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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

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ClinicalTrials.gov Identifier: NCT02964507
Recruitment Status : Completed
First Posted : November 16, 2016
Results First Posted : January 27, 2022
Last Update Posted : January 27, 2022
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: GSK525762 Drug: Placebo Drug: Fulvestrant Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 124 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : February 2, 2017
Actual Primary Completion Date : September 29, 2020
Actual Study Completion Date : July 19, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Fulvestrant

Arm Intervention/treatment
Experimental: GSK525762 + Fulvestrant (Phase I) Drug: GSK525762
GSK525762 will be administered.

Drug: Fulvestrant
Fulvestrant will be administered.

Experimental: GSK525762 + Fulvestrant (Phase II) Drug: GSK525762
GSK525762 will be administered.

Drug: Fulvestrant
Fulvestrant will be administered.

Placebo Comparator: Placebo + Fulvestrant (Phase II) Drug: Placebo
Placebo will be administered.

Drug: Fulvestrant
Fulvestrant will be administered.




Primary Outcome Measures :
  1. Phase I: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 3 year and 8 months ]
    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.

  2. Phase I: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Up to 28 days ]
    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.

  3. Phase I: Number of Participants With Dose Reductions and Dose Interruption/Delays [ Time Frame: Up to 3 year and 8 months ]
    Number of participants with dose reductions and dose interruption or delay due to any reason is presented.

  4. Phase I: Objective Response Rate-Investigator Assessment [ Time Frame: Up to 3 year and 8 months ]
    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.

  5. Phase I: Plasma Concentration 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 ]
    Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK525762.

  6. Phase II: Progression Free Survival (PFS) [ Time Frame: Up to 3 year and 8 months ]
    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.


Secondary Outcome Measures :
  1. Phase I: Number of Participants Who Withdrew Due to Toxicity and Changes in Safety Assessment [ Time Frame: Up to 3 year and 8 months ]
    Number of participants who withdrew due to toxicity and changes in safety assessment including laboratory parameters and vital signs have been presented.

  2. Phase I: Disease Control Rate (DCR) [ Time Frame: Up to 3 year and 8 months ]
    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.

  3. Phase I: Duration of Response (DoR) [ Time Frame: Up to 3 year and 8 months ]
    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.

  4. Phase I: Progression-free Survival (PFS) [ Time Frame: Up to 3 year and 8 months ]
    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.

  5. Phase I: Plasma Concentration of GSK3529246 [ 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 ]
    Blood samples were collected at indicated time points for PK analysis of GSK3529246. GSK3529246 is an active metabolite of GSK525762.

  6. Phase I: Plasma Concentration of Fulvestrant [ Time Frame: Day 1: Pre-dose on Weeks 1, 3, 5, 9, 17, 25 ]
    Blood samples were collected at indicated time points for PK analysis of Fulvestrant.

  7. Phase II: Overall Survival (OS) [ Time Frame: Up to 3 year and 8 months ]
    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.

  8. Phase II: Overall Response Rate (ORR) [ Time Frame: Up to 3 year and 8 months ]
    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.

  9. Phase II: Disease Control Rate (DCR) [ Time Frame: Up to 3 year and 8 months ]
    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.

  10. Phase II: Plasma Concentration of GSK525762 and GSK3529246 [ 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 ]
    Blood samples were planned to be collected for PK analysis of GSK525762 and GSK3529246. GSK3529246 is metabolite of GSK525762.

  11. Phase II: Plasma Concentration of Fulvestrant [ Time Frame: Day 1: Pre-dose on Weeks 1, 3, 5, 9, 17, 25 ]
    Blood samples were planned to be collected for PK analysis of fulvestrant.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02964507


Locations
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United States, Alabama
GSK Investigational Site
Birmingham, Alabama, United States, 35294
United States, Arizona
GSK Investigational Site
Gilbert, Arizona, United States, 85234
GSK Investigational Site
Scottsdale, Arizona, United States, 85259
United States, California
GSK Investigational Site
San Diego, California, United States, 92123
United States, Florida
GSK Investigational Site
Plantation, Florida, United States, 33324
United States, Illinois
GSK Investigational Site
Chicago, Illinois, United States, 60611
United States, Louisiana
GSK Investigational Site
New Orleans, Louisiana, United States, 70121
United States, Minnesota
GSK Investigational Site
Rochester, Minnesota, United States, 55905
United States, Missouri
GSK Investigational Site
Kansas City, Missouri, United States, 64111
GSK Investigational Site
Saint Louis, Missouri, United States, 63110
United States, New York
GSK Investigational Site
Bronx, New York, United States, 10461
GSK Investigational Site
White Plains, New York, United States, 10601
United States, Rhode Island
GSK Investigational Site
Providence, Rhode Island, United States, 02903
United States, Texas
GSK Investigational Site
Houston, Texas, United States, 77030
United States, Washington
GSK Investigational Site
Seattle, Washington, United States, 98101
Australia, New South Wales
GSK Investigational Site
Port Macquarie, New South Wales, Australia, 2444
Australia, South Australia
GSK Investigational Site
Bedford Park, South Australia, Australia, 5042
Australia, Victoria
GSK Investigational Site
Heidelberg, Victoria, Australia, 3084
Canada, Ontario
GSK Investigational Site
Ottawa, Ontario, Canada, K1H 8L6
GSK Investigational Site
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
GSK Investigational Site
Montreal, Quebec, Canada, H2L 4M1
GSK Investigational Site
Montreal, Quebec, Canada, H3T 1E2
Canada
GSK Investigational Site
Quebec, Canada, G1S 4L8
France
GSK Investigational Site
Bordeaux Cedex, France, 33076
GSK Investigational Site
Saint-Herblain cedex, France, 44805
GSK Investigational Site
Saint-Herblain, France, 44805
Korea, Republic of
GSK Investigational Site
Gyeonggi-do, Korea, Republic of, 410-769
GSK Investigational Site
Seoul, Korea, Republic of, 120-752
GSK Investigational Site
Seoul, Korea, Republic of, 135-710
GSK Investigational Site
Seoul, Korea, Republic of, 138-736
Spain
GSK Investigational Site
A Coruna, Spain, 15006
GSK Investigational Site
Barcelona, Spain, 8035
GSK Investigational Site
Lerida, Spain, 25198
United Kingdom
GSK Investigational Site
Manchester, Lancashire, United Kingdom, M20 4BX
GSK Investigational Site
Northwood, Middlesex, United Kingdom, HA6 2RN
GSK Investigational Site
Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
GSK Investigational Site
Glasgow, United Kingdom, G12 OYN
GSK Investigational Site
London, United Kingdom, EC1M 6BQ
GSK Investigational Site
London, United Kingdom, NW1 2PG
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] May 6, 2020
Statistical Analysis Plan  [PDF] August 11, 2020

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02964507    
Other Study ID Numbers: 201973
2016-003074-40 ( EudraCT Number )
First Posted: November 16, 2016    Key Record Dates
Results First Posted: January 27, 2022
Last Update Posted: January 27, 2022
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
GSK525762
HR+/HER2- advanced or metastatic breast cancer
mTPI
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs