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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 : Active, not recruiting
First Posted : November 16, 2016
Last Update Posted : July 22, 2021
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE November 12, 2016
First Posted Date  ICMJE November 16, 2016
Last Update Posted Date July 22, 2021
Actual Study Start Date  ICMJE February 2, 2017
Actual Primary Completion Date September 29, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 16, 2021)
  • Phase I: Number of participants with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    AEs and SAEs will be collected.
  • Phase I: Number of participants with dose limiting toxicities (DLT) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    An event will be considered a DLT if it occurs within the first 28 days of treatment and meets at least one of the DLT criteria.
  • Phase I: Number of participants with dose reductions or delays [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    Participants who experience toxicity may require dose delay and/or reduction of dose based on which phase II dose will be determined.
  • Phase I: Overall response rate (ORR) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    ORR is defined as percentage of participants with confirmed complete response (CR) rate or a partial response (PR) rate at any time.
  • Phase I: Plasma concentration of GSK525762 [ Time Frame: Day 1 of Weeks 1, 3, 5, 9, 16, and 24 ]
    Blood samples will be collected for the concentration of GSK525762.
  • Phase I: Plasma concentration of fulvestrant [ Time Frame: Day 1 of Weeks 1, 3, 5, 9, 16, and 24 ]
    Blood samples will be collected for the concentration of fulvestrant.
  • Phase II: Progression free survival (PFS) [ Time Frame: From Day 1 until disease progression or death (approximately 16 months) ]
    PFS is defined as the time from study treatment start until the first date of either disease progression or death due to any cause. Phase II of the study is terminated, hence this outcome will not be captured.
Original Primary Outcome Measures  ICMJE
 (submitted: November 12, 2016)
  • Phase I: Number of subjects with adverse events (AE) and serious adverse events (SAE), for the determination of recommended Phase II dose of GSK525762 [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of subjects with dose limiting toxicities (DLT) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of subjects with dose reductions or delays, for the determination of recommended Phase II dose of GSK525762 [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Overall response rate (ORR) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    ORR is defined as complete response (CR) rate plus partial response (PR) rate.
  • Phase I: Plasma concentration of GSK525762, for the determination of recommended Phase II dose of GSK525762 [ Time Frame: Day 1 of Weeks 1, 3, 5, 9, 16, and 24 ]
  • Phase I: Plasma concentration of fulvestrant, for the determination of recommended Phase II dose of GSK525762 [ Time Frame: Day 1 of Weeks 1, 3, 5, 9, 16, and 24 ]
  • Phase II: Progression free survival (PFS) [ Time Frame: From Day 1 until disease progression or death (approximately 16 months) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 16, 2021)
  • Phase I: Number of participants with AEs or SAEs [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    AEs and SAEs will be collected.
  • Phase I: Number of participants with dose reductions or delays [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of participants withdrawn due to toxicity [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of participants with clinically significant changes in clinical laboratory parameters, vital signs, electrocardiogram (ECG), cardiotoxicity and gastrointestinal parameters [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Disease control rate (DCR) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    DCR is defined as complete response (CR) plus partial response (PR) plus stable disease (SD) rate.
  • Phase I: Duration of response [ Time Frame: From Day 1 until disease progression or death (approximately 15 months) ]
    Duration of response is the subset of participants who show a confirmed CR or PR, the time from first documented evidence of CR or PR until the first documented sign of disease progression or death.
  • Phase I: Progression-free survival [ Time Frame: From Day 1 until disease progression or death (approximately 15 months) ]
    Progression-free survival (PFS) will be defined as the time from study treatment start until the first date of either disease progression or death due to any cause.
  • Phase I: Plasma concentration of GSK525762, its metabolites and fulvestrant [ Time Frame: Day 1 of Weeks 1, 3, 5, 9, 16, and 24 ]
    Blood samples will be collected for the concentration of GSK525762, its metabolites and fulvestrant.
  • Phase II: Overall Survival (OS) [ Time Frame: From Day 1 until death (approximately 16 months) ]
    For the analysis of OS, the last date of known contact will be used for those participants who have not died at the time of analysis; such participants will be considered censored. Phase II of the study is terminated, hence this outcome will not be captured.
  • Phase II: Overall response rate [ Time Frame: From Day 1 until end of treatment (approximately 16 months) ]
    ORR is defined as the percentage of participants with a confirmed CR or a PR at any time. Phase II of the study is terminated, hence this outcome will not be captured.
  • Phase II: Disease control rate [ Time Frame: From Day 1 until end of treatment (approximately 16 months) ]
    DCR is defined as CR plus PR plus stable disease (SD) rate. Phase II of the study is terminated, hence this outcome will not be captured.
  • Phase II: Plasma concentration of GSK525762, its metabolites and fulvestrant [ Time Frame: Day 1 of Weeks 1, 5, 9, 16, and 24 ]
    Blood samples for PK analysis will be collected for the concentration of GSK525762, its metabolites and fulvestrant. Phase II of the study is terminated, hence this outcome will not be captured.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2016)
  • Phase I: Number of subjects with AEs or SAEs, as a measure of safety and tolerability [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of subjects with dose reductions or delays, as a measure of safety and tolerability [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of subjects withdrawn due to toxicity [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of subjects with abnormality in laboratory parameters [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of subjects with abnormality in vital signs [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of subjects with abnormality in electrocardiogram (ECG) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of subjects with abnormality in any cardiotoxicity parameters [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Number of subjects with abnormality in gastrointestinal parameters [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Disease control rate (DCR) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
  • Phase I: Duration of response [ Time Frame: From Day 1 until disease progression or death (approximately 15 months) ]
  • Phase I: PFS [ Time Frame: From Day 1 until disease progression or death (approximately 15 months) ]
  • Phase I: Time to progression (TTP) [ Time Frame: From Day 1 until disease progression or death (approximately 15 months) ]
  • Phase I: Plasma concentration of GSK525762 and its metabolites, as a measure of drug exposure [ Time Frame: Day 1 of Weeks 1, 3, 5, 9, 16, and 24 ]
  • Phase I: Plasma concentration of fulvestrant, as a measure of drug exposure [ Time Frame: Day 1 of Weeks 1, 3, 5, 9, 16, and 24 ]
  • Phase I: Correlation between ESR1 mutations and clinical response, determined by targeted sequencing of tumor tissue [ Time Frame: Over a period of approximately 15 months ]
  • Phase II: Overall Survival (OS) [ Time Frame: From Day 1 until death (approximately 16 months) ]
  • Phase II: TTP [ Time Frame: From Day 1 until disease progression or death (approximately 16 months) ]
  • Phase II: ORR [ Time Frame: From Day 1 until end of treatment (approximately 16 months) ]
  • Phase II: DCR [ Time Frame: From Day 1 until end of treatment (approximately 16 months) ]
  • Phase II: Plasma concentration of GSK525762 and its metabolites, as a measure of drug exposure [ Time Frame: Day 1 of Weeks 1, 5, 9, 16, and 24 ]
  • Phase II: Plasma concentration of fulvestrant, as a measure of drug exposure [ Time Frame: Day 1 of Weeks 1, 5, 9, 16, and 24 ]
  • Phase II: Correlation between ESR1 mutations and clinical response, determined by targeted sequencing of tumor tissue [ Time Frame: Screening, and (optionally) at end of treatment (approximately 16 months) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE
  • Drug: GSK525762
    GSK525762 will be administered.
  • Drug: Placebo
    Placebo will be administered.
  • Drug: Fulvestrant
    Fulvestrant will be administered.
Study Arms  ICMJE
  • Experimental: GSK525762 + Fulvestrant (Phase I)
    Interventions:
    • Drug: GSK525762
    • Drug: Fulvestrant
  • Experimental: GSK525762 + Fulvestrant (Phase II)
    Interventions:
    • Drug: GSK525762
    • Drug: Fulvestrant
  • Placebo Comparator: Placebo + Fulvestrant (Phase II)
    Interventions:
    • Drug: Placebo
    • Drug: Fulvestrant
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 23, 2020)
123
Original Estimated Enrollment  ICMJE
 (submitted: November 12, 2016)
294
Estimated Study Completion Date  ICMJE August 20, 2021
Actual Primary Completion Date September 29, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   France,   Korea, Republic of,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02964507
Other Study ID Numbers  ICMJE 201973
2016-003074-40 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: 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
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP