Adverse Events

Dasatinib Plus Letrozole

Serious events: 14 serious events

Other events: 56 other events

Deaths: 0 deaths

Letrozole

Serious events: 2 serious events

Other events: 57 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Dasatinib Plus Letrozole n=57 participants at risk Dasatinib + Letrozole: Tablets, Oral, once daily, up to 2 years Dasatinib 100 mg + Letrozole 2.5 mg	Letrozole n=63 participants at risk Letrozole: Tablets, Oral, 2.5 mg, once daily, up to 2 years
Immune system disorders Hypersensitivity Reaction	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Blood and lymphatic system disorders Anemia	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Cardiac disorders Cardiac Insufficiency	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Cardiac disorders Congestive Heart Failure	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Cardiac disorders Coronary Insufficiency	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Cardiac disorders Effusion Pericardial	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Blood and lymphatic system disorders CVA	3.5% 2/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Gastrointestinal disorders Cholelithiasis	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Gastrointestinal disorders Colitis	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Gastrointestinal disorders Dehydration	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Gastrointestinal disorders Diverticulitis	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Gastrointestinal disorders Nausea	3.5% 2/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Gastrointestinal disorders Nausea and Vomiting	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Gastrointestinal disorders Vomiting	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Hepatobiliary disorders Cholecystitis	3.5% 2/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Infections and infestations Cellulitis	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Infections and infestations Fever	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Infections and infestations Infection	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Infections and infestations Meningitis	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Infections and infestations Sepsis	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Metabolism and nutrition disorders Failure Liver	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Metabolism and nutrition disorders Hyperbilirubinemia	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Musculoskeletal and connective tissue disorders Back Pain	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Musculoskeletal and connective tissue disorders Fracture Bone	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Nervous system disorders Aphasia	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Nervous system disorders Body Numbness	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Nervous system disorders Discomfort Abdominal	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Nervous system disorders Headache	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Nervous system disorders Mood Altered	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Nervous system disorders Seizure	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Nervous system disorders Spinal Cord Compression	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Nervous system disorders Syncope	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Musculoskeletal and connective tissue disorders Chest pain	3.5% 2/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Respiratory, thoracic and mediastinal disorders Disease Heart Pulmonary	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Respiratory, thoracic and mediastinal disorders Effusion Pleural	5.3% 3/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Respiratory, thoracic and mediastinal disorders Hypoxia	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Respiratory, thoracic and mediastinal disorders Pneumonia	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Disease Progression	3.5% 2/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Vascular disorders Cerebral Infarction	1.8% 1/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	0.00% 0/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.
Vascular disorders Failure Heart	0.00% 0/57 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.	1.6% 1/63 • First dose of study drug to last dose plus 30 days Study initiated 2008 and completed 2014.