Clinical Trials

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 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 [Wolff, 2013]. 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/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.
  • 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;
  • 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;
  • 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:
  • 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;
  • 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 mo) 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:
  • NOTE: If pre- or peri-menopausal at time of enrollment (refer to Section 6.10.2.1 for menopause definition), subject must be willing to initiate therapy or continue ongoing therapy with goserelin for at least 28 days prior to the first  dose of fulvestrant.
  • Subjects on an alternative Luteinizing hormone-releasing hormone (LHRH) agent do not have to start goserelin prior to the first dose of fulvestrant, but they must agree to change to goserelin at the next scheduled dose and remain on goserelin for the remainder of the trial.
• 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 NCI-CTCAE v4 ≤ 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.
• Able to swallow and retain orally administered medication.
• A female subject is eligible to participate if she is of:
  • Non-childbearing potential defined in Section 6.10.2.1;
  • Child-bearing potential as defined in Section 6.10.2.2, and agrees to use one of the contraception methods as described in Appendix 4, from the time of the screening pregnancy test until 7 months after the last dose of study medication;
  • Negative serum pregnancy test ≤7 days prior to first study drug dose;
  • 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.

5.2. Exclusion Criteria

• Prior therapy with any BET inhibitor, any selective estrogen receptor degrader (SERD) including fulvestrant, or inhibitors of the PI3K/AKT/mTOR pathway.
• Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis of advanced/metastatic disease.
• ≥3 lines of systemic anti-cancer therapy in the advanced or metastatic setting.
  • NOTE:  Prior systemic anti-cancer therapy (cytotoxic chemotherapy, hormonal, CD4/6K inhibitor therapies) in the neoadjuvant/adjuvant setting does not count toward the lines of therapy.
• Recent prior therapy, defined as:
  • 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;
  • Any nitrosoureas or mitomycin C within 42 days prior to the first dose of GSK525762 and fulvestrant;
  • Any anti-cancer biologic agents within 42 days prior to the first dose of GSK525762 and fulvestrant;
  • 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;
  • Any major surgery within 28 days prior to the first dose of GSK525762 and fulvestrant.
• Concomitant active malignancy other than HR+/HER2- BC.
  • NOTE: Subjects who have been disease-free and off therapy for 2 years, or subjects with a history of treated early stage cancers such as completely resected non-melanoma skin cancer or successfully treated in situ carcinoma of the cervix are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled even if less than 2 years have elapsed since treatment. Consult Medical Monitor if unsure whether second malignancies meet requirements specified above.
• 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 low molecular weight heparin (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 (see Section 6.11.2.1 for the list of prohibited medications).
• 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.
  • Systolic blood pressure higher than 150 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;
  • Uncontrolled diabetes mellitus (despite therapeutic; compliance to intervention) as defined by a haemoglobin 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.
  • NOTE: Subjects previously treated for Central nervous system (CNS) metastases that have had stable CNS disease (verified with consecutive imaging studies) for at least 1 month, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 4 weeks prior to study Day 1 are permitted. Subjects currently taking enzyme-inducing anticonvulsant (EIAC) must be transitioned to nonenzyme inducing anticonvulsants prior to enrollment.
• Cardiac abnormalities as evidenced by any of the following:
  • Baseline QTcF interval ≥480 msec;
  • Clinically significant conduction abnormalities or arrhythmias;
    • NOTE: Any clinically significant ECG assessments should be reviewed by the site cardiologist prior to study entry.
  • Presence of cardiac pacemaker or defibrillator with a paced ventricular rhythm limiting ECG 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.
  • NOTE: Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C RNA PCR is obtained.
• History of known 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 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 mg PO daily). Details are available in 6.11.2.1.
• Subjects with history of known bleeding disorder(s) including clinically significant hemorrhage (e.g., GI, neurologic), within the past 6 months.
• Any clinically significant gastrointestinal (GI) 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.