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Clinical Trial Results:
A two-arm randomized open label phase 2 study of CP-751,871 in combination with Exemestane versus Exemestane alone as first line treatment for postmenopausal patients with hormone receptor positive advanced breast cancer

Summary
EudraCT number	2006-005573-21
Trial protocol	BE NL GB SE IT
Global end of trial date	10 Jun 2014

Results information
Results version number	v1
This version publication date	01 Mar 2016
First version publication date	02 Aug 2015
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

A4021004

ISRCTN number

US NCT number

NCT00372996

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.govCallCenter@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.govCallCenter@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

27 Oct 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Jun 2014

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objective of this two arm randomized trial is to compare the efficacy, in terms of progression free survival (PFS), of CP-751,871 in combination with exemestane versus exemestane alone as first line treatment of postmenopausal women with hormone-dependent advanced breast cancer with low risk for the development of diabetes Glycated hemoglobin (Hb A1C) less than (<) 5.7 percent (%).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Feb 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

5 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

United Kingdom: 2

Country: Number of subjects enrolled

Belgium: 52

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

Brazil: 47

Country: Number of subjects enrolled

Canada: 28

Country: Number of subjects enrolled

United States: 52

Country: Number of subjects enrolled

Argentina: 29

Worldwide total number of subjects

219

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

130

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 219 subjects were enrolled in the study from 8 countries. The study started on 19 February 2007 and ended on 10 June 2014.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

CP-751,871 plus (+) Exemestane

Arm description

Subjects received CP-751,871 on Day 1 of each 3-week cycle in combination with exemestane once daily, until disease progression.

Arm type

Experimental

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane was administered at a dose of 25 mg once in a daily.

Investigational medicinal product name

CP-751,871

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

CP-751,871 was administered at dose of 20 milligrams per kilogram (mg/Kg).

CP-751,871 + Exemestane/CP-751,871 + Fulvestrant

Arm description

Subjects received CP-751,871 on day 1 of each 3-week cycle in combination with exemestane once daily, until disease progression. Subjects who experienced disease progression received salvage therapy with CP-751,871 20 mg/kg on Day 1 of each 4-week cycle in combination with fulvestrant, administered according to the local label and standard clinical practice. Subjects continued salvage treatment if safety and clinical benefit were observed for up to a total of 26 cycles or beyond, if there was continued clinical benefit, safety, and tolerability.

Arm type

Experimental

Investigational medicinal product name

CP-751,871

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

CP-751,871 was administered at dose of 20 mg/Kg.

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane was administered at a dose of 25 mg once in a day.

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant was administered at a dose of 50 mg/ml.

Exemestane

Arm description

Subjects received exemestane once daily, until disease progression.

Arm type

Active comparator

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane was administered at a dose of 25 mg once in a day.

Exemestane/CP-751,871 + Exemestane

Arm description

Subjects received exemestane once daily, until disease progression. Subjects who experienced disease progression received salvage therapy with CP-751,871 20 mg/kg on Day 1 of each 3-week cycle in combination with exemestane for up to a total of 20 months or beyond if safety and clinical benefit were observed.

Arm type

Active comparator

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane was administered at a dose of 25 mg once in a day.

Investigational medicinal product name

CP-751,871

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

CP-751,871 was administered at dose of 20 mg/Kg.

Number of subjects in period 1	CP-751,871 plus (+) Exemestane	CP-751,871 + Exemestane/CP-751,871 + Fulvestrant	Exemestane	Exemestane/CP-751,871 + Exemestane
Started	79	36	61	43
Completed	42	22	33	23
Not completed	37	14	28	20
Death	11	4	8	7
Not specified	10	2	7	7
Study terminated by sponsor	4	-	4	-
Lost to follow-up	-	2	-	1
Withdrawal by subject	12	6	9	5

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

Reporting group values	Overall Study	Total
Number of subjects	219	219
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	61.9 ( 10.82 )	-
Gender categorical
Units: Subjects
Female	219	219
Male	0	0

Subject analysis set title

CP-751,871 + Exemestane

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received CP-751,871 20 mg/kg on Day 1 of each 3-week cycle as an IV infusion in combination with exemestane 25 mg tablets, by mouth, once daily, until disease progression. Participants who experienced disease progression could have received salvage therapy with CP-751,871 20 mg/kg on Day 1 of each 4-week cycle in combination with fulvestrant, administered according to the local label and standard clinical practice. Participants continued salvage treatment if safety and clinical benefit were observed for up to a total of 26 cycles or beyond, if there was continued clinical benefit, safety, and tolerability.

Subject analysis set title

Exemestane

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received exemestane 25 mg tablets, by mouth, once daily, until disease progression. Participants who experienced disease progression could have received salvage therapy with CP-751,871 20 mg/kg on Day 1 of each 3 -week cycle in combination with exemestane 25 mg tablets, by mouth, once daily, for up to a total of 20 months or beyond if safety and clinical benefit were observed.

Subject analysis sets values	CP-751,871 + Exemestane	Exemestane
Number of subjects	115	104
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	61.2 ( 10.77 )	62.7 ( 10.86 )
Gender categorical
Units: Subjects
Female	115	104
Male	0	0

End points

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Reporting group title

CP-751,871 plus (+) Exemestane

Reporting group description

Subjects received CP-751,871 on Day 1 of each 3-week cycle in combination with exemestane once daily, until disease progression.

Reporting group title

CP-751,871 + Exemestane/CP-751,871 + Fulvestrant

Reporting group description

Reporting group title

Exemestane

Reporting group description

Subjects received exemestane once daily, until disease progression.

Reporting group title

Exemestane/CP-751,871 + Exemestane

Reporting group description

Subject analysis set title

CP-751,871 + Exemestane

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Exemestane

Subject analysis set type

Safety analysis

Subject analysis set description

Primary: Primary: Progression-Free Survival (PFS)

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End point title

Primary: Progression-Free Survival (PFS)

End point description

PFS was calculated from time of randomization to progression of disease, death or treatment discontinuation because of unsatisfactory results. Disease progression:radiographic progression(20 percent [%] increase in measurable lesions, appearance of new lesions or unequivocal progression of evaluable lesions as defined by Response Evaluation Criteria in Solid Tumors [RECIST]); occurrence of new pleural/pericardial effusions or ascites confirmed by positive cytology; persistent hypercalcemia requiring more than 2 IV treatments with bisphosphonates; intervention for any cancer-related events or symptoms related to tumor growth requiring subject discontinuation, development of brain metastasis or death. Median PFS was estimated from Kaplan-Meier curve. 95% confidence interval (CI) is based on Brookmeyer and Crowley method. Full Analysis Set(FAS): all enrolled subjects; grouped by randomized arm, where first 10 subjects enrolled but not randomly assigned to treatment were not included.

End point type

Primary

End point timeframe

Baseline, Day 1 of Cycles 2 and 4 and then Day 1 of every 3rd cycle starting at Cycle 7 up to 60 months.

End point values	CP-751,871 + Exemestane	Exemestane
Number of subjects analysed	106	103
Units: months
median (confidence interval 95%)	11 (8.1 to 12.9)	9.2 (7 to 13)

Exemestane, CP-751,871 + Exemestane

Statistical analysis description

2-sided p-value from an unstratified log-rank text. Hazard ratio was based on Cox proportional hazards model.

Comparison groups

CP-751,871 + Exemestane v Exemestane

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.56

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.912

Confidence interval

level

80%

sides

2-sided

lower limit

0.744

upper limit

1.118

Primary: PFS in Subjects with Hemoglobin A1c (HbA1c) Less than (<) 5.7% at Baseline

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End point title

PFS in Subjects with Hemoglobin A1c (HbA1c) Less than (<) 5.7% at Baseline

End point description

PFS was calculated from the time of randomization to either progression of disease, death, or treatment discontinuation because of unsatisfactory therapy results (such as global deterioration of health status). Disease progression was defined as 1 or more of the following: radiographic progression (20% increase in measurable lesions, appearance of new lesions or unequivocal progression of evaluable lesions as defined by RECIST); occurrence of new pleural/pericardial effusions or ascites confirmed by positive cytology; persistent hypercalcemia requiring more than 2 IV treatments with bisphosphonates; intervention for any cancer-related events (radiations, surgery) or new symptoms related to tumor growth requiring subject discontinuation; development of brain metastasis; or death for any cause. Median PFS was estimated from the Kaplan-Meier curve. 95% CI is based on the Brookmeyer and Crowley method. FAS; only subjects with baseline HbA1c <5.7% were included in the analysis.

End point type

Primary

End point timeframe

Baseline, Day 1 of Cycles 2 and 4 and then Day 1 of every 3rd cycle starting at Cycle 7 up to 60 months

End point values	CP-751,871 + Exemestane	Exemestane
Number of subjects analysed	39	40
Units: months
median (confidence interval 95%)	13.2 (8.1 to 19.5)	9.9 (7 to 13.6)

Exemestane, CP-751,871 + Exemestane

Statistical analysis description

2-sided p-value from unstratified log-rank test. Hazard ratio was based on the Cox proportional hazards model.

Comparison groups

Exemestane v CP-751,871 + Exemestane

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.331

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.764

Confidence interval

level

70%

sides

2-sided

lower limit

0.572

upper limit

1.02

Secondary: Percentage of Subjects Achieving Complete Response (CR), Partial Response (PR), or Stable Disease (SD) Maintained for at Least 6 Months

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End point title

Percentage of Subjects Achieving Complete Response (CR), Partial Response (PR), or Stable Disease (SD) Maintained for at Least 6 Months

End point description

Objective responses were defined using RECIST as CR: disappearance of all target and non target lesions. PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD. Non target lesions may persist provided there is no unequivocal progression in these lesions. SD: measurements demonstrating neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease (PD) during the first 6 weeks after the start of treatment taking as reference the smallest sum LD since the treatment started. During this time, non target lesions may persist provided there is no unequivocal progression in these lesions. FAS

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycles 2 and 4 and then Day 1 of every 3rd cycle starting at Cycle 7 up to 60 months

End point values	CP-751,871 + Exemestane	Exemestane
Number of subjects analysed	106	103
Units: Percentage of subjects
number (confidence interval 95%)	68.9 (59.1 to 77.5)	64.1 (54 to 73.3)

CP-751,871 + Exemestane, Exemestane

Comparison groups

CP-751,871 + Exemestane v Exemestane

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.463

Method

Pearson chi-square test

Parameter type

Mean difference (net)

Point estimate

4.79

Confidence interval

level

95%

sides

2-sided

lower limit

-8

upper limit

17.6

Secondary: Maximum Plasma Concentration of CP-751,871

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End point title

Maximum Plasma Concentration of CP-751,871

End point description

The analysis population included all subjects treated with CP-751,871. However, the study was terminated early due to strategic reasons and pharmacokinetic (PK) sampling was discontinued by Protocol Amendment 6. Therefore, the analysis was not performed. Data from samples that were collected and analyzed were listed descriptively.

End point type

Secondary

End point timeframe

Predose on Day 1 at Cycles 1, 2, 4, and 5 and 150 days post last dose of CP-751,871 and for salvage therapy, at Day 1 and 150 days post last dose of CP-751,871

End point values	CP-751,871 + Exemestane
Number of subjects analysed	0 ^[1]
Units: ng/mL (nanogram per milliliter)
arithmetic mean (standard deviation)	( )

Notes
[1] - Although some samples were collected, analysis was not performed due to study termination.

No statistical analyses for this end point

Secondary: Minimum Plasma Concentration of CP-751,871

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End point title

Minimum Plasma Concentration of CP-751,871

End point description

End point type

Secondary

End point timeframe

Predose on Day 1 at Cycles 1, 2, 4, and 5 and 150 days post last dose of CP-751,871 and for salvage therapy, at Day 1 and 150 days post last dose of CP-751,871

End point values	CP-751,871 + Exemestane
Number of subjects analysed	0 ^[2]
Units: ng/mL
arithmetic mean (standard deviation)	( )

Notes
[2] - Although some samples were collected, analysis was not performed due to study termination.

No statistical analyses for this end point

Secondary: Area Under the Concentration Time Curve from Time 0 to the Last Time Point with Quantifiable Concentration

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End point title

Area Under the Concentration Time Curve from Time 0 to the Last Time Point with Quantifiable Concentration

End point description

The analysis population included all subjects treated with CP-751,871. However, the study was terminated early due to strategic reasons and PK sampling was discontinued by Protocol Amendment 6. Therefore, the analysis was not performed. Data from samples that were collected and analyzed were listed descriptively.

End point type

Secondary

End point timeframe

Predose on Day 1 at Cycles 1, 2, 4, and 5 and 150 days post last dose of CP-751,871 and for salvage therapy, at Day 1 and 150 days post last dose of CP-751,871

End point values	CP-751,871 + Exemestane
Number of subjects analysed	0 ^[3]
Units: ngh/mL (naonogramhour/ milliliter)
arithmetic mean (standard deviation)	( )

Notes
[3] - Although some samples were collected, analysis was not performed due to study termination.

No statistical analyses for this end point

Secondary: Number of Subjects with Negative Human Anti-Human Antibodies (HAHAs)

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End point title

Number of Subjects with Negative Human Anti-Human Antibodies (HAHAs)

End point description

Negative human anti-human antibodies were defined as <6.64. All randomized subjects who started treatment and who had at least 1 sample submitted for the biomarker; collection of samples for this analysis was stopped after Amendment 6. All samples were negative to HAHA.

End point type

Secondary

End point timeframe

Predose on Day 1 of Cycle 1 and at 150 days post last CP-751,871 infusion

End point values	CP-751,871 + Exemestane
Number of subjects analysed	37
Units: subjects
Number of Subjects Analyzed:	37
Number of Samples Analyzed	66

No statistical analyses for this end point

Secondary: Percentage of subjects with Circulating Tumor Cells Expressing Insulin-Like Growth Factor 1 Receptor (IGF-IR)

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End point title

Percentage of subjects with Circulating Tumor Cells Expressing Insulin-Like Growth Factor 1 Receptor (IGF-IR)

End point description

The analysis population included all subjects treated with CP-751,871. However, the study was terminated early due to strategic reasons and biomarker sampling was discontinued by Protocol Amendment 6. Therefore, the analysis was not performed. Data from samples that were collected and analyzed were listed descriptively.

End point type

Secondary

End point timeframe

Predose on Day 1 of Cycle 1

End point values	CP-751,871 + Exemestane	Exemestane
Number of subjects analysed	0 ^[4]	0 ^[5]
Units: percentage of subjects
number (not applicable)

Notes
[4] - Although some samples were collected, analysis was not performed due to study termination.
[5] - Although some samples were collected, analysis was not performed due to study termination.

No statistical analyses for this end point

Secondary: Percentage of Subjects with Serum Markers Relevant to the IGF-1R Pathway

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End point title

Percentage of Subjects with Serum Markers Relevant to the IGF-1R Pathway

End point description

End point type

Secondary

End point timeframe

Predose on Day 1 of Cycles 1 and 4 and at end of treatment prior to beginning salvage therapy

End point values	CP-751,871 + Exemestane	Exemestane
Number of subjects analysed	0 ^[6]	0 ^[7]
Units: subjects

Notes
[6] - Although some samples were collected, analysis was not performed due to study termination.
[7] - Although some samples were collected, analysis was not performed due to study termination.

No statistical analyses for this end point

Secondary: European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 (QLQ-C30) Scores

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End point title

European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 (QLQ-C30) Scores

End point description

EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score equals (=) better level of functioning or greater degree of symptoms.The study was terminated early secondary to strategic reasons and the questionnaires were discontinued by Protocol Amendment 6. Data already collected were not analyzed`.

End point type

Secondary

End point timeframe

Predose on Day 1 of each cycle, at the end of treatment and at follow-up, up to 60 months

End point values	CP-751,871 + Exemestane	Exemestane
Number of subjects analysed	0 ^[8]	0 ^[9]
Units: scores on a scale
arithmetic mean (standard deviation)	( )	( )

Notes
[8] - Although some questionnaires were collected, analysis was not done due to termination of the study
[9] - Although some questionnaires were collected, analysis was not done due to termination of the study

No statistical analyses for this end point

Secondary: EORTC QLQ Breast Cancer Module (BR23) Scores

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End point title

EORTC QLQ Breast Cancer Module (BR23) Scores

End point description

EORTC-QLQ-BR23: included functional scales (body image, sexual functioning, sexual enjoyment, and future perspective) and single item symptoms scales (systemic therapy side effects, breast symptoms, arm symptoms, and upset by hair loss). Questions used 4-point Likert scale (1 â€˜Not at Allâ€™ to 4 â€˜Very Muchâ€™). Scores averaged and transformed to 0-100 scale. High score for functional scale=high/healthy level of functioning. High score for single item=high level of symptomatology/problems. Change from baseline=Cycle/Day score minus baseline score. The study was terminated early secondary to strategic reasons and the questionnaires were discontinued by Protocol Amendment 6. Data already collected were not analyzed.

End point type

Secondary

End point timeframe

Predose on Day 1, at end of treatment, and at Follow-up, up to 60 months

End point values	CP-751,871 + Exemestane	Exemestane
Number of subjects analysed	0 ^[10]	0 ^[11]
Units: scores on a scale
arithmetic mean (standard deviation)	( )	( )

Notes
[10] - Although some samples were collected, analysis was not performed due to study termination.
[11] - Although some samples were collected, analysis was not performed due to study termination.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events (AEs) recorded from informed consent through and including 150 calendar days after the last administration of investigational product. Active reporting period for exemestane/fulvestrant clarified to 28 days after last dose in Amendment 6.

Adverse event reporting additional description

The same event may appear as both an AE and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in 1 subject and as nonserious in another subject, or 1 subject may have experienced both a serious and nonserious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

CP-751,871 + Exemestane

Reporting group description

Subjects received CP-751,871 20 mg/kg on Day 1 of each 3-week cycle as an IV infusion in combination with exemestane 25 mg tablets, by mouth, once daily, until disease progression.

Reporting group title

CP-751,871 + Fulvestrant (after CP-751,871+Exemestane)

Reporting group description

Subjects received CP-751,871 20 mg/kg on Day 1 of each 3-week cycle as an IV infusion in combination with exemestane 25 mg tablets, by mouth, once daily, until disease progression. Subjects who experienced disease progression received salvage therapy with CP-751,871 20 mg/kg on Day 1 of each 4-week cycle in combination with fulvestrant, administered according to the local label and standard clinical practice. Subjects continued salvage treatment if safety and clinical benefit were observed for up to a total of 26 cycles or beyond, if there was continued clinical benefit, safety, and tolerability. Adverse events are presented from the period of time when the subject was receiving salvage therapy treatment only.

Reporting group title

Exemestane

Reporting group description

Subjects received exemestane 25 mg tablets, by mouth, once daily, until disease progression.

Reporting group title

CP-751,871 + Exemestane (after Exemestane)

Reporting group description

Subjects received exemestane 25 mg tablets, by mouth, once daily, until disease progression. Subjects who experienced disease progression received salvage therapy with CP-751,871 20 mg/kg on Day 1 of each 3-week cycle in combination with exemestane 25 mg tablets, by mouth, once daily, for up to a total of 20 months or beyond if safety and clinical benefit were observed. Adverse events are presented from the period of time when the subject was receiving salvage therapy treatment only.

Serious adverse events	CP-751,871 + Exemestane	CP-751,871 + Fulvestrant (after CP-751,871+Exemestane)	Exemestane	CP-751,871 + Exemestane (after Exemestane)
Total subjects affected by serious adverse events
subjects affected / exposed	38 / 115 (33.04%)	11 / 36 (30.56%)	23 / 104 (22.12%)	15 / 43 (34.88%)
number of deaths (all causes)	12	3	8	6
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 7	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphangiosis carcinomatosa
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	2 / 104 (1.92%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord neoplasm
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vulval cancer
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Haemorrhage
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Venous insufficiency
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Open reduction of fracture
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	5 / 115 (4.35%)	2 / 36 (5.56%)	4 / 104 (3.85%)	6 / 43 (13.95%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 4	0 / 7
deaths causally related to treatment / all	1 / 7	0 / 2	0 / 7	0 / 6
Asthenia
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	2 / 115 (1.74%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Apnoea
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Organising pneumonia
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	2 / 104 (1.92%)	2 / 43 (4.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Insomnia
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Subdural haematoma
subjects affected / exposed	2 / 115 (1.74%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 115 (0.87%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scapula fracture
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Balance disorder
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Grand mal convulsion
subjects affected / exposed	2 / 115 (1.74%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sensory loss
subjects affected / exposed	2 / 115 (1.74%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	2 / 115 (1.74%)	0 / 36 (0.00%)	2 / 104 (1.92%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Macular fibrosis
subjects affected / exposed	1 / 115 (0.87%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 115 (0.87%)	1 / 36 (2.78%)	1 / 104 (0.96%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal rigidity
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	0 / 104 (0.00%)	2 / 43 (4.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal toxicity
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	3 / 115 (2.61%)	0 / 36 (0.00%)	1 / 104 (0.96%)	2 / 43 (4.65%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Portal vein thrombosis
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin mass
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	3 / 104 (2.88%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	2 / 115 (1.74%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphangitis
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	2 / 115 (1.74%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 115 (1.74%)	0 / 36 (0.00%)	2 / 104 (1.92%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 115 (0.00%)	1 / 36 (2.78%)	2 / 104 (1.92%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	8 / 115 (6.96%)	0 / 36 (0.00%)	0 / 104 (0.00%)	2 / 43 (4.65%)
occurrences causally related to treatment / all	8 / 10	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	CP-751,871 + Exemestane	CP-751,871 + Fulvestrant (after CP-751,871+Exemestane)	Exemestane	CP-751,871 + Exemestane (after Exemestane)
Total subjects affected by non serious adverse events
subjects affected / exposed	113 / 115 (98.26%)	34 / 36 (94.44%)	96 / 104 (92.31%)	43 / 43 (100.00%)
Vascular disorders
Hot flush
subjects affected / exposed	13 / 115 (11.30%)	5 / 36 (13.89%)	25 / 104 (24.04%)	7 / 43 (16.28%)
occurrences all number	18	7	35	13
Hypertension
subjects affected / exposed	14 / 115 (12.17%)	3 / 36 (8.33%)	4 / 104 (3.85%)	3 / 43 (6.98%)
occurrences all number	17	6	6	3
General disorders and administration site conditions
Asthenia
subjects affected / exposed	17 / 115 (14.78%)	3 / 36 (8.33%)	13 / 104 (12.50%)	8 / 43 (18.60%)
occurrences all number	28	5	18	10
Chest pain
subjects affected / exposed	8 / 115 (6.96%)	2 / 36 (5.56%)	8 / 104 (7.69%)	1 / 43 (2.33%)
occurrences all number	11	3	10	2
Fatigue
subjects affected / exposed	35 / 115 (30.43%)	11 / 36 (30.56%)	33 / 104 (31.73%)	16 / 43 (37.21%)
occurrences all number	66	17	57	36
Influenza like illness
subjects affected / exposed	6 / 115 (5.22%)	1 / 36 (2.78%)	2 / 104 (1.92%)	0 / 43 (0.00%)
occurrences all number	7	1	2	0
Injection site pain
subjects affected / exposed	0 / 115 (0.00%)	2 / 36 (5.56%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences all number	0	2	0	0
Oedema peripheral
subjects affected / exposed	5 / 115 (4.35%)	1 / 36 (2.78%)	10 / 104 (9.62%)	3 / 43 (6.98%)
occurrences all number	7	2	19	3
Pain
subjects affected / exposed	7 / 115 (6.09%)	2 / 36 (5.56%)	8 / 104 (7.69%)	6 / 43 (13.95%)
occurrences all number	10	2	10	15
Pyrexia
subjects affected / exposed	11 / 115 (9.57%)	1 / 36 (2.78%)	5 / 104 (4.81%)	1 / 43 (2.33%)
occurrences all number	13	1	5	1
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	6 / 115 (5.22%)	2 / 36 (5.56%)	10 / 104 (9.62%)	5 / 43 (11.63%)
occurrences all number	8	5	15	6
Pelvic pain
subjects affected / exposed	4 / 115 (3.48%)	2 / 36 (5.56%)	3 / 104 (2.88%)	1 / 43 (2.33%)
occurrences all number	5	2	4	1
Vulvovaginal dryness
subjects affected / exposed	6 / 115 (5.22%)	3 / 36 (8.33%)	3 / 104 (2.88%)	1 / 43 (2.33%)
occurrences all number	6	4	3	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	23 / 115 (20.00%)	4 / 36 (11.11%)	17 / 104 (16.35%)	7 / 43 (16.28%)
occurrences all number	33	6	26	7
Dyspnoea
subjects affected / exposed	19 / 115 (16.52%)	6 / 36 (16.67%)	14 / 104 (13.46%)	0 / 43 (0.00%)
occurrences all number	29	9	22	0
Dyspnoea exertional
subjects affected / exposed	7 / 115 (6.09%)	0 / 36 (0.00%)	2 / 104 (1.92%)	1 / 43 (2.33%)
occurrences all number	11	0	3	1
Epistaxis
subjects affected / exposed	15 / 115 (13.04%)	3 / 36 (8.33%)	2 / 104 (1.92%)	1 / 43 (2.33%)
occurrences all number	23	3	2	1
Oropharyngeal pain
subjects affected / exposed	8 / 115 (6.96%)	0 / 36 (0.00%)	0 / 104 (0.00%)	3 / 43 (6.98%)
occurrences all number	8	0	0	3
Psychiatric disorders
Anxiety
subjects affected / exposed	8 / 115 (6.96%)	2 / 36 (5.56%)	4 / 104 (3.85%)	3 / 43 (6.98%)
occurrences all number	11	2	8	9
Confusional state
subjects affected / exposed	7 / 115 (6.09%)	2 / 36 (5.56%)	3 / 104 (2.88%)	2 / 43 (4.65%)
occurrences all number	8	2	4	3
Depression
subjects affected / exposed	13 / 115 (11.30%)	4 / 36 (11.11%)	15 / 104 (14.42%)	12 / 43 (27.91%)
occurrences all number	17	4	18	22
Insomnia
subjects affected / exposed	13 / 115 (11.30%)	2 / 36 (5.56%)	15 / 104 (14.42%)	5 / 43 (11.63%)
occurrences all number	19	3	21	12
Investigations
Alanine aminotransferase increased
subjects affected / exposed	9 / 115 (7.83%)	1 / 36 (2.78%)	3 / 104 (2.88%)	0 / 43 (0.00%)
occurrences all number	14	1	3	0
Aspartate aminotransferase increased
subjects affected / exposed	6 / 115 (5.22%)	1 / 36 (2.78%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences all number	8	1	1	0
Blood creatinine increased
subjects affected / exposed	6 / 115 (5.22%)	2 / 36 (5.56%)	1 / 104 (0.96%)	2 / 43 (4.65%)
occurrences all number	9	4	3	3
Gamma-glutamyltransferase increased
subjects affected / exposed	15 / 115 (13.04%)	3 / 36 (8.33%)	2 / 104 (1.92%)	2 / 43 (4.65%)
occurrences all number	32	7	2	3
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 115 (0.00%)	0 / 36 (0.00%)	1 / 104 (0.96%)	3 / 43 (6.98%)
occurrences all number	0	0	1	5
Weight decreased
subjects affected / exposed	34 / 115 (29.57%)	10 / 36 (27.78%)	5 / 104 (4.81%)	14 / 43 (32.56%)
occurrences all number	65	20	13	28
Cardiac disorders
Palpitations
subjects affected / exposed	7 / 115 (6.09%)	1 / 36 (2.78%)	6 / 104 (5.77%)	0 / 43 (0.00%)
occurrences all number	10	2	7	0
Nervous system disorders
Amnesia
subjects affected / exposed	3 / 115 (2.61%)	2 / 36 (5.56%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences all number	3	2	0	0
Dizziness
subjects affected / exposed	21 / 115 (18.26%)	3 / 36 (8.33%)	13 / 104 (12.50%)	6 / 43 (13.95%)
occurrences all number	37	3	16	6
Dysgeusia
subjects affected / exposed	21 / 115 (18.26%)	2 / 36 (5.56%)	1 / 104 (0.96%)	7 / 43 (16.28%)
occurrences all number	29	3	1	10
Headache
subjects affected / exposed	29 / 115 (25.22%)	7 / 36 (19.44%)	23 / 104 (22.12%)	13 / 43 (30.23%)
occurrences all number	87	8	30	14
Hypoaesthesia
subjects affected / exposed	2 / 115 (1.74%)	4 / 36 (11.11%)	3 / 104 (2.88%)	1 / 43 (2.33%)
occurrences all number	5	4	3	1
Neuropathy peripheral
subjects affected / exposed	6 / 115 (5.22%)	3 / 36 (8.33%)	5 / 104 (4.81%)	1 / 43 (2.33%)
occurrences all number	7	4	5	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	8 / 115 (6.96%)	3 / 36 (8.33%)	9 / 104 (8.65%)	5 / 43 (11.63%)
occurrences all number	13	5	13	6
Thrombocytopenia
subjects affected / exposed	5 / 115 (4.35%)	2 / 36 (5.56%)	1 / 104 (0.96%)	1 / 43 (2.33%)
occurrences all number	10	3	1	1
Ear and labyrinth disorders
Deafness
subjects affected / exposed	7 / 115 (6.09%)	2 / 36 (5.56%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences all number	8	4	0	0
Ear pain
subjects affected / exposed	2 / 115 (1.74%)	2 / 36 (5.56%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences all number	3	4	0	0
Hypoacusis
subjects affected / exposed	6 / 115 (5.22%)	1 / 36 (2.78%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences all number	7	1	0	0
Tinnitus
subjects affected / exposed	7 / 115 (6.09%)	0 / 36 (0.00%)	2 / 104 (1.92%)	2 / 43 (4.65%)
occurrences all number	13	0	2	3
Vertigo
subjects affected / exposed	8 / 115 (6.96%)	3 / 36 (8.33%)	2 / 104 (1.92%)	0 / 43 (0.00%)
occurrences all number	9	5	2	0
Eye disorders
Dry eye
subjects affected / exposed	7 / 115 (6.09%)	1 / 36 (2.78%)	4 / 104 (3.85%)	1 / 43 (2.33%)
occurrences all number	8	2	4	2
Eye pain
subjects affected / exposed	3 / 115 (2.61%)	2 / 36 (5.56%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences all number	3	2	0	2
Lacrimation increased
subjects affected / exposed	6 / 115 (5.22%)	1 / 36 (2.78%)	3 / 104 (2.88%)	1 / 43 (2.33%)
occurrences all number	8	1	3	1
Vision blurred
subjects affected / exposed	7 / 115 (6.09%)	2 / 36 (5.56%)	1 / 104 (0.96%)	1 / 43 (2.33%)
occurrences all number	8	3	1	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	12 / 115 (10.43%)	3 / 36 (8.33%)	11 / 104 (10.58%)	3 / 43 (6.98%)
occurrences all number	17	4	12	4
Abdominal pain upper
subjects affected / exposed	9 / 115 (7.83%)	1 / 36 (2.78%)	6 / 104 (5.77%)	3 / 43 (6.98%)
occurrences all number	12	2	8	4
Constipation
subjects affected / exposed	29 / 115 (25.22%)	8 / 36 (22.22%)	16 / 104 (15.38%)	7 / 43 (16.28%)
occurrences all number	39	9	23	13
Diarrhoea
subjects affected / exposed	37 / 115 (32.17%)	8 / 36 (22.22%)	22 / 104 (21.15%)	12 / 43 (27.91%)
occurrences all number	66	14	42	22
Dry mouth
subjects affected / exposed	15 / 115 (13.04%)	2 / 36 (5.56%)	5 / 104 (4.81%)	5 / 43 (11.63%)
occurrences all number	17	2	5	6
Dyspepsia
subjects affected / exposed	9 / 115 (7.83%)	4 / 36 (11.11%)	9 / 104 (8.65%)	3 / 43 (6.98%)
occurrences all number	11	4	12	4
Dysphagia
subjects affected / exposed	3 / 115 (2.61%)	2 / 36 (5.56%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences all number	3	2	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	4 / 115 (3.48%)	2 / 36 (5.56%)	1 / 104 (0.96%)	2 / 43 (4.65%)
occurrences all number	5	3	1	3
Haemorrhoids
subjects affected / exposed	6 / 115 (5.22%)	2 / 36 (5.56%)	2 / 104 (1.92%)	1 / 43 (2.33%)
occurrences all number	8	3	2	1
Nausea
subjects affected / exposed	35 / 115 (30.43%)	8 / 36 (22.22%)	19 / 104 (18.27%)	15 / 43 (34.88%)
occurrences all number	66	9	31	24
Stomatitis
subjects affected / exposed	8 / 115 (6.96%)	4 / 36 (11.11%)	0 / 104 (0.00%)	1 / 43 (2.33%)
occurrences all number	15	5	0	1
Toothache
subjects affected / exposed	10 / 115 (8.70%)	2 / 36 (5.56%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences all number	11	3	1	0
Vomiting
subjects affected / exposed	23 / 115 (20.00%)	4 / 36 (11.11%)	6 / 104 (5.77%)	7 / 43 (16.28%)
occurrences all number	32	4	8	20
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	16 / 115 (13.91%)	2 / 36 (5.56%)	8 / 104 (7.69%)	3 / 43 (6.98%)
occurrences all number	20	3	12	4
Dry skin
subjects affected / exposed	15 / 115 (13.04%)	2 / 36 (5.56%)	3 / 104 (2.88%)	2 / 43 (4.65%)
occurrences all number	20	2	3	3
Hypertrichosis
subjects affected / exposed	2 / 115 (1.74%)	2 / 36 (5.56%)	0 / 104 (0.00%)	0 / 43 (0.00%)
occurrences all number	3	2	0	0
Onychoclasis
subjects affected / exposed	25 / 115 (21.74%)	11 / 36 (30.56%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences all number	33	16	1	0
Pruritus
subjects affected / exposed	16 / 115 (13.91%)	2 / 36 (5.56%)	6 / 104 (5.77%)	4 / 43 (9.30%)
occurrences all number	23	3	6	9
Rash
subjects affected / exposed	7 / 115 (6.09%)	0 / 36 (0.00%)	4 / 104 (3.85%)	2 / 43 (4.65%)
occurrences all number	11	0	4	4
Skin lesion
subjects affected / exposed	1 / 115 (0.87%)	2 / 36 (5.56%)	3 / 104 (2.88%)	1 / 43 (2.33%)
occurrences all number	1	2	4	2
Renal and urinary disorders
Dysuria
subjects affected / exposed	11 / 115 (9.57%)	1 / 36 (2.78%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences all number	17	1	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	29 / 115 (25.22%)	10 / 36 (27.78%)	41 / 104 (39.42%)	16 / 43 (37.21%)
occurrences all number	61	18	80	25
Back pain
subjects affected / exposed	30 / 115 (26.09%)	6 / 36 (16.67%)	18 / 104 (17.31%)	11 / 43 (25.58%)
occurrences all number	48	12	30	21
Bone pain
subjects affected / exposed	7 / 115 (6.09%)	3 / 36 (8.33%)	11 / 104 (10.58%)	4 / 43 (9.30%)
occurrences all number	9	3	18	5
Flank pain
subjects affected / exposed	5 / 115 (4.35%)	2 / 36 (5.56%)	3 / 104 (2.88%)	3 / 43 (6.98%)
occurrences all number	6	2	5	5
Joint stiffness
subjects affected / exposed	3 / 115 (2.61%)	0 / 36 (0.00%)	3 / 104 (2.88%)	3 / 43 (6.98%)
occurrences all number	4	0	3	4
Muscle spasms
subjects affected / exposed	41 / 115 (35.65%)	12 / 36 (33.33%)	4 / 104 (3.85%)	8 / 43 (18.60%)
occurrences all number	69	18	5	24
Muscular weakness
subjects affected / exposed	6 / 115 (5.22%)	0 / 36 (0.00%)	1 / 104 (0.96%)	0 / 43 (0.00%)
occurrences all number	8	0	1	0
Musculoskeletal chest pain
subjects affected / exposed	7 / 115 (6.09%)	2 / 36 (5.56%)	10 / 104 (9.62%)	7 / 43 (16.28%)
occurrences all number	11	2	18	16
Musculoskeletal pain
subjects affected / exposed	18 / 115 (15.65%)	5 / 36 (13.89%)	15 / 104 (14.42%)	9 / 43 (20.93%)
occurrences all number	28	8	23	13
Myalgia
subjects affected / exposed	11 / 115 (9.57%)	2 / 36 (5.56%)	9 / 104 (8.65%)	9 / 43 (20.93%)
occurrences all number	22	2	9	10
Neck pain
subjects affected / exposed	9 / 115 (7.83%)	1 / 36 (2.78%)	7 / 104 (6.73%)	5 / 43 (11.63%)
occurrences all number	15	1	9	8
Pain in extremity
subjects affected / exposed	19 / 115 (16.52%)	7 / 36 (19.44%)	16 / 104 (15.38%)	8 / 43 (18.60%)
occurrences all number	24	11	30	18
Pain in jaw
subjects affected / exposed	1 / 115 (0.87%)	2 / 36 (5.56%)	2 / 104 (1.92%)	2 / 43 (4.65%)
occurrences all number	1	3	2	3
Infections and infestations
Cystitis
subjects affected / exposed	6 / 115 (5.22%)	0 / 36 (0.00%)	5 / 104 (4.81%)	3 / 43 (6.98%)
occurrences all number	9	0	8	3
Nasopharyngitis
subjects affected / exposed	13 / 115 (11.30%)	0 / 36 (0.00%)	9 / 104 (8.65%)	0 / 43 (0.00%)
occurrences all number	17	0	13	0
Sinusitis
subjects affected / exposed	6 / 115 (5.22%)	1 / 36 (2.78%)	2 / 104 (1.92%)	0 / 43 (0.00%)
occurrences all number	6	1	2	0
Upper respiratory tract infection
subjects affected / exposed	7 / 115 (6.09%)	0 / 36 (0.00%)	7 / 104 (6.73%)	2 / 43 (4.65%)
occurrences all number	10	0	7	2
Urinary tract infection
subjects affected / exposed	21 / 115 (18.26%)	3 / 36 (8.33%)	8 / 104 (7.69%)	8 / 43 (18.60%)
occurrences all number	35	3	10	8
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	41 / 115 (35.65%)	13 / 36 (36.11%)	13 / 104 (12.50%)	13 / 43 (30.23%)
occurrences all number	64	25	20	18
Dehydration
subjects affected / exposed	1 / 115 (0.87%)	0 / 36 (0.00%)	1 / 104 (0.96%)	3 / 43 (6.98%)
occurrences all number	1	0	1	3
Hyperglycaemia
subjects affected / exposed	50 / 115 (43.48%)	9 / 36 (25.00%)	4 / 104 (3.85%)	9 / 43 (20.93%)
occurrences all number	134	23	23	20
Hyperuricaemia
subjects affected / exposed	4 / 115 (3.48%)	0 / 36 (0.00%)	0 / 104 (0.00%)	3 / 43 (6.98%)
occurrences all number	4	0	0	4

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Were there any global substantial amendments to the protocol? Yes

21 Dec 2009

1. Patients with any history of unstable angina, myocardial infarction or symptomatic congestive heart failure were to be excluded from study entry. In addition, future patients with a requirement for inotropic support or serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation) within 3 years prior to screening would be excluded from study entry. Patients requiring the use of pacemakers and/or implanted defibrillators were excluded from study participations. 2. Patients must have a screening hemoglobin A1C lower than 5.7% for their inclusion.

09 Dec 2010

1. Stop collection of blood samples for circulating tumor cell evaluation, biomarker analysis, PK and HAHA analysis. 2. Patients who experienced disease progression would no longer be allowed to routinely cross over to receive Salvage Therapy.

19 Jun 2012

Definition of adverse event updated to include addition of medication error.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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A two-arm randomized open label phase 2 study of CP-751,871 in combination with Exemestane versus Exemestane alone as first line treatment for postmenopausal patients with hormone receptor positive advanced breast cancer

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End points

End points

Primary: Primary: Progression-Free Survival (PFS)

Primary: Primary: Progression-Free Survival (PFS)

Primary: PFS in Subjects with Hemoglobin A1c (HbA1c) Less than (<) 5.7% at Baseline

Primary: PFS in Subjects with Hemoglobin A1c (HbA1c) Less than (<) 5.7% at Baseline

Secondary: Percentage of Subjects Achieving Complete Response (CR), Partial Response (PR), or Stable Disease (SD) Maintained for at Least 6 Months

Secondary: Percentage of Subjects Achieving Complete Response (CR), Partial Response (PR), or Stable Disease (SD) Maintained for at Least 6 Months

Secondary: Maximum Plasma Concentration of CP-751,871

Secondary: Maximum Plasma Concentration of CP-751,871

Secondary: Minimum Plasma Concentration of CP-751,871

Secondary: Minimum Plasma Concentration of CP-751,871

Secondary: Area Under the Concentration Time Curve from Time 0 to the Last Time Point with Quantifiable Concentration

Secondary: Area Under the Concentration Time Curve from Time 0 to the Last Time Point with Quantifiable Concentration

Secondary: Number of Subjects with Negative Human Anti-Human Antibodies (HAHAs)

Secondary: Number of Subjects with Negative Human Anti-Human Antibodies (HAHAs)

Secondary: Percentage of subjects with Circulating Tumor Cells Expressing Insulin-Like Growth Factor 1 Receptor (IGF-IR)

Secondary: Percentage of subjects with Circulating Tumor Cells Expressing Insulin-Like Growth Factor 1 Receptor (IGF-IR)

Secondary: Percentage of Subjects with Serum Markers Relevant to the IGF-1R Pathway

Secondary: Percentage of Subjects with Serum Markers Relevant to the IGF-1R Pathway

Secondary: European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 (QLQ-C30) Scores

Secondary: European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 (QLQ-C30) Scores

Secondary: EORTC QLQ Breast Cancer Module (BR23) Scores

Secondary: EORTC QLQ Breast Cancer Module (BR23) Scores

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A two-arm randomized open label phase 2 study of CP-751,871 in combination with Exemestane versus Exemestane alone as first line treatment for postmenopausal patients with hormone receptor positive advanced breast cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary: Progression-Free Survival (PFS)

Primary: Primary: Progression-Free Survival (PFS)

Primary: PFS in Subjects with Hemoglobin A1c (HbA1c) Less than (<) 5.7% at Baseline

Primary: PFS in Subjects with Hemoglobin A1c (HbA1c) Less than (<) 5.7% at Baseline

Secondary: Percentage of Subjects Achieving Complete Response (CR), Partial Response (PR), or Stable Disease (SD) Maintained for at Least 6 Months

Secondary: Percentage of Subjects Achieving Complete Response (CR), Partial Response (PR), or Stable Disease (SD) Maintained for at Least 6 Months

Secondary: Maximum Plasma Concentration of CP-751,871

Secondary: Maximum Plasma Concentration of CP-751,871

Secondary: Minimum Plasma Concentration of CP-751,871

Secondary: Minimum Plasma Concentration of CP-751,871

Secondary: Area Under the Concentration Time Curve from Time 0 to the Last Time Point with Quantifiable Concentration

Secondary: Area Under the Concentration Time Curve from Time 0 to the Last Time Point with Quantifiable Concentration

Secondary: Number of Subjects with Negative Human Anti-Human Antibodies (HAHAs)

Secondary: Number of Subjects with Negative Human Anti-Human Antibodies (HAHAs)

Secondary: Percentage of subjects with Circulating Tumor Cells Expressing Insulin-Like Growth Factor 1 Receptor (IGF-IR)

Secondary: Percentage of subjects with Circulating Tumor Cells Expressing Insulin-Like Growth Factor 1 Receptor (IGF-IR)

Secondary: Percentage of Subjects with Serum Markers Relevant to the IGF-1R Pathway

Secondary: Percentage of Subjects with Serum Markers Relevant to the IGF-1R Pathway

Secondary: European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 (QLQ-C30) Scores

Secondary: European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30 (QLQ-C30) Scores

Secondary: EORTC QLQ Breast Cancer Module (BR23) Scores

Secondary: EORTC QLQ Breast Cancer Module (BR23) Scores

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A two-arm randomized open label phase 2 study of CP-751,871 in combination with Exemestane versus Exemestane alone as first line treatment for postmenopausal patients with hormone receptor positive advanced breast cancer