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Dose Escalation and Expansion Study of GSK525762 in Combination With Fulvestrant in Subjects 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 : Recruiting
First Posted : November 16, 2016
Last Update Posted : June 20, 2019
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.

Approximately, up to 140 subjects and 154 subjects will receive study treatment in Phase I and Phase II respectively. A completed subject will be one who is followed until death.


Condition or disease Intervention/treatment Phase
Neoplasms Drug: GSK525762 Drug: Placebo Drug: Fulvestrant Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 294 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 HR+/HER2- Advanced or Metastatic Breast Cancer
Actual Study Start Date : February 2, 2017
Estimated Primary Completion Date : January 16, 2021
Estimated Study Completion Date : September 15, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Fulvestrant

Arm Intervention/treatment
Experimental: GSK525762 + Fulvestrant (Phase I)
In Phase I, all subjects will receive treatment with GSK525762 in combination with fulvestrant. Dosing will be continued until unacceptable toxicity, progression of disease, death, or withdrawal of consent.
Drug: GSK525762
For Phase I, GSK525762 will be available as 5 mg and 25 mg oral tablets. Subjects will be initially dosed at 60 mg daily (Dose Level 1). Further subjects will be dosed based on the dose limiting toxicity rate, at a higher 'Dose Level 2' (or still higher, based on PK data), same 'Dose Level 1', or lower 'Dose Level 1'.

Drug: Fulvestrant
Fulvestrant will be supplied as a solution for injection in a prefilled syringe, at a strength of 250 milligrams (mg) per 5 milliliters (mL), for slow intramuscular (IM) injection into the buttocks. Two 5 mL injections (total 500 mg of fulvestrant) will be administered, one in each buttock, on Day 1, Day 15, Day 29, and once monthly thereafter.

Experimental: GSK525762 + Fulvestrant (Phase II)
Subjects will receive treatment with GSK525762 in combination with fulvestrant, at a GSK525762-dose level selected from Phase I. Dosing will be continued until unacceptable toxicity, progression of disease, death, or withdrawal of consent.
Drug: GSK525762
For Phase I, GSK525762 will be available as 5 mg and 25 mg oral tablets. Subjects will be initially dosed at 60 mg daily (Dose Level 1). Further subjects will be dosed based on the dose limiting toxicity rate, at a higher 'Dose Level 2' (or still higher, based on PK data), same 'Dose Level 1', or lower 'Dose Level 1'.

Drug: Fulvestrant
Fulvestrant will be supplied as a solution for injection in a prefilled syringe, at a strength of 250 milligrams (mg) per 5 milliliters (mL), for slow intramuscular (IM) injection into the buttocks. Two 5 mL injections (total 500 mg of fulvestrant) will be administered, one in each buttock, on Day 1, Day 15, Day 29, and once monthly thereafter.

Placebo Comparator: Placebo + Fulvestrant (Phase II)
In Phase II, subjects will receive treatment with placebo in combination with fulvestrant. Dosing will be continued until unacceptable toxicity, progression of disease, death, or withdrawal of consent.
Drug: Placebo
Placebo will match GSK525762 tablets, and will be provided in Phase II only. Dosing will be done until unacceptable toxicity, progression of disease, death, or withdrawal of consent.

Drug: Fulvestrant
Fulvestrant will be supplied as a solution for injection in a prefilled syringe, at a strength of 250 milligrams (mg) per 5 milliliters (mL), for slow intramuscular (IM) injection into the buttocks. Two 5 mL injections (total 500 mg of fulvestrant) will be administered, one in each buttock, on Day 1, Day 15, Day 29, and once monthly thereafter.




Primary Outcome Measures :
  1. 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) ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.

  2. Phase I: Number of subjects 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.

  3. 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) ]
    Subjects who experience toxicity may require dose delay and/or reduction of dose based on which phase II dose will be determined.

  4. 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.

  5. 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 ]
    Subjects will be instructed to withhold their dose of orally administered study drugs, including GSK525762 and fulvestrant, until after the pre-dose pharmacokinetic blood sample is collected.

  6. 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 ]
    Blood samples for PK analysis will be collected at the indicated timepoints.

  7. Phase II: Progression free survival (PFS) [ Time Frame: From Day 1 until disease progression or death (approximately 16 months) ]
    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.


Secondary Outcome Measures :
  1. 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) ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.

  2. 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) ]
    Subjects who experience toxicity may require dose delay and/or reduction of dose which will be determined as a measure of safety and tolerability.

  3. Phase I: Number of subjects withdrawn due to toxicity [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    To determine the safety, tolerability, and maximum tolerated dose (MTD) of GSK525762, when given in combination with fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer.

  4. Phase I: Number of subjects with abnormality in hematology parameters [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    hematology parameters included white blood cells (WBCs), hemoglobin, platelet count, neutrophils, lymphocytes, monocytes, eosinophils and basophils.

  5. Phase I: Number of subjects with abnormality in clinical chemistry parameters [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    Clinical chemistry parameters included sodium, potassium, chloride, total carbondioxide, blood urea nitrogen, creatinine, fasting glucose, magnesium, calcium, total protein, albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase.

  6. Phase I: Number of subjects with abnormality in urinalysis parameters [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    Urianalysis parameters included Specific gravity, pH, glucose, protein, blood, and ketones by dipstick Microscopic examination (if urinalysis is abnormal, if available at participating site) Urine hCG pregnancy test (only for women of child bearing potential.

  7. Phase I: Number of subjects with abnormality in systolic and diastolic blood pressure [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    Systolic and diastolic blood pressure should be measured in semi-supine position after 5 minutes rest

  8. Phase I: Number of subjects with abnormality in pulse rate [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    Pulse rate should be measured in semi-supine position after 5 minutes rest

  9. Phase I: Number of subjects with abnormality in respiratory rate [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    Respiratory rate should be measured in semi-supine position after 5 minutes rest

  10. Phase I: Number of subjects with abnormality in electrocardiogram (ECG) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    Twelve-lead ECGs will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals.

  11. Phase I: Number of subjects with abnormality in any cardiotoxicity parameters [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    Cardiotoicity parameters included troponin (I or T at local laboratory), NT-proBNP, Total Cholesterol, low density lipoprotein (LDL), high density lipoprotien (HDL) and triglycerides.

  12. Phase I: Number of subjects with abnormality in gastrointestinal parameters [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    During clinical studies, medical history, physical examination (including weight) and clinical laboratory assessments will be used to identify and assess toxicity in the GI tract.

  13. Phase I: Disease control rate (DCR) [ Time Frame: From Day 1 until end of treatment (approximately 15 months) ]
    DCR is defined as CR plus PR plus stable disease [SD] rate.

  14. 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 subjects 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.

  15. Phase I: PFS [ 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.

  16. 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 ]
    Blood samples for PK analysis will be collected at the indicated timepoints.

  17. 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 ]
    Blood samples for PK analysis will be collected at the indicated timepoints.

  18. 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 subjects who have not died at the time of analysis; such subjects will be considered censored.

  19. Phase II: ORR [ Time Frame: From Day 1 until end of treatment (approximately 16 months) ]
    ORR is defined as the percentage of subjects with a confirmed CR or a PR at any time.

  20. Phase II: DCR [ Time Frame: From Day 1 until end of treatment (approximately 16 months) ]
    DCR is defined as CR plus PR plus stable disease [SD] rate.

  21. 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 ]
    Blood samples for PK analysis will be collected at the indicated timepoints.

  22. Phase II: Plasma concentration of fulvestrant, as a measure of drug exposure [ Time Frame: Day 1 of Weeks 1, 5, 9, 16, and 24 ]
    Blood samples for PK analysis will be collected at the indicated timepoints.



Information from the National Library of Medicine

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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 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. 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.

    1. 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.
    2. Subjects 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.
    3. Bone biopsies are not acceptable. Biopsies should be obtained from bone with metastatic soft-tissue component. Subjects with bone only disease may be enrolled upon review by Medical Monitor.
  • History of prior therapy that satisfies one of the following criteria:

    1. 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.
    2. 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. Subjects 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 + AI is required.
  • Any menopausal status.
  • Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria is required except for subjects 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 subject is eligible to participate if she is of: i) Non-childbearing potential and agrees to use one of the contraception methods, from the time of the screening pregnancy test until 7 months after the last dose of study medication. ii) Negative serum pregnancy test <=7 days prior to first study drug dose. iii) Female subjects 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:

    1. 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.
    2. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of GSK525762 and fulvestrant
    3. Any anti-cancer biologic agents within 42 days prior to the first dose of GSK525762 and fulvestrant
    4. Any radiotherapy within 14 days prior to the first dose of GSK525762 and fulvestrant. If the subject received radiotherapy <90 days prior to study treatment, the irradiated lesion cannot be the only lesion used for evaluating response.
    5. 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 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 subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator.

    1. 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.
    2. 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.
  • Subjects with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term including subjects with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50% 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. Subjects 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).
  • Subjects 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


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

  Show 46 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02964507     History of Changes
Other Study ID Numbers: 201973
2016-003074-40 ( EudraCT Number )
First Posted: November 16, 2016    Key Record Dates
Last Update Posted: June 20, 2019
Last Verified: June 2019

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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