Clinical trial using GSK525762 in combination with fulvestrant in subjects with breast cancer.

Phase 1

Conditions: ER-positive Breast Cancer
MedDRA version: 23.0Level: LLTClassification code 10070575Term: Estrogen receptor positive breast cancerSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2016-003074-40-GB

Lead Sponsor: GlaxoSmithKline Research & Development Limited

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Female

Target Recruitment: 300

Inclusion Criteria

1. Written informed consent provided
2. Females 18 years old and greater (at the time of written consent)
3. Histologically or cytologically confirmed diagnosis of advanced or metastatic adenocarcinoma of the breast.
4. Documentation of ER-positive and/or PR-positive tumor based on local testing of the most recent tumor biopsy
5. Documentation of HER2-negative tumor based on local testing of the most recent tumor biopsy
6. 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. 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.
c. 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.
7. History of prior therapy that satisfies one of the following criteria:
a. 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.CDK 4/6 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 CDF4/6 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.
8. Documented progression on last line of systemic anti-cancer therapy with CDF4/6 inhibitor +AI is required.
9. Any menopausal status
10. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria is required except for subjects with bone only disease.
11. 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
12. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1
13. Adequate organ function
14. Able to swallow and retain orally administered medication
15. A female subject is eligible to participate if she is of:
- non-childbearing potential
- child-bearing 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
- 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 195
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 105

Exclusion Criteria

1. Prior therapy with any BET inhibitor, any selective estrogen receptor degrader (SERD) including fulvestrant, or inhibitors of the PI3K/AKT/mTOR pathway.
2. Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis of advanced/metastatic disease.
3. =3 lines of systemic anti-cancer therapy in the advanced or metastatic setting
NOTE:
a. Prior systemic anti-cancer therapy (cytotoxic chemotherapy, hormonal, CDK4/6 inhibitor therapies) in the neoadjuvant/adjuvant setting does not count toward the lines of therapy.
4. 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
5.Concomitant active malignancy other than ER+BC
6.Therapeutic-dose anticoagulation must be discontinued and coagulation parameters must be normalized prior to the first dose of GSK525762 and fulvestrant. Prophylactic anticoagulation is permitted.
7.Current use of a prohibited medication or planned use of any forbidden medications during treatment with GSK525762 and fulvestrant.
8.Evidence of severe or uncontrolled systemic diseases. 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.
a. Systolic blood pressure higher than 150 mmHg or diastolic blood pressure higher than 90 mmHg fond 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 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.
9.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.
10.Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
11. Cardiac abnormalities as evidenced by any of the following:
·Baseline QTcF interval =480 msec
·Clinically significant conduction abnormalities or arrhythmias
·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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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