This is a combination Phase I and Phase II study, with an aim to evaluate the combination of GSK525762 and fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer, who have disease that has progressed after prior treatment with at least one line of endocrine therapy. The objectives of the study are to first identify, in open-label single-arm Phase I, a recommended Phase II dose of GSK525762 that may be combined safely with fulvestrant. Phase I will follow a modified toxicity probability interval (mTPI) design, and a sentinel group will be evaluated first for dose-limiting toxicity and further expanded to collect additional safety data. This will be followed by a double-blind, randomized controlled Phase II, to identify the clinical activity of the two study treatments when given in combination. The composition of Phase II will be selected at the end of Phase I.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
124
GSK525762 will be administered.
Placebo will be administered.
Fulvestrant will be administered.
GSK Investigational Site
Birmingham, Alabama, United States
GSK Investigational Site
Gilbert, Arizona, United States
GSK Investigational Site
Scottsdale, Arizona, United States
GSK Investigational Site
San Diego, California, United States
GSK Investigational Site
Plantation, Florida, United States
Phase I: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: Up to 3 year and 8 months
Phase I: Number of Participants With Dose Limiting Toxicities (DLTs)
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 \>=2x ULN (\>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.
Time frame: Up to 28 days
Phase I: Number of Participants With Dose Reductions and Dose Interruption/Delays
Number of participants with dose reductions and dose interruption or delay due to any reason is presented.
Time frame: Up to 3 year and 8 months
Phase I: Objective Response Rate-Investigator Assessment
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.
Time frame: Up to 3 year and 8 months
Phase I: Plasma Concentration of GSK525762
Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK525762.
Time frame: 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
Phase II: Progression Free Survival (PFS)
PFS is defined as the time (in months) from the date of first dose until the date of first documented progressive disease (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 taking as a reference the smallest sum of diameters for this study.
Time frame: Up to 3 year and 8 months
Phase I: Number of Participants Who Withdrew Due to Toxicity and Changes in Safety Assessment
Number of participants who withdrew due to toxicity and changes in safety assessment including laboratory parameters and vital signs have been presented.
Time frame: Up to 4 year and 4 months
Phase I: Disease Control Rate (DCR)
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.
Time frame: Up to 3 year and 8 months
Phase I: Duration of Response (DoR)
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.
Time frame: Up to 3 year and 8 months
Phase I: Progression-free Survival (PFS)
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 taking as a reference the smallest sum of diameters for this study.
Time frame: Up to 3 year and 8 months
Phase I: Plasma Concentration of GSK3529246
Blood samples were collected at indicated time points for PK analysis of GSK3529246. GSK3529246 is an active metabolite of GSK525762.
Time frame: 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
Phase I: Plasma Concentration of Fulvestrant
Blood samples were collected at indicated time points for PK analysis of Fulvestrant.
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GSK Investigational Site
Chicago, Illinois, United States
GSK Investigational Site
New Orleans, Louisiana, United States
GSK Investigational Site
Rochester, Minnesota, United States
GSK Investigational Site
Kansas City, Missouri, United States
GSK Investigational Site
St Louis, Missouri, United States
...and 28 more locations
Time frame: Day 1: Pre-dose on Weeks 1, 3, 5, 9, 17, 25
Phase II: Overall Survival (OS)
OS is defined as the interval of time (in months) between the date of first dose and the date of death due to any cause.
Time frame: Up to 3 year and 8 months
Phase II: Overall Response Rate (ORR)
ORR is defined as the percentage of participants in the population who demonstrate a BOR of confirmed CR or PR, as assessed by the investigator per RECIST v1.1 criteria.
Time frame: Up to 3 year and 8 months
Phase II: Disease Control Rate (DCR)
DCR is defined as the percentage of participants in the population with a confirmed CR, confirmed PR, or SD lasting \>=6 months, as assessed by the investigator per RECIST v1.1 criteria.
Time frame: Up to 3 year and 8 months
Phase II: Plasma Concentration of GSK525762 and GSK3529246
Blood samples were planned to be collected for PK analysis of GSK525762 and GSK3529246. GSK3529246 is metabolite of GSK525762.
Time frame: 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
Phase II: Plasma Concentration of Fulvestrant
Blood samples were planned to be collected for PK analysis of fulvestrant.
Time frame: Day 1: Pre-dose on Weeks 1, 3, 5, 9, 17, 25