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Clinical Trial Results:
A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced or metastatic breast cancer

Summary
EudraCT number	2016-003074-40
Trial protocol	GB ES FR
Global end of trial date	19 Jul 2021

Results information
Results version number	v4(current)
This version publication date	14 Sep 2022
First version publication date	13 Oct 2021
Other versions	v1 , v2 , v3
Version creation reason

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

201973

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS

Public contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.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

Interim

Date of interim/final analysis

05 Aug 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

29 Sep 2020

Global end of trial reached?

Yes

Global end of trial date

19 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

Main obj:Ph1-To determine recommended Ph2 dose of GSK525762,when given in combination with fulvestrant in women with advanced/metastatic hormone receptor positive human epidermal receptor 2 negative breast cancer (HR+/HER2-BC).Ph2-Evaluate effect of treatment with GSK525762&fulvestrant,when given in combination,on PFS in women with advanced/metastatic HR+/HER2-BC.

Protection of trial subjects

Not applicable

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Feb 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Korea, Republic of: 23

Country: Number of subjects enrolled

United Kingdom: 12

Country: Number of subjects enrolled

United States: 31

Country: Number of subjects enrolled

Canada: 30

Country: Number of subjects enrolled

Spain: 16

Worldwide total number of subjects

123

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This is Phase I/II study of GSK525762 in combination with fulvestrant in participants with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced/metastatic breast cancer.

Screening details

Per protocol, an interim analysis was conducted during ph 1, and following assessment of data, ph 2 was not initiated. But, all existing participants receiving treatment in ph 1, deriving benefit were continued on study (at investigators decision), until progression or death/withdrawal. 124 participants were enrolled and 1 of them was not treated.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)

Arm description

Participants with aromatose inhibitor (AI) failure received GSK525762 60 milligrams (mg) tablet orally once daily and Fulvestrant (FUL) 500 mg was administered intramuscularly (IM) on days 1, 15, 29, and once monthly thereafter.

Arm type

Experimental

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant was available as clear, colorless to yellow, viscous liquid. Participants received fulvestrant intramuscularly on days 1, 15, 29 and once a month thereafter.

Investigational medicinal product name

GSK525762

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

GSK525762 was available as white to slightly colored, round, biconvex tablet. Participants received GSK525762 orally once daily.

Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)

Arm description

Participants with Cyclin-Dependent Kinase (CDK4/6)/AI failure within 12 months received GSK525762 60 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Arm type

Experimental

Investigational medicinal product name

GSK525762

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

GSK525762 was available as white to slightly colored, round, biconvex tablet. Participants received GSK525762 orally once daily.

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant was available as clear, colorless to yellow, viscous liquid. Participants received fulvestrant intramuscularly on days 1, 15, 29 and once a month thereafter.

Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)

Arm description

Participants with CDK4/6/AI failure >=12 months received GSK525762 60 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Arm type

Experimental

Investigational medicinal product name

GSK525762

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

GSK525762 was available as white to slightly colored, round, biconvex tablet. Participants received GSK525762 orally once daily.

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant was available as clear, colorless to yellow, viscous liquid. Participants received fulvestrant intramuscularly on days 1, 15, 29 and once a month thereafter.

PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis

Arm description

Participants with CDK4/6/AI failure >=12 months with bone only disease received GSK525762 60 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Arm type

Experimental

Investigational medicinal product name

GSK525762

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

GSK525762 was available as white to slightly colored, round, biconvex tablet. Participants received GSK525762 orally once daily.

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant was available as clear, colorless to yellow, viscous liquid. Participants received fulvestrant intramuscularly on days 1, 15, 29 and once a month thereafter.

Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)

Arm description

Participants with AI failure received GSK525762 80 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Arm type

Experimental

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant was available as clear, colorless to yellow, viscous liquid. Participants received fulvestrant intramuscularly on days 1, 15, 29 and once a month thereafter.

Investigational medicinal product name

GSK525762

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

GSK525762 was available as white to slightly colored, round, biconvex tablet. Participants received GSK525762 orally once daily.

Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)

Arm description

Participants with CDK4/6/AI failure received GSK525762 80 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Arm type

Experimental

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant was available as clear, colorless to yellow, viscous liquid. Participants received fulvestrant intramuscularly on days 1, 15, 29 and once a month thereafter.

Investigational medicinal product name

GSK525762

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

GSK525762 was available as white to slightly colored, round, biconvex tablet. Participants received GSK525762 orally once daily.

Number of subjects in period 1	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Started	33	12	42	7	18	11
Completed	7	1	17	1	2	3
Not completed	26	11	25	6	16	8
Adverse event, serious fatal	11	9	12	2	10	5
Consent withdrawn by subject	1	-	1	1	-	1
Physician decision	2	-	3	-	1	-
Study terminated by Sponsor	9	1	9	3	3	2
Protocol specified Withdrawal criteria met	-	1	-	-	1	-
Unknown	3	-	-	-	1	-

Baseline characteristics

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Reporting group title

Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)

Reporting group description

Reporting group title

Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)

Reporting group description

Reporting group title

Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)

Reporting group description

Participants with CDK4/6/AI failure >=12 months received GSK525762 60 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Reporting group title

PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis

Reporting group description

Reporting group title

Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)

Reporting group description

Participants with AI failure received GSK525762 80 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Reporting group title

Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)

Reporting group description

Participants with CDK4/6/AI failure received GSK525762 80 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Reporting group values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)	Total
Number of subjects	33	12	42	7	18	11	123
Age categorical
The interim analysis failed to demonstrate clinically meaningful activity, hence Phase II was not initiated.
Units: Participants
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	19	12	34	5	15	11	96
From 65-84 years	14	0	8	2	3	0	27
85 years and over	0	0	0	0	0	0	0
Age Continuous
The interim analysis failed to demonstrate clinically meaningful activity, hence Phase II was not initiated.
Units: years
arithmetic mean (standard deviation)	60.6 ± 9.40	53.3 ± 8.48	55.7 ± 9.82	58.7 ± 7.97	54.4 ± 8.45	51.5 ± 12.04	-
Sex: Female, Male
The interim analysis failed to demonstrate clinically meaningful activity, hence Phase II was not initiated.
Units: Participants
Female	33	12	42	7	18	11	123
Male	0	0	0	0	0	0	0
Race/Ethnicity, Customized
The interim analysis failed to demonstrate clinically meaningful activity, hence Phase II was not initiated.
Units: Subjects
Central south Asian Heritage	0	0	1	0	0	0	1
East Asian Heritage	7	2	8	1	6	2	26
Japanese Heritage	1	0	0	0	0	0	1
South East Asian Heritage	1	0	0	0	0	1	2
Black or African American	2	1	2	1	1	1	8
Arabic/North African Heritage	1	0	2	0	0	0	3
White/Caucasian/European Heritage	19	8	28	5	11	7	78
Multiple	1	1	0	0	0	0	2
Missing	1	0	1	0	0	0	2

End points

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Reporting group title

Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)

Reporting group description

Reporting group title

Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)

Reporting group description

Reporting group title

Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)

Reporting group description

Participants with CDK4/6/AI failure >=12 months received GSK525762 60 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Reporting group title

PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis

Reporting group description

Reporting group title

Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)

Reporting group description

Participants with AI failure received GSK525762 80 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Reporting group title

Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)

Reporting group description

Participants with CDK4/6/AI failure received GSK525762 80 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Primary: Phase I: Number of participants with adverse events (AEs) and serious adverse events (SAEs)

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End point title

Phase I: Number of participants with adverse events (AEs) and serious adverse events (SAEs) ^[1]

End point description

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, any other situation such as important medical events according to medical or scientific judgement or is associated with liver injury and impaired liver function. Any other adverse event apart from SAE is considered as non-SAE. All Treated Population consisted of participants who received at least one dose of study treatment (GSK525762 or fulvestrant).

End point type

Primary

End point timeframe

Up to 3 year and 8 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There are no statistical data to report

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	33 ^[2]	12 ^[3]	42 ^[4]	7 ^[5]	18 ^[6]	11 ^[7]
Units: Participants
Non-serious AEs	33	12	42	7	18	11
SAEs	5	1	10	3	6	2

Notes
[2] - All Treated Population
[3] - All Treated Population
[4] - All Treated Population
[5] - All Treated Population
[6] - All Treated Population
[7] - All Treated Population

No statistical analyses for this end point

Primary: Phase I: Number of participants with dose limiting toxicities (DLTs)

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End point title

Phase I: Number of participants with dose limiting toxicities (DLTs) ^[8]

End point description

An event was considered DLT if it occurred within first 28 days of treatment and met one of following DLT criteria: Grade3 or greater neutropenia for >=5 days, febrile neutropenia, Grade4 anemia of any duration, Grade4 thrombocytopenia of any duration or Grade3 thrombocytopenia with bleeding, alanine aminotransferase (ALT) >3 times (x) upper limit of normal (ULN)+bilirubin >=2xULN (>35% direct) or ALT between 3-5xULN with bilirubin <2xULN but with hepatitis symptoms or rash, Grade3 nausea,vomiting or diarrhea that did not improve within 72hour despite appropriate supportive treatment(s), Grade4 nausea,vomiting,or diarrhea, Grade3 hypertension (uncontrolled despite addition of upto 2 antihypertensive medications), Grade4 hypertension, other Grade3 or greater clinically significant non-hematologic toxicity (including QT duration corrected for heart rate by Fridericia’s formula (QTcF), ejection fraction <lower limit of normal (LLN) with an absolute decrease of >10% from Baseline.

End point type

Primary

End point timeframe

Up to 28 days

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There are no statistical data to report

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	33 ^[9]	12 ^[10]	42 ^[11]	7 ^[12]	18 ^[13]	11 ^[14]
Units: Participants	2	0	1	1	0	2

Notes
[9] - All Treated Population
[10] - All Treated Population
[11] - All Treated Population
[12] - All Treated Population
[13] - All Treated Population
[14] - All Treated Population

No statistical analyses for this end point

Primary: Phase I: Number of participants with dose reductions and dose interruption/delays

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End point title

Phase I: Number of participants with dose reductions and dose interruption/delays ^[15]

End point description

Number of participants with dose reductions and dose interruption or delay due to any reason is presented.

End point type

Primary

End point timeframe

Up to 3 year and 8 months

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There are no statistical data to report

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	33 ^[16]	12 ^[17]	42 ^[18]	7 ^[19]	18 ^[20]	11 ^[21]
Units: Participants
Dose reduction	9	3	14	3	7	8
Dose interruption/delay	23	9	23	4	15	9

Notes
[16] - All Treated Population
[17] - All Treated Population
[18] - All Treated Population
[19] - All Treated Population
[20] - All Treated Population
[21] - All Treated Population

No statistical analyses for this end point

Primary: Phase I: Objective response rate-Investigator assessment

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End point title

Phase I: Objective response rate-Investigator assessment ^[22]

End point description

Objective Response Rate is defined as the percentage of participants who demonstrate a Best Response of confirmed complete response (CR) or partial response (PR), as assessed by the investigator per response evaluation criteria in solid tumors (RECIST) version (v) 1.1 criteria. Modified All Treated Population consisted of all participants who received at least one dose of GSK525762 and fulvestrant.

End point type

Primary

End point timeframe

Up to 3 year and 8 months

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There are no statistical data to report

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	33 ^[23]	12 ^[24]	42 ^[25]	7 ^[26]	18 ^[27]	11 ^[28]
Units: Percentage of participants
number (confidence interval 95%)	21 (9.0 to 38.9)	0 (0.0 to 26.5)	12 (4.0 to 25.6)	0 (0.0 to 41.0)	17 (3.6 to 41.4)	9 (0.2 to 41.3)

Notes
[23] - Modified All Treated Population
[24] - Modified All Treated Population
[25] - Modified All Treated Population
[26] - Modified All Treated Population
[27] - Modified All Treated Population
[28] - Modified All Treated Population

No statistical analyses for this end point

Primary: Phase I: Plasma concentration of GSK525762

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End point title

Phase I: Plasma concentration of GSK525762 ^[29]

End point description

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK525762. PK Population comprised of participants from the All Treated Population for whom a PK sample was obtained and analyzed. Only those participants with data available at the indicated time points were analyzed (indicated by n=X in category titles). 99999 indicates no concentration values were detected for pre-dose. 88888 indicates standard deviation could not be calculated due to single participant. 77777 indicates standard deviation could not be calculated due to high proportion of non-quantifiable (NQ) values (more than [>] 30 percent [%] of values were imputed. 66666 indicates data is not available.

End point type

Primary

End point timeframe

Day 1: Pre-dose, 0.5, 1, 3 hours on Weeks 1 and 3; Day 1: Pre-dose, 0.5-1, 4-8 hours on Week 5; Day 1: Pre-dose, 0.5-1 hour on Weeks 9, 17, 25

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There are no statistical data to report

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	31 ^[30]	12 ^[31]	41 ^[32]	7 ^[33]	18 ^[34]	11 ^[35]
Units: Nanograms per milliliter
arithmetic mean (standard deviation)
Week 1 Day 1, Pre-dose, n=30,11,41,7,17,11	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999
Week 1 Day 1, 0.5 hour, n=31,11,40,7,17,10	895.466 ± 520.7900	814.364 ± 465.7197	824.081 ± 605.1745	646.251 ± 537.3585	969.265 ± 659.5862	1155.300 ± 329.8983
Week 1 Day 1, 1 hour, n=31,10,40,7,18,10	855.734 ± 374.3789	828.800 ± 216.0544	947.343 ± 443.7234	634.300 ± 331.3116	1061.722 ± 397.9207	1069.400 ± 269.4864
Week 1 Day 1, 3 hours, n=31,10,39,6,17,10	637.097 ± 220.5013	526.400 ± 106.3591	717.769 ± 293.5412	732.833 ± 394.3660	831.176 ± 293.0363	782.600 ± 191.9283
Week 3 Day 1, Pre-dose, n=29,12,31,5,16,8	7.046 ± 8.2049	15.797 ± 20.7736	8.598 ± 13.2639	150.410 ± 295.0514	11.371 ± 17.8450	6.799 ± 5.7108
Week 3 Day 1, 0.5 hour, n=28,11,29,4,13,7	766.179 ± 330.0370	680.936 ± 435.2668	504.516 ± 342.6658	730.250 ± 410.6356	808.846 ± 548.7639	917.714 ± 498.7183
Week 3 Day 1, 1 hour, n=28,11,30,5,13,7	737.536 ± 310.4540	576.427 ± 298.5082	581.073 ± 273.6803	596.800 ± 134.6540	875.077 ± 343.5570	895.286 ± 358.3172
Week 3 Day 1, 3 hours, n=28,10,29,5,13,7	423.500 ± 190.6163	447.700 ± 179.1889	369.179 ± 171.4981	422.800 ± 120.6512	471.154 ± 160.2908	523.714 ± 207.9308
Week 5 Day 1, Pre-dose, n=26,9,34,5,14,10	5.804 ± 7.7777	15.251 ± 18.1145	66.527 ± 198.8847	15.814 ± 21.5282	14.603 ± 17.0653	77.465 ± 217.4469
Week 5 Day 1, 0.5-1 hour, n=24,7,26,3,11,7	640.700 ± 380.5152	463.854 ± 476.0195	555.237 ± 336.1938	705.667 ± 208.2218	685.773 ± 446.6621	457.229 ± 301.9096
Week 5 Day 1, 4-8 hours, n=6,1,9,1,5,0	306.900 ± 153.8008	145.000 ± 88888	303.000 ± 177.1489	431.000 ± 88888	352.400 ± 98.5890	66666 ± 66666
Week 9 Day 1, Pre-dose, n=17,2,23,2,10,4	7.257 ± 11.2876	5.055 ± 0.7142	9.000 ± 13.3106	3.265 ± 77777	16.469 ± 23.7102	6.640 ± 7.0298
Week 9 Day 1, 0.5-1 hour, n=13,1,17,2,6,3	607.408 ± 528.6891	69.400 ± 88888	445.291 ± 388.9562	817.000 ± 287.0854	621.867 ± 440.4829	309.627 ± 375.4223
Week 17 Day 1, Pre-dose, n=11,2,8,2,6,3	9.401 ± 13.0880	1.365 ± 77777	3.591 ± 77777	16.850 ± 2.0506	7.217 ± 10.1456	7.270 ± 77777
Week 17 Day 1, 0.5-1 hour, n=9,2,9,2,4,1	372.778 ± 214.7812	32.100 ± 30.2642	521.241 ± 404.3103	270.000 ± 354.9676	640.000 ± 273.7846	214.000 ± 88888
Week 25 Day 1, Pre-dose, n=9,1,5,2,4,1	34.847 ± 92.3723	99999 ± 99999	10.198 ± 10.4909	10.740 ± 9.1358	1.560 ± 77777	99999 ± 99999
Week 25 Day 1, 0.5-1 hour, n=5,0,6,2,2,1	418.000 ± 173.5439	66666 ± 66666	380.483 ± 338.1430	251.350 ± 225.7792	314.000 ± 90.5097	186.000 ± 88888

Notes
[30] - PK Population
[31] - PK Population
[32] - PK Population
[33] - PK Population
[34] - PK Population
[35] - PK Population

No statistical analyses for this end point

Secondary: Phase I: Number of participants who withdrew due to toxicity and changes in Safety Assessment

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End point title

Phase I: Number of participants who withdrew due to toxicity and changes in Safety Assessment

End point description

Number of participants who withdrew due to toxicity and changes in safety assessment including laboratory parameters and vital signs have been presented.

End point type

Secondary

End point timeframe

Up to 4 year and 4 months

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	33 ^[36]	12 ^[37]	42 ^[38]	7 ^[39]	18 ^[40]	11 ^[41]
Units: Participants	6	0	6	2	1	2

Notes
[36] - All Treated Population
[37] - All Treated Population
[38] - All Treated Population
[39] - All Treated Population
[40] - All Treated Population
[41] - All Treated Population

No statistical analyses for this end point

Secondary: Phase I: Disease control rate (DCR)

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End point title

Phase I: Disease control rate (DCR)

End point description

DCR is defined as the percentage of participants in the population with a confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) lasting >=6 months, as assessed by the investigator per RECIST v1.1 criteria.

End point type

Secondary

End point timeframe

Up to 3 year and 8 months

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	33 ^[42]	12 ^[43]	42 ^[44]	7 ^[45]	18 ^[46]	11 ^[47]
Units: Percentage of participants
number (confidence interval 95%)	36 (20.4 to 54.9)	0 (0.0 to 26.5)	17 (7.0 to 31.4)	14 (0.4 to 57.9)	28 (9.7 to 53.5)	9 (0.2 to 41.3)

Notes
[42] - Modified All Treated Population.
[43] - Modified All Treated Population.
[44] - Modified All Treated Population.
[45] - Modified All Treated Population.
[46] - Modified All Treated Population.
[47] - Modified All Treated Population.

No statistical analyses for this end point

Secondary: Phase I: Duration of response (DoR)

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End point title

Phase I: Duration of response (DoR)

End point description

DoR is defined as the time (in months) from date of first documented evidence of confirmed CR or PR to the date of first documented PD, as assessed by the investigator per RECIST v1.1 criteria, or to the date of death due to any cause among participants with a Best overall response (BOR) of confirmed CR or PR. Only those participants with a BOR of confirmed CR or PR based on RECIST v1.1 were analyzed hence N=0 for Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M) and Phase I-GSK525762 60+FUL500mg CDK4/6+AI Failure>=12M Bone Only Disease arms. 55555 indicates <75% of participants experienced the event within the treatment arm. Hence, third-quartile could not be derived. 99999 indicates that Inter-quartile range is not applicable due to single participant, and the median value presented here is the actual DOR for this single participant.

End point type

Secondary

End point timeframe

Up to 3 year and 8 months

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	7 ^[48]	0 ^[49]	5 ^[50]	0 ^[51]	3 ^[52]	1 ^[53]
Units: Months
median (inter-quartile range (Q1-Q3))	13.1 (6.5 to 26.3)	( to )	5.8 (5.7 to 55555)	( to )	14.0 (5.4 to 16.4)	4.3 (-99999 to 99999)

Notes
[48] - Modified All Treated Population.
[49] - Modified All Treated Population.
[50] - Modified All Treated Population.
[51] - Modified All Treated Population.
[52] - Modified All Treated Population.
[53] - Modified All Treated Population.

No statistical analyses for this end point

Secondary: Phase I: Progression-free survival (PFS)

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End point title

Phase I: Progression-free survival (PFS)

End point description

PFS is defined as the time (in months) from the date of first dose until the date of first documented PD, as assessed by the investigator per RECIST v1.1 criteria, or date of death due to any cause, whichever occurs first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions. 55555 indicates <75% of participants experienced the event within the treatment arm. Hence, third-quartile could not be derived.

End point type

Secondary

End point timeframe

Up to 3 year and 8 months

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	33 ^[54]	12 ^[55]	42 ^[56]	7 ^[57]	18 ^[58]	11 ^[59]
Units: Months
median (inter-quartile range (Q1-Q3))	5.6 (3.5 to 14.1)	1.7 (1.6 to 2.1)	2.1 (1.7 to 7.1)	7.2 (3.7 to 55555)	4.0 (1.8 to 9.4)	1.8 (1.7 to 3.6)

Notes
[54] - Modified All Treated Population
[55] - Modified All Treated Population
[56] - Modified All Treated Population
[57] - Modified All Treated Population
[58] - Modified All Treated Population
[59] - Modified All Treated Population

No statistical analyses for this end point

Secondary: Phase I: Plasma concentration of GSK3529246

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End point title

Phase I: Plasma concentration of GSK3529246

End point description

Blood samples were collected at indicated time points for PK analysis of GSK3529246. GSK3529246 is an active metabolite of GSK525762. Only those participants with data available at the indicated time points were analyzed (indicated by n=X in category titles). 99999 indicates no concentration values were detected for pre-dose. 88888 indicates standard deviation could not be calculated due to single participant. 77777 indicates standard deviation could not be calculated due to high proportion of non-quantifiable (NQ) values (more than [>] 30 percent [%] of values were imputed. 66666 indicates data is not available.

End point type

Secondary

End point timeframe

Day 1: Pre-dose, 0.5, 1, 3 hours on Weeks 1 and 3; Day 1: Pre-dose, 0.5-1, 4-8 hours on Week 5, Day 1: pre-dose, 0.5-1 hour on Weeks 9, 17, 25

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	31 ^[60]	12 ^[61]	41 ^[62]	7 ^[63]	18 ^[64]	11 ^[65]
Units: Nanograms per milliliter
arithmetic mean (standard deviation)
Week 1 Day 1, Pre-dose, n=30,11,41,7,17,11	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999
Week 1 Day 1, 0.5 hour, n=31,11,39, 7,17,10	174.474 ± 143.3693	126.818 ± 84.5894	135.012 ± 128.9738	115.419 ± 108.8723	202.224 ± 225.2895	186.970 ± 108.3133
Week 1 Day 1, 1 hour, n=31,11,41,7,18,10	249.793 ± 128.5670	205.364 ± 70.6856	228.597 ± 118.1550	175.197 ± 154.0632	327.072 ± 186.8822	299.100 ± 92.9043
Week 1 Day 1, 3 hours, n=31,11,39,6,17,10	276.516 ± 67.1798	216.364 ± 50.0685	262.044 ± 91.2467	243.517 ± 136.5840	365.059 ± 130.8231	300.000 ± 95.1595
Week 3 Day 1, Pre-dose, n=29,12,31,5,16,8	37.972 ± 31.9814	58.708 ± 64.1009	42.213 ± 30.7403	121.820 ± 190.5127	48.013 ± 39.6626	49.230 ± 40.3798
Week 3 Day 1, 0.5 hour, n=28,11,30,4,13,7	290.482 ± 155.8106	243.736 ± 130.5650	195.037 ± 147.9176	192.275 ± 149.9568	256.669 ± 173.4439	288.671 ± 166.5404
Week 3 Day 1, 1 hour, n=28,11,30,5,13,7	414.143 ± 118.8203	294.573 ± 102.1516	323.767 ± 169.5878	271.200 ± 145.3227	511.692 ± 196.3468	441.571 ± 140.2353
Week 3 Day 1, 3 hours, n=28,10,29,5,13,7	369.821 ± 85.0124	341.500 ± 95.5118	321.404 ± 131.8554	252.000 ± 96.1587	438.692 ± 91.5946	403.571 ± 96.7348
Week 5 Day 1, Pre-dose, n=26,9,34,5,14,10	37.480 ± 32.2441	41.600 ± 24.1873	56.659 ± 70.2933	36.620 ± 26.8511	52.243 ± 44.0710	54.231 ± 57.2752
Week 5 Day 1, 0.5-1 hour, n=24,7,26,3,11,7	270.979 ± 153.7445	237.614 ± 211.1272	211.846 ± 171.4081	170.800 ± 66.2851	295.518 ± 235.4897	203.486 ± 111.2642
Week 5 Day 1, 4-8 hours, n=6,1,9,1,5,0	263.833 ± 52.9619	208.000 ± 88888	322.778 ± 166.2354	292.000 ± 88888	382.400 ± 98.2588	66666 ± 66666
Week 9 Day 1, Pre-dose, n=17,2,23,2,10,4	31.041 ± 28.3504	33.850 ± 19.4454	39.323 ± 40.8779	22.700 ± 77777	58.890 ± 62.2330	69.625 ± 53.3875
Week 9 Day 1, 0.5-1 hour, n=13,1,17,2,6,3	244.162 ± 189.0153	36.000 ± 88888	178.914 ± 148.8777	228.000 ± 140.0071	283.667 ± 177.1211	161.367 ± 113.1437
Week 17 Day 1, Pre-dose, n=11,2,8,2,6,3	41.445 ± 35.8541	21.450 ± 5.4447	21.214 ± 27.8382	72.450 ± 55.9321	44.483 ± 48.7589	84.600 ± 74.6129
Week 17 Day 1, 0.5-1 hour, n=9,2,9,2,4,1	189.422 ± 146.0021	71.800 ± 66.7509	183.671 ± 149.1568	129.050 ± 135.6938	322.500 ± 237.0787	301.000 ± 88888
Week 25 Day 1, Pre-dose, n=9,1,5,2,4,1	65.756 ± 125.0011	30.100 ± 88888	49.700 ± 26.2679	64.500 ± 60.1041	20.508 ± 29.5669	99999 ± 99999
Week 25 Day 1, 0.5-1 hour, n=5,0,6,2,2,1	203.160 ± 192.2849	66666 ± 66666	220.367 ± 195.6110	204.950 ± 164.1195	121.300 ± 90.0854	76.300 ± 88888

Notes
[60] - PK Population
[61] - PK Population
[62] - PK Population
[63] - PK Population
[64] - PK Population
[65] - PK Population

No statistical analyses for this end point

Secondary: Phase I: Plasma concentration of Fulvestrant

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End point title

Phase I: Plasma concentration of Fulvestrant

End point description

Blood samples were collected at indicated time points for PK analysis of Fulvestrant. Only those participants with data available at the indicated time points were analyzed (indicated by n=X in category titles). 99999 indicates no concentration values were detected for pre-dose. 88888 indicates standard deviation could not be calculated due to single participant.

End point type

Secondary

End point timeframe

Day 1: Pre-dose on Weeks 1, 3, 5, 9, 17, 25

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	30 ^[66]	11 ^[67]	40 ^[68]	7 ^[69]	17 ^[70]	11 ^[71]
Units: Nanograms per milliliter
arithmetic mean (standard deviation)
Week 1 Day 1, Pre-dose, n=30,11,40,6,17,11	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999
Week 3 Day 1, Pre-dose, n=30,11,32,7,16,10	13.32481 ± 6.603131	9.42742 ± 3.584881	12.44415 ± 5.669148	11.34839 ± 2.085675	12.41568 ± 4.873113	10.25047 ± 3.121508
Week 5 Day 1, Pre-dose, n=25,9,31,5,16,10	19.82642 ± 6.917439	14.72467 ± 3.338039	16.51574 ± 5.957079	15.35394 ± 5.395372	16.87293 ± 8.018589	13.83940 ± 4.449118
Week 9 Day 1, Pre-dose, n=19,3,19,1,10,5	16.33764 ± 5.719390	13.05750 ± 4.266495	13.98242 ± 4.138764	20.43840 ± 88888	11.10370 ± 2.864192	11.84244 ± 4.615995
Week 17 Day 1, Pre-dose, n=15,2,6,1,6,3	16.70103 ± 5.826390	20.63475 ± 7.753497	13.62853 ± 1.536930	12.59940 ± 88888	12.81337 ± 3.550671	16.33830 ± 4.410823
Week 25 Day 1, Pre-dose, n=10,1,4,1,4,1	18.07473 ± 5.933472	14.21220 ± 88888	18.60548 ± 5.300211	19.05100 ± 88888	16.05110 ± 2.384935	12.24970 ± 88888

Notes
[66] - PK Population
[67] - PK Population
[68] - PK Population
[69] - PK Population
[70] - PK Population
[71] - PK Population

No statistical analyses for this end point

Other pre-specified: Phase I: Number of participants with non-serious adverse events (AEs) and serious adverse events (SAEs) until End of the study

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End point title

Phase I: Number of participants with non-serious adverse events (AEs) and serious adverse events (SAEs) until End of the study

End point description

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, any other situation such as important medical events according to medical or scientific judgement or is associated with liver injury and impaired liver function. Any other adverse event apart from SAE is considered as non-SAE. Number of participants with non-serious AEs and SAEs collected from start of the treatment until end of the study were reported.

End point type

Other pre-specified

End point timeframe

Up to 4 year and 4 months

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	33 ^[72]	12 ^[73]	42 ^[74]	7 ^[75]	18 ^[76]	11 ^[77]
Units: Participants
Non-serious AEs	33	12	42	7	18	11
SAEs	5	1	10	3	6	2

Notes
[72] - All Treated Population
[73] - All Treated Population
[74] - All Treated Population
[75] - All Treated Population
[76] - All Treated Population
[77] - All Treated Population

No statistical analyses for this end point

Other pre-specified: Phase I: Number of participants with dose reductions and dose interruption/delays until End of the study

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End point title

Phase I: Number of participants with dose reductions and dose interruption/delays until End of the study

End point description

Number of participants with dose reductions and dose interruption or delay due to any reason is presented. Number of participants with dose reductions and dose interruption or delay due to any reason from start of the treatment until end of the study were reported.

End point type

Other pre-specified

End point timeframe

Up to 4 year and 4 months

End point values	Phase I-GSK525762 60 mg+FUL 500 mg (AI Failure)	Phase-I GSK525762 60 mg+FUL 500 mg (CDK4/6+AI Failure <12M)	Phase I-GSK525762 60 mg+FUL 500 mg (CDK4/6+ AI Failure >= 12M)	PhaseI-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone only dis	Phase I-GSK525762 80mg + FUL 500 mg (AI Failure)	Phase I-GSK525762 80 mg + FUL 500 mg (CDK4/6+AI Failure)
Number of subjects analysed	33 ^[78]	12 ^[79]	42 ^[80]	7 ^[81]	18 ^[82]	11 ^[83]
Units: Participants
Dose reduction	9	3	14	3	7	8
Dose interruption/delay	23	9	23	4	15	9

Notes
[78] - All Treated Population
[79] - All Treated Population
[80] - All Treated Population
[81] - All Treated Population
[82] - All Treated Population
[83] - All Treated Population

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All-cause mortality, serious and non-serious adverse events were collected up to 4 year and 4 months

Adverse event reporting additional description

All Treated Population. Results presented are approximately up to 4years & 4months. Interim analysis failed to demonstrate clinically meaningful activity hence Phase II was not initiated. Data is presented only for Phase I.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Phase I-GSK525762 60mg+FUL 500mg(AI Failure)

Reporting group description

Reporting group title

Phase I-GSK525762 60mg+FUL 500mg (CDK4/6+AI Failure < 12M)

Reporting group description

Reporting group title

Phase I-GSK525762 80mg+FUL 500mg (AI Failure)

Reporting group description

Participants with AI failure received GSK525762 80 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Reporting group title

Phase I-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone Disease

Reporting group description

Reporting group title

Phase I-GSK525762 80mg+FUL 500mg (CDK4/6+AI Failure)

Reporting group description

Participants with CDK4/6/AI failure received GSK525762 80 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Reporting group title

Phase I-GSK525762 60mg+FUL 500mg (CDK4/6+AI Failure >=12M)

Reporting group description

Participants with CDK4/6/AI failure >=12 months received GSK525762 60 mg tablet orally once daily and FUL 500 mg was administered IM on days 1, 15, 29, and once monthly thereafter.

Serious adverse events	Phase I-GSK525762 60mg+FUL 500mg(AI Failure)	Phase I-GSK525762 60mg+FUL 500mg (CDK4/6+AI Failure < 12M)	Phase I-GSK525762 80mg+FUL 500mg (AI Failure)	Phase I-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone Disease	Phase I-GSK525762 80mg+FUL 500mg (CDK4/6+AI Failure)	Phase I-GSK525762 60mg+FUL 500mg (CDK4/6+AI Failure >=12M)
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 33 (15.15%)	1 / 12 (8.33%)	6 / 18 (33.33%)	3 / 7 (42.86%)	2 / 11 (18.18%)	10 / 42 (23.81%)
number of deaths (all causes)	11	9	10	2	5	12
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Extramammary Paget's disease
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Catheter site haematoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Major depression
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Diaphragmatic injury
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Microangiopathic haemolytic anaemia
subjects affected / exposed	0 / 33 (0.00%)	1 / 12 (8.33%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	3 / 42 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Streptococcal sepsis
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Viral infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertriglyceridaemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase I-GSK525762 60mg+FUL 500mg(AI Failure)	Phase I-GSK525762 60mg+FUL 500mg (CDK4/6+AI Failure < 12M)	Phase I-GSK525762 80mg+FUL 500mg (AI Failure)	Phase I-GSK525762 60+FUL500mg CDK4/6+AI Fail>=12M Bone Disease	Phase I-GSK525762 80mg+FUL 500mg (CDK4/6+AI Failure)	Phase I-GSK525762 60mg+FUL 500mg (CDK4/6+AI Failure >=12M)
Total subjects affected by non serious adverse events
subjects affected / exposed	33 / 33 (100.00%)	12 / 12 (100.00%)	18 / 18 (100.00%)	7 / 7 (100.00%)	11 / 11 (100.00%)	42 / 42 (100.00%)
Vascular disorders
Hot flush
subjects affected / exposed	0 / 33 (0.00%)	1 / 12 (8.33%)	3 / 18 (16.67%)	0 / 7 (0.00%)	2 / 11 (18.18%)	9 / 42 (21.43%)
occurrences all number	0	1	4	0	2	9
Hypertension
subjects affected / exposed	4 / 33 (12.12%)	1 / 12 (8.33%)	1 / 18 (5.56%)	0 / 7 (0.00%)	3 / 11 (27.27%)	3 / 42 (7.14%)
occurrences all number	4	1	4	0	3	3
General disorders and administration site conditions
Fatigue
subjects affected / exposed	19 / 33 (57.58%)	4 / 12 (33.33%)	9 / 18 (50.00%)	1 / 7 (14.29%)	7 / 11 (63.64%)	25 / 42 (59.52%)
occurrences all number	24	6	12	1	10	38
Asthenia
subjects affected / exposed	4 / 33 (12.12%)	0 / 12 (0.00%)	3 / 18 (16.67%)	2 / 7 (28.57%)	1 / 11 (9.09%)	7 / 42 (16.67%)
occurrences all number	5	0	6	5	1	8
Chest pain
subjects affected / exposed	2 / 33 (6.06%)	0 / 12 (0.00%)	3 / 18 (16.67%)	1 / 7 (14.29%)	1 / 11 (9.09%)	1 / 42 (2.38%)
occurrences all number	2	0	3	1	1	1
Chills
subjects affected / exposed	2 / 33 (6.06%)	0 / 12 (0.00%)	2 / 18 (11.11%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences all number	3	0	2	1	0	1
Injection site pain
subjects affected / exposed	2 / 33 (6.06%)	2 / 12 (16.67%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 42 (4.76%)
occurrences all number	2	2	0	0	0	2
Pyrexia
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	1 / 18 (5.56%)	1 / 7 (14.29%)	0 / 11 (0.00%)	3 / 42 (7.14%)
occurrences all number	1	0	1	1	0	4
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	6 / 33 (18.18%)	2 / 12 (16.67%)	3 / 18 (16.67%)	2 / 7 (28.57%)	4 / 11 (36.36%)	13 / 42 (30.95%)
occurrences all number	7	4	4	2	5	17
Cough
subjects affected / exposed	9 / 33 (27.27%)	2 / 12 (16.67%)	1 / 18 (5.56%)	1 / 7 (14.29%)	3 / 11 (27.27%)	13 / 42 (30.95%)
occurrences all number	9	2	2	1	5	15
Epistaxis
subjects affected / exposed	4 / 33 (12.12%)	1 / 12 (8.33%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	8 / 42 (19.05%)
occurrences all number	4	1	0	0	0	9
Oropharyngeal pain
subjects affected / exposed	1 / 33 (3.03%)	1 / 12 (8.33%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	4 / 42 (9.52%)
occurrences all number	1	1	0	0	0	4
Psychiatric disorders
Insomnia
subjects affected / exposed	4 / 33 (12.12%)	1 / 12 (8.33%)	3 / 18 (16.67%)	0 / 7 (0.00%)	1 / 11 (9.09%)	5 / 42 (11.90%)
occurrences all number	4	1	3	0	1	6
Investigations
Platelet count decreased
subjects affected / exposed	6 / 33 (18.18%)	2 / 12 (16.67%)	6 / 18 (33.33%)	2 / 7 (28.57%)	4 / 11 (36.36%)	12 / 42 (28.57%)
occurrences all number	25	3	12	5	6	21
Blood bilirubin increased
subjects affected / exposed	5 / 33 (15.15%)	2 / 12 (16.67%)	10 / 18 (55.56%)	4 / 7 (57.14%)	2 / 11 (18.18%)	8 / 42 (19.05%)
occurrences all number	6	2	20	7	3	9
Alanine aminotransferase increased
subjects affected / exposed	5 / 33 (15.15%)	2 / 12 (16.67%)	5 / 18 (27.78%)	3 / 7 (42.86%)	2 / 11 (18.18%)	11 / 42 (26.19%)
occurrences all number	7	2	10	5	2	15
Aspartate aminotransferase increased
subjects affected / exposed	6 / 33 (18.18%)	3 / 12 (25.00%)	4 / 18 (22.22%)	3 / 7 (42.86%)	2 / 11 (18.18%)	10 / 42 (23.81%)
occurrences all number	7	3	5	8	2	12
Amylase increased
subjects affected / exposed	2 / 33 (6.06%)	2 / 12 (16.67%)	4 / 18 (22.22%)	2 / 7 (28.57%)	0 / 11 (0.00%)	4 / 42 (9.52%)
occurrences all number	3	3	5	3	0	5
Weight decreased
subjects affected / exposed	4 / 33 (12.12%)	1 / 12 (8.33%)	3 / 18 (16.67%)	1 / 7 (14.29%)	1 / 11 (9.09%)	4 / 42 (9.52%)
occurrences all number	6	1	3	1	1	5
International normalised ratio increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	4 / 18 (22.22%)	1 / 7 (14.29%)	0 / 11 (0.00%)	5 / 42 (11.90%)
occurrences all number	0	0	8	1	0	7
Lipase increased
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	2 / 18 (11.11%)	2 / 7 (28.57%)	0 / 11 (0.00%)	6 / 42 (14.29%)
occurrences all number	0	0	3	3	0	10
Troponin T increased
subjects affected / exposed	2 / 33 (6.06%)	1 / 12 (8.33%)	1 / 18 (5.56%)	1 / 7 (14.29%)	2 / 11 (18.18%)	3 / 42 (7.14%)
occurrences all number	3	2	5	1	6	3
Lymphocyte count decreased
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	0 / 18 (0.00%)	2 / 7 (28.57%)	0 / 11 (0.00%)	5 / 42 (11.90%)
occurrences all number	1	0	0	5	0	7
Neutrophil count decreased
subjects affected / exposed	2 / 33 (6.06%)	0 / 12 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)	1 / 11 (9.09%)	4 / 42 (9.52%)
occurrences all number	7	0	0	3	1	6
N-terminal prohormone brain natriuretic peptide increased
subjects affected / exposed	1 / 33 (3.03%)	1 / 12 (8.33%)	2 / 18 (11.11%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 42 (2.38%)
occurrences all number	2	3	2	1	0	1
White blood cell count decreased
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	0 / 18 (0.00%)	2 / 7 (28.57%)	0 / 11 (0.00%)	3 / 42 (7.14%)
occurrences all number	3	0	0	3	0	4
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 33 (6.06%)	1 / 12 (8.33%)	3 / 18 (16.67%)	0 / 7 (0.00%)	0 / 11 (0.00%)	4 / 42 (9.52%)
occurrences all number	3	1	4	0	0	4
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	2 / 33 (6.06%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	3 / 42 (7.14%)
occurrences all number	2	0	2	0	0	4
Nervous system disorders
Dysgeusia
subjects affected / exposed	14 / 33 (42.42%)	2 / 12 (16.67%)	10 / 18 (55.56%)	4 / 7 (57.14%)	7 / 11 (63.64%)	25 / 42 (59.52%)
occurrences all number	16	3	14	4	8	30
Headache
subjects affected / exposed	6 / 33 (18.18%)	3 / 12 (25.00%)	7 / 18 (38.89%)	1 / 7 (14.29%)	3 / 11 (27.27%)	10 / 42 (23.81%)
occurrences all number	6	4	10	1	5	11
Dizziness
subjects affected / exposed	2 / 33 (6.06%)	1 / 12 (8.33%)	2 / 18 (11.11%)	0 / 7 (0.00%)	1 / 11 (9.09%)	8 / 42 (19.05%)
occurrences all number	2	1	5	0	1	11
Taste disorder
subjects affected / exposed	6 / 33 (18.18%)	1 / 12 (8.33%)	1 / 18 (5.56%)	0 / 7 (0.00%)	2 / 11 (18.18%)	0 / 42 (0.00%)
occurrences all number	6	1	2	0	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 33 (12.12%)	1 / 12 (8.33%)	6 / 18 (33.33%)	3 / 7 (42.86%)	2 / 11 (18.18%)	15 / 42 (35.71%)
occurrences all number	4	1	9	4	2	19
Thrombocytopenia
subjects affected / exposed	8 / 33 (24.24%)	4 / 12 (33.33%)	3 / 18 (16.67%)	4 / 7 (57.14%)	1 / 11 (9.09%)	8 / 42 (19.05%)
occurrences all number	15	4	9	8	1	14
Neutropenia
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	3 / 18 (16.67%)	1 / 7 (14.29%)	0 / 11 (0.00%)	4 / 42 (9.52%)
occurrences all number	1	0	3	1	0	5
Eye disorders
Dry eye
subjects affected / exposed	2 / 33 (6.06%)	0 / 12 (0.00%)	3 / 18 (16.67%)	0 / 7 (0.00%)	0 / 11 (0.00%)	4 / 42 (9.52%)
occurrences all number	2	0	4	0	0	4
Gastrointestinal disorders
Nausea
subjects affected / exposed	12 / 33 (36.36%)	7 / 12 (58.33%)	11 / 18 (61.11%)	5 / 7 (71.43%)	9 / 11 (81.82%)	30 / 42 (71.43%)
occurrences all number	17	10	21	9	9	38
Diarrhoea
subjects affected / exposed	13 / 33 (39.39%)	4 / 12 (33.33%)	10 / 18 (55.56%)	6 / 7 (85.71%)	4 / 11 (36.36%)	20 / 42 (47.62%)
occurrences all number	19	4	24	10	4	28
Vomiting
subjects affected / exposed	7 / 33 (21.21%)	2 / 12 (16.67%)	7 / 18 (38.89%)	2 / 7 (28.57%)	2 / 11 (18.18%)	8 / 42 (19.05%)
occurrences all number	8	3	9	2	2	9
Dry mouth
subjects affected / exposed	8 / 33 (24.24%)	2 / 12 (16.67%)	3 / 18 (16.67%)	2 / 7 (28.57%)	3 / 11 (27.27%)	4 / 42 (9.52%)
occurrences all number	8	2	4	2	3	4
Constipation
subjects affected / exposed	3 / 33 (9.09%)	1 / 12 (8.33%)	3 / 18 (16.67%)	4 / 7 (57.14%)	4 / 11 (36.36%)	6 / 42 (14.29%)
occurrences all number	5	1	4	4	4	6
Abdominal pain
subjects affected / exposed	2 / 33 (6.06%)	1 / 12 (8.33%)	3 / 18 (16.67%)	2 / 7 (28.57%)	3 / 11 (27.27%)	4 / 42 (9.52%)
occurrences all number	3	1	6	2	3	4
Dyspepsia
subjects affected / exposed	7 / 33 (21.21%)	0 / 12 (0.00%)	4 / 18 (22.22%)	1 / 7 (14.29%)	0 / 11 (0.00%)	2 / 42 (4.76%)
occurrences all number	8	0	5	1	0	2
Abdominal pain upper
subjects affected / exposed	3 / 33 (9.09%)	1 / 12 (8.33%)	1 / 18 (5.56%)	2 / 7 (28.57%)	1 / 11 (9.09%)	5 / 42 (11.90%)
occurrences all number	4	1	2	2	1	7
Stomatitis
subjects affected / exposed	2 / 33 (6.06%)	1 / 12 (8.33%)	4 / 18 (22.22%)	0 / 7 (0.00%)	2 / 11 (18.18%)	4 / 42 (9.52%)
occurrences all number	2	1	7	0	2	4
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 33 (6.06%)	0 / 12 (0.00%)	1 / 18 (5.56%)	1 / 7 (14.29%)	1 / 11 (9.09%)	4 / 42 (9.52%)
occurrences all number	2	0	1	2	1	4
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	8 / 33 (24.24%)	4 / 12 (33.33%)	4 / 18 (22.22%)	1 / 7 (14.29%)	2 / 11 (18.18%)	10 / 42 (23.81%)
occurrences all number	10	4	7	1	2	11
Pruritus
subjects affected / exposed	6 / 33 (18.18%)	2 / 12 (16.67%)	5 / 18 (27.78%)	2 / 7 (28.57%)	1 / 11 (9.09%)	6 / 42 (14.29%)
occurrences all number	7	2	5	2	1	6
Dry skin
subjects affected / exposed	1 / 33 (3.03%)	1 / 12 (8.33%)	2 / 18 (11.11%)	0 / 7 (0.00%)	3 / 11 (27.27%)	8 / 42 (19.05%)
occurrences all number	1	1	2	0	3	8
Rash maculo-papular
subjects affected / exposed	1 / 33 (3.03%)	1 / 12 (8.33%)	1 / 18 (5.56%)	0 / 7 (0.00%)	3 / 11 (27.27%)	4 / 42 (9.52%)
occurrences all number	2	1	1	0	3	4
Dermatitis acneiform
subjects affected / exposed	0 / 33 (0.00%)	1 / 12 (8.33%)	2 / 18 (11.11%)	0 / 7 (0.00%)	3 / 11 (27.27%)	2 / 42 (4.76%)
occurrences all number	0	1	2	0	3	2
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	4 / 33 (12.12%)	1 / 12 (8.33%)	3 / 18 (16.67%)	3 / 7 (42.86%)	1 / 11 (9.09%)	8 / 42 (19.05%)
occurrences all number	5	1	3	4	1	9
Musculoskeletal pain
subjects affected / exposed	4 / 33 (12.12%)	0 / 12 (0.00%)	3 / 18 (16.67%)	3 / 7 (42.86%)	2 / 11 (18.18%)	3 / 42 (7.14%)
occurrences all number	4	0	3	3	2	3
Muscle spasms
subjects affected / exposed	6 / 33 (18.18%)	2 / 12 (16.67%)	3 / 18 (16.67%)	1 / 7 (14.29%)	0 / 11 (0.00%)	2 / 42 (4.76%)
occurrences all number	7	2	6	2	0	3
Arthralgia
subjects affected / exposed	4 / 33 (12.12%)	0 / 12 (0.00%)	2 / 18 (11.11%)	1 / 7 (14.29%)	1 / 11 (9.09%)	4 / 42 (9.52%)
occurrences all number	7	0	2	1	1	4
Pain in extremity
subjects affected / exposed	3 / 33 (9.09%)	0 / 12 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)	1 / 11 (9.09%)	5 / 42 (11.90%)
occurrences all number	3	0	0	1	1	6
Myalgia
subjects affected / exposed	3 / 33 (9.09%)	0 / 12 (0.00%)	3 / 18 (16.67%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 42 (4.76%)
occurrences all number	5	0	4	0	0	4
Bone pain
subjects affected / exposed	1 / 33 (3.03%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 11 (0.00%)	4 / 42 (9.52%)
occurrences all number	2	0	1	0	0	4
Flank pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	3 / 11 (27.27%)	2 / 42 (4.76%)
occurrences all number	0	0	1	0	3	2
Musculoskeletal chest pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 12 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	5 / 42 (11.90%)
occurrences all number	0	0	0	0	1	5
Infections and infestations
Urinary tract infection
subjects affected / exposed	4 / 33 (12.12%)	3 / 12 (25.00%)	2 / 18 (11.11%)	1 / 7 (14.29%)	2 / 11 (18.18%)	1 / 42 (2.38%)
occurrences all number	7	4	2	1	2	2
Herpes zoster
subjects affected / exposed	5 / 33 (15.15%)	0 / 12 (0.00%)	2 / 18 (11.11%)	2 / 7 (28.57%)	1 / 11 (9.09%)	2 / 42 (4.76%)
occurrences all number	5	0	2	2	1	2
Upper respiratory tract infection
subjects affected / exposed	2 / 33 (6.06%)	0 / 12 (0.00%)	4 / 18 (22.22%)	0 / 7 (0.00%)	0 / 11 (0.00%)	4 / 42 (9.52%)
occurrences all number	2	0	4	0	0	4
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	14 / 33 (42.42%)	2 / 12 (16.67%)	9 / 18 (50.00%)	3 / 7 (42.86%)	6 / 11 (54.55%)	18 / 42 (42.86%)
occurrences all number	18	3	15	5	7	19
Hyperglycaemia
subjects affected / exposed	13 / 33 (39.39%)	3 / 12 (25.00%)	6 / 18 (33.33%)	3 / 7 (42.86%)	2 / 11 (18.18%)	16 / 42 (38.10%)
occurrences all number	21	3	11	5	5	22
Hypertriglyceridaemia
subjects affected / exposed	0 / 33 (0.00%)	1 / 12 (8.33%)	0 / 18 (0.00%)	2 / 7 (28.57%)	0 / 11 (0.00%)	3 / 42 (7.14%)
occurrences all number	0	2	0	2	0	6
Hypokalaemia
subjects affected / exposed	2 / 33 (6.06%)	0 / 12 (0.00%)	1 / 18 (5.56%)	1 / 7 (14.29%)	0 / 11 (0.00%)	2 / 42 (4.76%)
occurrences all number	2	0	1	1	0	3
Hyponatraemia
subjects affected / exposed	0 / 33 (0.00%)	1 / 12 (8.33%)	0 / 18 (0.00%)	3 / 7 (42.86%)	0 / 11 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	1	0	5	0	2

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Were there any global substantial amendments to the protocol? Yes

21 Oct 2016

Amend1:Clarification of permitted prophylactic anticoagulation therapies in Excl Crit4;Correction of spelling of goserelin,Change to toxicity management guidelines for below:Update to dose interruption/reduction/discontinuation guidelines for Grade(G)4 thrombocytopenia;Dose reduction for participant if QTcF>=60 msec change from Baseline occurs/QTcF>=500;Permanent discontinuation of study medication for participant with troponin levels approaching threshold for MI;Clarification on length of followup for participant with LVEF increase;Monitoring of blood sugar&dose reduction guidelines for participant with moderate to severe hypoglycemia;Dose reduction&event management for participant with G3-4 diarrhea;Dose interruption&reduction for participant with G3-4 mucositis;Dose interruption/reduction/discontinuation&event management for all G of pneumonitis;Dose interruption&/reduction for participant with G3-4 other non-hematologic events.Clarification of timing for sites to report pregnancies to GSK(24h vs 2wks,based on reproductive toxicity seen in preclinical GSK525762 studies); Addition of clarifying language around survival follow up after EoT visit;Addition of clarifying language around fresh biopsies around timing of CBC draws in Wk1;& incl crit6&excl crit1-3 around prior treatment history;Clarified wording for disease assessment schedule after Wk52;Removal of Sect:Valvular Toxicity Stopping Criteria &there are no preclinical/clinical valvular toxicity findings for GSK525762.Update to option of scan(now ECHO/MUGA);Removal of Disease Related Events,this section is only to be included if there are predefined disease related events.Update to G3&4 thrombocytopenia management guideline to make it more stringent,based upon emerging data that will be provided in INDSR.Removal of fever management guideline as part of ongoing safety review for GSK525762,there is no apparent clinical correlation to preclinical in vitro findings suggesting a potential for fever.

31 Jan 2017

Amendment 02-Based upon review and comment on the protocol by the Medicines and Healthcare products Regulatory Agency (MHRA), the following changes are being implemented as a standalone amendment for the United Kingdom (UK): Clarification of the length of time, post treatment completion, that the approved list of contraceptives must be used by female participants of childbearing potential; clarification in Section 5.4 that pregnancy is a reason for participant discontinuation from the study. A forthcoming amendment (03) will include these revisions as part of a global protocol amendment.

07 Mar 2017

Amendment 03-Clarification to the prior treatment participants may have received; update to the timelines of the study, based upon new enrollment projections; clarification of inclusion criteria #6 regarding prior treatment participants may have received; clarification of exclusion criteria #1 and #3 regarding number of prior lines of therapy; addition of two new exclusion criteria regarding use of NSAIDS and history of bleeding events; clarification in Section 5.4 that pregnancy for participants of childbearing potential is a cause for study discontinuation; clarification regarding the liquid that participants are permitted to use when taking GSK525762; clarification around the dosing window for fulvestrant; addition of Table 3 which clarifies dose reductions; clarification around use of Aspirin; update to the prohibited meds table in Section 6.11.2.1 and the cautionary meds table in Section 6.11.2.3; clarification around use of medication containing acetaminophen; update to the schedule of assessments in the Time and Events tables for both Phase I and II of the study; update to the schedule of laboratory assessments in both Phase I and II of the study; update to the +- visit windows for Weeks 2, 3, 4, 5, and 9; added logistical and medical guidance around when on treatment fresh biopsies and planned surgical procedure can take place; updated the thrombocytopenia management guidelines in Table 13 to be in line with regulatory feedback; clarification of baseline imaging windows; clarification of approved contraception and length of time said contraception needs to be used post study treatment.

18 Oct 2017

Amendment 04-Based upon review and comment on the protocol by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM), the following changes are being implemented: language added to Section 6.11.2.3 around concomitant medications that are substrates of CYP3A4; update to the toxicity management guidelines for QTcF monitoring in Appendix 2, Table 13; Times and Events tables in Section 7.1, updated to clarify the schedule of assessments post week 49. Additional changes to the protocol include: update to protocol authors; update to the primary GlaxoSmithKline (GSK) medical monitor, update to Sponsor signatory; ERS1 mutational status in the objectives and endpoints has been updated to exploratory, and Section 7.7 has been updated to reflect the translational analysis changes; removal of the time to progression (TTP) endpoints; update to description of Phase I enrolment during the dose escalation phase and the definition of study completion in Phase II; update to statistical analysis descriptions throughout the protocol; addition of information around the dose escalation meetings; Section 6.6 on the handling of GSK525762; clarification in Section 5.1, Table 2, regarding acceptability of both Troponin I or T; Times and Events tables in Section 7.1, updated to clarify Echocardiogram (ECHO)/ Multigated Acquisition Scan (MUGA) scan requirements for screening and W1D1, timing of on treatment biopsy collection in Phase I, lab assessment requirements, and length of screening window (also updated throughout the document); update to the toxicity management guidelines for QT duration corrected for heart rate by Fridericia’s formula (QTcF) re-challenge in Appendix 2, Table 13; removal of predefined events of interest.

11 Sep 2018

Amend 05:Updating protocol title to HR+/HER2-Breast cancer (BC) to align with incl crit.which requires both ER+ & PR+BC participants. Update to clarify-dose level (DL)2 (80mg) has been discontinued. New sections added to address & update to PhaseI-include DL2 80mg discontinuation,update DL1(60mg) cohort2 population to include participants must have received >=12months of prior (CDK4/6+ AI) for metastatic disease&progressed while on treatment&allow bone only disease.encl/excl criteria:Provision of fresh tumor biopsy sample at screening;letrozole has been expanded to include all AI agents;prior treatment allowed in CDK4/6 participant population;participant must have received >=12month of prior CDK4/6+AI for metastatic disease&progressed while on treatment;bone only disease is allowed(screening biopsy not required after discussion with MM);update to criteria for severe/uncontrolled systemic diseases;Baseline QTcF.Update to QTc stopping criteria;removal of former Guidelines for Events of Special Interest;include granulocyte colony-stimulating factor as permitted medication;update to wording in Prohibited Medication&removal of former Table4;Cautionary Medication&removal of former T5;Clarification regarding both prescription&non-prescription herbal preparation/medication;Time&Event Table5&8:Update regarding ECG,requirement of fresh biopsies at screening&collection window,clarification of requirement around fresh tumor biopsies sample;Pregnancy Test-X is removed from Column for Q12wks(Wk49 &after).This was an error & Q4wks is correct.Clarification regarding PK sample collection for participants with interrupted dosing;update to guidelines for ECG assessment;Clinical Labs regarding collection of troponin; guidance on screening&on treatment biopsie;&toxicity management for QTcF events&explanation for reconsent;Collection of pregnancy information regarding elective termination is clarified that only those performed due to medical reasons are required to be reported.

06 May 2020

Amendment 06 applies to all global study sites. These changes are based on the decision to close out the study and stop all new enrolment based on interim data failing to demonstrate meaningful clinical benefit in the proposed participant population. The totality of Phase I data assessed at the interim analysis does not support continuing investigation of GSK525762 (molibresib) in combination with fulvestrant for the treatment of hormone receptor-positive/HER2-negative (HR+/HER2-) advanced or metastatic breast cancer patients. Enrolment into the study is now closed. The study will conclude when the last participant has completed/discontinued study treatment and completed the end of treatment visit. Changes to the protocol include: Enrolment into the study is now closed, Removes the requirement for specific protocol assessments and survival followup (Section 7.1 – Time and Events Tables) Updates to contraceptive measures required for study participants, based upon January 2020 updates to the fulvestrant Summary of Product Characteristics Update to the GSK signatory and GSK medical monitor, Provides updated guidance for participants who have discontinued combination treatment & are on fulvestrant monotherapy, Provides clarification on clinical supply dosages available for the study, Administrative changes including minor clarifications, formatting and typographical errors.

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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Clinical trials

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase I: Number of participants with adverse events (AEs) and serious adverse events (SAEs)

Primary: Phase I: Number of participants with adverse events (AEs) and serious adverse events (SAEs)

Primary: Phase I: Number of participants with dose limiting toxicities (DLTs)

Primary: Phase I: Number of participants with dose limiting toxicities (DLTs)

Primary: Phase I: Number of participants with dose reductions and dose interruption/delays

Primary: Phase I: Number of participants with dose reductions and dose interruption/delays

Primary: Phase I: Objective response rate-Investigator assessment

Primary: Phase I: Objective response rate-Investigator assessment

Primary: Phase I: Plasma concentration of GSK525762

Primary: Phase I: Plasma concentration of GSK525762

Secondary: Phase I: Number of participants who withdrew due to toxicity and changes in Safety Assessment

Secondary: Phase I: Number of participants who withdrew due to toxicity and changes in Safety Assessment

Secondary: Phase I: Disease control rate (DCR)

Secondary: Phase I: Disease control rate (DCR)

Secondary: Phase I: Duration of response (DoR)

Secondary: Phase I: Duration of response (DoR)

Secondary: Phase I: Progression-free survival (PFS)

Secondary: Phase I: Progression-free survival (PFS)

Secondary: Phase I: Plasma concentration of GSK3529246

Secondary: Phase I: Plasma concentration of GSK3529246

Secondary: Phase I: Plasma concentration of Fulvestrant

Secondary: Phase I: Plasma concentration of Fulvestrant

Other pre-specified: Phase I: Number of participants with non-serious adverse events (AEs) and serious adverse events (SAEs) until End of the study

Other pre-specified: Phase I: Number of participants with non-serious adverse events (AEs) and serious adverse events (SAEs) until End of the study

Other pre-specified: Phase I: Number of participants with dose reductions and dose interruption/delays until End of the study

Other pre-specified: Phase I: Number of participants with dose reductions and dose interruption/delays until End of the study

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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