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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02964507




Registration number
NCT02964507
Ethics application status
Date submitted
12/11/2016
Date registered
16/11/2016
Date last updated
25/07/2023

Titles & IDs
Public title
Dose Escalation and Expansion Study of GSK525762 in Combination With Fulvestrant in Participants With Hormone Receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 Negative (HER2-) Advanced or Metastatic Breast Cancer
Scientific title
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
Secondary ID [1] 0 0
2016-003074-40
Secondary ID [2] 0 0
201973
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - GSK525762
Treatment: Drugs - Placebo
Treatment: Drugs - Fulvestrant

Experimental: GSK525762 + Fulvestrant (Phase I) -

Experimental: GSK525762 + Fulvestrant (Phase II) -

Placebo Comparator: Placebo + Fulvestrant (Phase II) -


Treatment: Drugs: GSK525762
GSK525762 will be administered.

Treatment: Drugs: Placebo
Placebo will be administered.

Treatment: Drugs: Fulvestrant
Fulvestrant will be administered.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase I: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)
Timepoint [1] 0 0
Up to 3 year and 8 months
Primary outcome [2] 0 0
Phase I: Number of Participants With Dose Limiting Toxicities (DLTs)
Timepoint [2] 0 0
Up to 28 days
Primary outcome [3] 0 0
Phase I: Number of Participants With Dose Reductions and Dose Interruption/Delays
Timepoint [3] 0 0
Up to 3 year and 8 months
Primary outcome [4] 0 0
Phase I: Objective Response Rate-Investigator Assessment
Timepoint [4] 0 0
Up to 3 year and 8 months
Primary outcome [5] 0 0
Phase I: Plasma Concentration of GSK525762
Timepoint [5] 0 0
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
Primary outcome [6] 0 0
Phase II: Progression Free Survival (PFS)
Timepoint [6] 0 0
Up to 3 year and 8 months
Secondary outcome [1] 0 0
Phase I: Number of Participants Who Withdrew Due to Toxicity and Changes in Safety Assessment
Timepoint [1] 0 0
Up to 4 year and 4 months
Secondary outcome [2] 0 0
Phase I: Disease Control Rate (DCR)
Timepoint [2] 0 0
Up to 3 year and 8 months
Secondary outcome [3] 0 0
Phase I: Duration of Response (DoR)
Timepoint [3] 0 0
Up to 3 year and 8 months
Secondary outcome [4] 0 0
Phase I: Progression-free Survival (PFS)
Timepoint [4] 0 0
Up to 3 year and 8 months
Secondary outcome [5] 0 0
Phase I: Plasma Concentration of GSK3529246
Timepoint [5] 0 0
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
Secondary outcome [6] 0 0
Phase I: Plasma Concentration of Fulvestrant
Timepoint [6] 0 0
Day 1: Pre-dose on Weeks 1, 3, 5, 9, 17, 25
Secondary outcome [7] 0 0
Phase II: Overall Survival (OS)
Timepoint [7] 0 0
Up to 3 year and 8 months
Secondary outcome [8] 0 0
Phase II: Overall Response Rate (ORR)
Timepoint [8] 0 0
Up to 3 year and 8 months
Secondary outcome [9] 0 0
Phase II: Disease Control Rate (DCR)
Timepoint [9] 0 0
Up to 3 year and 8 months
Secondary outcome [10] 0 0
Phase II: Plasma Concentration of GSK525762 and GSK3529246
Timepoint [10] 0 0
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
Secondary outcome [11] 0 0
Phase II: Plasma Concentration of Fulvestrant
Timepoint [11] 0 0
Day 1: Pre-dose on Weeks 1, 3, 5, 9, 17, 25

Eligibility
Key inclusion criteria
- Written informed consent provided.

- Females 18 years old and greater (at the time of written consent)

- Histologically or cytologically confirmed diagnosis of advanced or metastatic
adenocarcinoma of the breast.

- Documentation of estrogen receptor (ER)-positive and/or progesterone receptor
(PR)-positive tumor (>=1% positive stained tumor cell nuclei) based on local testing
of the most recent tumor biopsy, using an assay consistent with local standards.

- Documentation of HER2-negative tumor based on local testing of the most recent tumor
biopsy as per most recent American Society of Clinical Oncology (ASCO)/College of
American Pathologists (CAP) guidelines. At the time of writing, HER2-negative tumor is
defined as immunohistochemistry (IHC) score of 0 or 1+, or negative by in situ
hybridization defined as a HER2/chromosome enumeration probe 17 (CEP17) ratio <2 or
for single probe assessment of an average HER2 copy number <4.

- Provision of mandatory screening fresh tumor biopsy sample during the screening
period: a. Screening biopsy can be waived if a biopsy was collected within 3 months
prior to first dose of study drug and was collected after the last anti-cancer
treatment before coming into this study; b. Participants with inaccessible site of
biopsy or who have a significant medical risk of obtaining the biopsy should be
discussed with the Medical Monitor if they can qualify; c. Bone biopsies are not
acceptable. Biopsies should be obtained from bone with metastatic soft-tissue
component. Participants with bone only disease may be enrolled upon review by Medical
Monitor.

- History of prior therapy that satisfies one of the following criteria: a. Aromatase
inhibitor (AI) failures: Disease that relapsed during treatment or within 12 months of
completion of adjuvant therapy with an AI, OR disease that progressed during treatment
with an AI for advanced/metastatic disease. Prior ovarian suppression and/or tamoxifen
are allowed as long as other criteria are met; b. Cyclin-dependent kinase 4/6 (CDK4/6)
inhibitor plus AI failures: Disease that progressed on a CDK4/6 inhibitor plus AI, for
advanced/metastatic disease with a minimum duration of treatment of 12 months (>=12
months) with CDK4/6 inhibitor plus AI. Participants with either measurable disease or
bone only disease are allowed. Prior ovarian suppression and/or tamoxifen are allowed
as long as other criteria are met.

- Documented progression on last line of systemic anti-cancer therapy with CDK4/6
inhibitor plus AI is required.

- Any menopausal status.

- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria is required except for participants with bone only disease.

- All prior treatment- related toxicities must be National Cancer Institute-Common
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 <=Grade 1 (except
alopecia (permitted at any grade) and peripheral neuropathy (permitted at <=Grade 2)
at the time of treatment allocation.

- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1.

- Adequate organ function.

- Able to swallow and retain orally administered medication.

- A female participant is eligible to participate if she is of: i) Non-childbearing
potential. ii) Child-bearing potential and agrees to use one of the contraception
methods. iii) Negative serum pregnancy test <=7 days prior to first study drug dose.
iv) Female participants who are lactating must discontinue nursing prior to the first
dose of study treatment and must refrain from nursing throughout the treatment period
and for at least 28 days following the last dose of study treatment.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- Prior therapy with any Bromodomain and extra-terminal (BET) inhibitor, any selective
estrogen receptor degrader (SERD) including fulvestrant, or inhibitors of the
Phosphoinositide-3-kinase (PI3K)/ serine/threonine-specific protein kinase
(AKT)/Mammalian Target of Rapamycin (mTOR) pathway.

- Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis of
advanced/metastatic disease.

- More than or equal to 3 lines of systemic anti-cancer therapy in the advanced or
metastatic setting.

- Recent prior therapy, defined as: a. Any investigational or approved non-biologic
anti-cancer drug within 14 days or five half-life (whichever is greater) prior to the
first dose of GSK525762 and fulvestrant. b. Any nitrosoureas or mitomycin C within 42
days prior to the first dose of GSK525762 and fulvestrant c. Any anti-cancer biologic
agents within 42 days prior to the first dose of GSK525762 and fulvestrant. d. Any
radiotherapy within 14 days prior to the first dose of GSK525762 and fulvestrant. If
the participant received radiotherapy <90 days prior to study treatment, the
irradiated lesion cannot be the only lesion used for evaluating response.

e. Any major surgery within 28 days prior to the first dose of GSK525762 and
fulvestrant

- Concomitant active malignancy other than HR+/HER2- breast cancer

- Therapeutic-dose anticoagulation (e.g., warfarin, low-molecular weight heparin [LMWH],
or novel oral anticoagulants) must be discontinued and coagulation parameters must be
normalized prior to the first dose of GSK525762 and fulvestrant. Prophylactic
anticoagulation, with low doses (per standard practice) of agents such as LMWH, direct
thrombin inhibitors, or factor Xa inhibitors is permitted.

- Current use of a prohibited medication or planned use of any forbidden medications
during treatment with GSK525762 and fulvestrant. This includes medications with
significant risk of Torsades de pointes as well as those that are potent inducers or
inhibitors of Cytochrome P3A4 (CYP3A4) enzymes.

- Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding
episodes). Any serious and/or unstable pre-existing medical (aside from malignancy),
psychiatric disorder, or other conditions that could interfere with participant's
safety, obtaining informed consent or compliance to the study procedures, in the
opinion of the Investigator. a) Systolic blood pressure higher than 150 millimeters of
mercury (mmHg) or diastolic blood pressure higher than 90 mmHg found on 2 separate
occasions separated by 1 week, despite adequate therapy, will be defined as
uncontrolled hypertension. b) Uncontrolled diabetes mellitus (despite therapeutic;
compliance to intervention) as defined by a hemoglobin A1c (HbA1c) level more than 8%
and/or occurrence of more than two episodes of ketoacidosis in the 12 months prior to
the first dose of study drug.

- Participants with advanced/metastatic, symptomatic, visceral spread, that are at risk
of life-threatening complications in the short term including participants with
massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary
lymphangitis, and over 50 percent (%) of liver involvement in metastases.

- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression.

- Cardiac abnormalities as evidenced by any of the following: Baseline QT interval
corrected by Fridericia's formula (QTcF) interval >=480 milliseconds (msec);
Clinically significant conduction abnormalities or arrhythmias; Presence of cardiac
pacemaker or defibrillator with a paced ventricular rhythm limiting electrocardiogram
analysis; History or evidence of current >=Class II congestive heart failure as
defined by New York Heart Association (NYHA); History of acute coronary syndromes
(including unstable angina and myocardial infarction), coronary angioplasty, or
stenting within the past 3 months. Participants with a history of stent placement
requiring ongoing antithrombotic therapy (e.g., clopidogrel, prasugrel) will not be
permitted to enroll; Clinically significant cardiomegaly, ventricular hypertrophy, or
cardiomyopathy.

- Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
per investigator assessment).

- Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test
result at screening.

- History of known human immunodeficiency virus (HIV) infection.

- Any serious known immediate or delayed hypersensitivity reaction(s) to GSK525762 or
fulvestrant, or idiosyncrasy to drugs chemically related to the investigational drugs.

- Hemoptysis >1 teaspoon in 24 hours within the last 28 days.

- Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) (except for cases
where NSAIDs provide benefit over other analgesics and in these cases, consideration
should be given to the prophylactic administration of a proton pump inhibitor) and
high dose aspirin (allowed up to <=100 milligrams orally daily).

- Participants with history of known bleeding disorder(s) including clinically
significant hemorrhage (e.g., gastrointestinal, neurologic), within the past 6 months.

- Any clinically significant gastrointestinal abnormalities that may alter absorption,
such as malabsorption syndrome, chronic gastrointestinal disease, or major resection
of the stomach and/or bowels that could preclude adequate absorption of the study
medication.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
2/02/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
19/07/2021
Sample size
Target
Accrual to date
Final
124
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Port Macquarie
Recruitment hospital [2] 0 0
GSK Investigational Site - Bedford Park
Recruitment hospital [3] 0 0
GSK Investigational Site - Heidelberg
Recruitment postcode(s) [1] 0 0
2444 - Port Macquarie
Recruitment postcode(s) [2] 0 0
5042 - Bedford Park
Recruitment postcode(s) [3] 0 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Louisiana
Country [7] 0 0
United States of America
State/province [7] 0 0
Minnesota
Country [8] 0 0
United States of America
State/province [8] 0 0
Missouri
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
Rhode Island
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
Country [12] 0 0
United States of America
State/province [12] 0 0
Washington
Country [13] 0 0
Canada
State/province [13] 0 0
Ontario
Country [14] 0 0
Canada
State/province [14] 0 0
Quebec
Country [15] 0 0
France
State/province [15] 0 0
Bordeaux Cedex
Country [16] 0 0
France
State/province [16] 0 0
Saint-Herblain cedex
Country [17] 0 0
France
State/province [17] 0 0
Saint-Herblain
Country [18] 0 0
Korea, Republic of
State/province [18] 0 0
Gyeonggi-do
Country [19] 0 0
Korea, Republic of
State/province [19] 0 0
Seoul
Country [20] 0 0
Spain
State/province [20] 0 0
A Coruna
Country [21] 0 0
Spain
State/province [21] 0 0
Barcelona
Country [22] 0 0
Spain
State/province [22] 0 0
Lerida
Country [23] 0 0
United Kingdom
State/province [23] 0 0
Lancashire
Country [24] 0 0
United Kingdom
State/province [24] 0 0
Middlesex
Country [25] 0 0
United Kingdom
State/province [25] 0 0
Nottinghamshire
Country [26] 0 0
United Kingdom
State/province [26] 0 0
Glasgow
Country [27] 0 0
United Kingdom
State/province [27] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT02964507
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT02964507