Trial Outcomes & Findings for First Line Therapy for Patients With Metastatic Breast Cancer (NCT NCT00456846)

Last Updated: 2019-11-22

Results Overview

Overall response rate (ORR) is complete response (CR) + partial response (PR). Complete response (CR): The disappearance of all known disease and no new sites or disease related symptoms confirmed at least 4 weeks after initial documentation. All sites must be assessed, including non-measurable sites, such as effusions, or markers. Disappearance of all non-target lesions. The normalization of tumor marker level confirmed at least 4 weeks after initial documentation. Partial response (PR): At least a 30% decrease in the sum of the longest diameters of target lesions, taking as a reference the baseline sum of the longest diameters confirmed at least 4 weeks after initial documentation. PR is also recorded when all measurable disease has completely disappeared, but a non-measurable component (i.e., ascites) is still present but not progressing. As well as persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

123 participants

Primary outcome timeframe

Every 8 weeks from study start until disease progression; Up to 61 months

Results posted on

2019-11-22

Participant Flow

Participant milestones

Participant milestones
Measure	Abraxane (Prior Taxane Therapy) Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest. Therapy continued until disease progression or unacceptable toxicity.	Abraxane (No Prior Taxane Therapy) Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest. Therapy continued until disease progression or unacceptable toxicity.
Overall Study STARTED	47	76
Overall Study COMPLETED	31	48
Overall Study NOT COMPLETED	16	28

Reasons for withdrawal

Reasons for withdrawal
Measure	Abraxane (Prior Taxane Therapy) Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest. Therapy continued until disease progression or unacceptable toxicity.	Abraxane (No Prior Taxane Therapy) Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest. Therapy continued until disease progression or unacceptable toxicity.
Overall Study Adverse Event	2	15
Overall Study Physician Decision	11	6
Overall Study Protocol Deviation	2	0
Overall Study Participant Discretion	1	5
Overall Study Other	0	2

Baseline Characteristics

First Line Therapy for Patients With Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Abraxane (Prior Taxane Therapy) n=47 Participants Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=76 Participants Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Total n=123 Participants Total of all reporting groups
Age, Continuous	55.3 years STANDARD_DEVIATION 9.78 • n=99 Participants	58.3 years STANDARD_DEVIATION 10.88 • n=107 Participants	57.2 years STANDARD_DEVIATION 10.54 • n=206 Participants
Sex: Female, Male Female	47 Participants n=99 Participants	76 Participants n=107 Participants	123 Participants n=206 Participants
Sex: Female, Male Male	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race/Ethnicity, Customized Asian	0 participants n=99 Participants	5 participants n=107 Participants	5 participants n=206 Participants
Race/Ethnicity, Customized Black, of African Heritage	2 participants n=99 Participants	3 participants n=107 Participants	5 participants n=206 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 participants n=99 Participants	0 participants n=107 Participants	1 participants n=206 Participants
Race/Ethnicity, Customized White, Non-Hispanic/Non Latino	41 participants n=99 Participants	60 participants n=107 Participants	101 participants n=206 Participants
Race/Ethnicity, Customized White, Hispanic or Latino	0 participants n=99 Participants	5 participants n=107 Participants	5 participants n=206 Participants
Race/Ethnicity, Customized Other-Unspecified	3 participants n=99 Participants	3 participants n=107 Participants	6 participants n=206 Participants
Menopausal Status Premenopausal	12 participants n=99 Participants	12 participants n=107 Participants	24 participants n=206 Participants
Menopausal Status Postmenopausal	35 participants n=99 Participants	64 participants n=107 Participants	99 participants n=206 Participants
Stage at Primary Diagnosis Stage I	4 participants n=99 Participants	12 participants n=107 Participants	16 participants n=206 Participants
Stage at Primary Diagnosis Stage IIa	7 participants n=99 Participants	12 participants n=107 Participants	19 participants n=206 Participants
Stage at Primary Diagnosis Stage IIb	14 participants n=99 Participants	13 participants n=107 Participants	27 participants n=206 Participants
Stage at Primary Diagnosis Stage IIIa	11 participants n=99 Participants	8 participants n=107 Participants	19 participants n=206 Participants
Stage at Primary Diagnosis Stage IIIb	6 participants n=99 Participants	4 participants n=107 Participants	10 participants n=206 Participants
Stage at Primary Diagnosis Stage IIIc	5 participants n=99 Participants	5 participants n=107 Participants	10 participants n=206 Participants
Stage at Primary Diagnosis Stage IV	0 participants n=99 Participants	19 participants n=107 Participants	19 participants n=206 Participants
Stage at Primary Diagnosis Unknown	0 participants n=99 Participants	3 participants n=107 Participants	3 participants n=206 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (fully active)	21 participants n=99 Participants	38 participants n=107 Participants	59 participants n=206 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (restrictive but ambulatory)	22 participants n=99 Participants	30 participants n=107 Participants	52 participants n=206 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (ambulatory but unable to work)	4 participants n=99 Participants	8 participants n=107 Participants	12 participants n=206 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 3 (limited self-care) + 4 (completely disabled)	0 participants n=99 Participants	0 participants n=107 Participants	0 participants n=206 Participants
Physician Assessment of Peripheral Neuropathy] [2] Grade 0	37 participants n=99 Participants	69 participants n=107 Participants	106 participants n=206 Participants
Physician Assessment of Peripheral Neuropathy] [2] Grade 1	10 participants n=99 Participants	7 participants n=107 Participants	17 participants n=206 Participants

PRIMARY outcome

Timeframe: Every 8 weeks from study start until disease progression; Up to 61 months

Population: Treated Population: The Treated population consisted of all enrolled participants who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Abraxane (Prior Taxane Therapy) n=47 Participants Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=76 Participants Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest
Percentage of Participants With Objective Confirmed Complete or Partial Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 Based on Investigator and Independent Reviewers Investigator Assessment	30 percentage of participants Interval 16.7 to 42.9	28 percentage of participants Interval 17.6 to 37.7
Percentage of Participants With Objective Confirmed Complete or Partial Overall Response According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 Based on Investigator and Independent Reviewers Independent Reviewer Assessment	32 percentage of participants Interval 18.6 to 45.2	32 percentage of participants Interval 21.1 to 42.0

SECONDARY outcome

Timeframe: Every 8 weeks from study start until disease progression; Up to 61 months

Population: Treated Population: The Treated population consisted of all enrolled participants who received at least one dose of study drug.

Disease control was defined as stable disease (SD) for ≥ 16 weeks or complete response (CR) or partial response (PR). Response was evaluated by the Investigator and by an independent reviewer using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.0. See Outcome #1 for definitions of CR and PR. RECIST defines SD for target lesions as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, no occurrence of progression disease for non-target lesions, and no new lesions.

Outcome measures

Outcome measures
Measure	Abraxane (Prior Taxane Therapy) n=47 Participants Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=76 Participants Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest
Percentage of Participants With Disease Control Investigator Assessment	51 percentage of participants Interval 36.8 to 65.4	57 percentage of participants Interval 45.4 to 67.7
Percentage of Participants With Disease Control Independent Reviewer Assessment	55 percentage of participants Interval 41.1 to 69.5	57 percentage of participants Interval 45.4 to 67.7

SECONDARY outcome

Timeframe: Study start until disease progression, death, or up to data cut off of 31 May 2013; up to 61 months

Population: Treated Population: The Treated population consisted of all enrolled participants who received at least one dose of study drug.

PFS was defined as the time from the first dose of study drug to the start of progression or patient death (any cause), whichever occurred first. Participants who did not have progression or did not die were censored at the last known time the participant was progression free. Participants who initiated other anticancer therapy prior to progression were censored at the time when new anticancer therapy was initiated.

Outcome measures

Outcome measures
Measure	Abraxane (Prior Taxane Therapy) n=47 Participants Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=76 Participants Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest
Progression-free Survival (PFS) Investigator Assessment	6.0 months Interval 3.5 to 8.8	6.7 months Interval 5.3 to 7.3
Progression-free Survival (PFS) Independent Reviewer Assessment	5.3 months Interval 3.3 to 7.3	5.3 months Interval 3.5 to 6.6

SECONDARY outcome

Timeframe: Initial response until disease progression; or until data cut off 31 May 2013; up to 61 months

Population: Treated Population: The Treated population with a confirmed complete response or partial response.

Duration of response was defined as progression-free survival in responders, i.e. as the time between the start of a complete response (CR) or partial response (PR) and the start of progressive disease (PD) or patient death from any cause, whichever occurred first. Participants who did not have progression or had not died were censored at the last known time the participant was progression free. Participants who had initiated other anticancer therapy prior to progression were censored at the time when new anticancer therapy was initiated. CR and PR were defined in outcome #1. Progressive disease was defined as at least a 20% increase in the sum of the longest diameters of target lesions; or the appearance of one or more new lesions; or the unequivocal progression of a non-target lesion. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST).

Outcome measures

Outcome measures
Measure	Abraxane (Prior Taxane Therapy) n=15 Participants Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=24 Participants Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest
Duration of Response Based on Independent Reviewer Assessment	10.9 months Interval 7.3 to 18.9	9.2 months Interval 7.4 to 14.2

SECONDARY outcome

Timeframe: Initial response until disease progression; or until data cut off 31 May 2013; up to 61 months

Population: Treated Population: The Treated population consisted of all enrolled participants that received at least one dose of study drug.

Duration of response was defined as progression-free survival in responders, i.e. as the time between the start of a complete response (CR) or partial response (PR) and the start of progressive disease (PD) or patient death from any cause, whichever occurred first. Participants who did not have progression or had not died were censored at the last known time the participant was progression free. Participants who had initiated other anticancer therapy prior to progression were censored at the time when new anticancer therapy was initiated. Complete response (CR) and partial response (PR) were defined in outcome #1. Progressive disease was defined as at least a 20% increase in the sum of the longest diameters of target lesions; or the appearance of one or more new lesions; or the unequivocal progression of a non-target lesion. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST).

Outcome measures

Outcome measures
Measure	Abraxane (Prior Taxane Therapy) n=14 Participants Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=21 Participants Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest
Duration of Response Based on Investigator Assessment	10.5 months Interval 8.8 to 25.4	10.8 months Interval 8.7 to 22.4

SECONDARY outcome

Timeframe: Study start until death, or until data cut-off 31 May 2013; up to 61 months

Population: Treated Population: The Treated population consisted of all enrolled participants that received at least one dose of study drug.

Participant survival was the time from the first dose of study drug to participant death from any cause. Participants who did not die were censored at the last known time the participant was alive.

Outcome measures

Outcome measures
Measure	Abraxane (Prior Taxane Therapy) n=47 Participants Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=76 Participants Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest
Patient Survival	20.9 months Interval 14.3 to 28.0	20.0 months Interval 13.8 to 28.6

SECONDARY outcome

Timeframe: Day 1 of study drug to Day 940; data cut off 31 May 2013

Population: Treated Population: The Treated population consisted of all enrolled participants who received at least one dose of study drug.

The number of participants with dose reductions, dose interruptions and dose delays that occurred during the treatment period. Dose reductions, interruptions and delays are typically caused by clinically significant laboratory abnormalities and /or treatment emergent adverse events/toxicities.

Outcome measures

Outcome measures
Measure	Abraxane (Prior Taxane Therapy) n=47 Participants Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=76 Participants Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest
Number of Participants Experiencing Dose Reductions, Interruptions, or Dose Delays of Study Drug Patients with at Least One Dose Reduction	11 participants	19 participants
Number of Participants Experiencing Dose Reductions, Interruptions, or Dose Delays of Study Drug Patients with at Least One Dose Interruption	3 participants	2 participants
Number of Participants Experiencing Dose Reductions, Interruptions, or Dose Delays of Study Drug Patients with at Least One Dose Delay/Not Given	20 participants	39 participants

SECONDARY outcome

Timeframe: Day 1 to Day 940

Population: Treated Population: The Treated population consisted of all enrolled participants who received at least one dose of study drug.

Count of study participants who had at least one treatment-emergent adverse event (TEAE) defined as any adverse event that began or worsened in grade after the start of study drug through 30 days after the last dose of study drug. The National Cancer Institute (NCI)'s Common Terminology Criteria for AEs (CTCAE) was used to grade AE severity: severity grade 3= severe and undesirable AE. Severity grade 4= life-threatening or disabling AE. Severity grade 5 = death.

Outcome measures

Outcome measures
Measure	Abraxane (Prior Taxane Therapy) n=47 Participants Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=76 Participants Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest
Number of Participants With Treatment-Emergent Adverse Events ≥ 1 Serious Adverse Event	5 participants	14 participants
Number of Participants With Treatment-Emergent Adverse Events ≥1 Adverse Event (AE)	46 participants	75 participants
Number of Participants With Treatment-Emergent Adverse Events ≥1 Treatment related Adverse Event	41 participants	74 participants
Number of Participants With Treatment-Emergent Adverse Events Treatment related Serious Adverse Event	2 participants	7 participants
Number of Participants With Treatment-Emergent Adverse Events ≥1 One Grade 3/4 Adverse Event	25 participants	36 participants
Number of Participants With Treatment-Emergent Adverse Events ≥1 One Grade 3 or Higher Adverse Event	25 participants	36 participants
Number of Participants With Treatment-Emergent Adverse Events ≥1 AE leading to treatment discontinuation	2 participants	16 participants
Number of Participants With Treatment-Emergent Adverse Events ≥1 AE leading to death	0 participants	2 participants
Number of Participants With Treatment-Emergent Adverse Events ≥1 AE leading to dose reduction of study drug	11 participants	18 participants
Number of Participants With Treatment-Emergent Adverse Events ≥1 AE leading to dose interruption of study drug	2 participants	0 participants
Number of Participants With Treatment-Emergent Adverse Events ≥1 AE leading to dose delay of study drug	15 participants	29 participants

Adverse Events

Abraxane (Prior Taxane Therapy)

Serious events: 5 serious events

Other events: 46 other events

Deaths: 0 deaths

Abraxane (No Prior Taxane Therapy)

Serious events: 14 serious events

Other events: 75 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Anne McClain

Celgene Corporation

Phone: 888-260-1599

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Institution may publish the results of its findings if a multicenter publication is not forthcoming within 18 months after study completion. Institution shall provide Celgene with a copy of the papers prior to their submission; Celgene shall complete its review within 60 days after receipt. Upon Celgene's request, proposed publication or presentation will be delayed up to 60 additional days to enable Celgene to secure adequate intellectual property protection of patentable material.
Publication restrictions are in place

Restriction type: OTHER

Measure	Abraxane (Prior Taxane Therapy) n=47 participants at risk Participants who had received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest	Abraxane (No Prior Taxane Therapy) n=76 participants at risk Participants who had not received a taxane as part of their adjuvant therapy received Abraxane (ABI-007) at 100 mg/m\^2 given intravenously (IV) over 30 minutes weekly for 3 weeks followed by 1 week rest
Infections and infestations Pneumonia	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	3.9% 3/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Infections and infestations Bacteraemia	2.1% 1/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	0.00% 0/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Infections and infestations Bronchopneumonia	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Infections and infestations Cellulitis	2.1% 1/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	0.00% 0/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Infections and infestations Histoplasmosis	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Infections and infestations Lung infection	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	2.6% 2/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	2.6% 2/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Respiratory, thoracic and mediastinal disorders Pneumothorax	2.1% 1/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	0.00% 0/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Injury, poisoning and procedural complications Cervical vertebral fracture	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
General disorders Chest pain	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
General disorders General physical health deterioration	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
General disorders Mucosal inflammation	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Musculoskeletal and connective tissue disorders Chondrocalcinosis pyrophosphate	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	2.1% 1/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	0.00% 0/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Musculoskeletal and connective tissue disorders Pathological fracture	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Cardiac disorders Left ventricular dysfunction	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Cardiac disorders Pericardial effusion	2.1% 1/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	0.00% 0/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Gastrointestinal disorders Diarrhoea	2.1% 1/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	0.00% 0/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	2.1% 1/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	0.00% 0/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	2.1% 1/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	0.00% 0/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Hepatobiliary disorders Hepatic cirrhosis	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Nervous system disorders Somnolence	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Psychiatric disorders Confusional state	2.1% 1/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	0.00% 0/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.
Skin and subcutaneous tissue disorders Stevens-Johnson syndrome	0.00% 0/47 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.	1.3% 1/76 • Any Adverse Event (AE) that started after initial study drug administration through the end of the study or 30 days after the last treatment, whichever was later, were followed until the AE had resolved or stabilized. Upt to 61 months.