ER-positive Breast Cancer MedDRA version: 23.0 Level: LLT Classification code 10070575 Term: Estrogen receptor positive breast cancer System Organ Class: 100000004864
Conditions
Interventions
Product Code: GSK525762
Pharmaceutical Form: Tablet
INN or Proposed INN: Molibresib
Current Sponsor code: GSK525762
Other descriptive name: GSK525762
Concentration unit: mg milligram(s)
Concentration
Sponsors
GlaxoSmithKline Research & Development Limited
Eligibility
Sex/Gender
All
Inclusion criteria
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 =65 years) yes F.1.3.1 Number of subjects for this age range 105
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I To determine a recommended Phase 2 dose of GSK525762, when given in combination with fulvestrant, in women with advanced or metastatic hormone receptor positive breast cancer (HR+/HER2- BC). Phase II To evaluate the effect of treatment with GSK525762 and fulvestrant, when given in combination, on progression-free survival in women with advanced or metastatic HR+/HER2- BC.;Secondary Objective: Phase I - To determine the safety, tolerability, and maximum tolerated dose (MTD) of GSK525762, when given in combination with fulvestrant - To evaluate the clinical activity of GSK525762 and fulvestrant, when given in combination - To characterize the exposure to GSK525762 and fulvestrant, when given in combination Phase II - To evaluate the effect of treatment with GSK525762 and fulvestrant, when given in combination on additional metrics of subject survival - To evaluate the clinical activity of GSK525762 and fulvestrant, when given in combination - To characterize the exposure to GSK525762, when given in combination with fulvestrant - To characterize the exposure to fulvestrant when given alone or with GSK525762;Primary end point(s): Phase I - Safety profile (e.g. adverse events [AEs], serious adverse events [SAEs], dose-limiting toxicities (DLTs], dose reductions or delays), Overall Response Rate [ORR], defined as complete response [CR] rate plus partial response [PR] rate, pharmacokinetic [PK] data. Phase II - Progression free survival [PFS], defined as the median time from the first dose of study treatment until objective tumor progression or death from any cause, whichever comes first. ;Timepoint(s) of evaluation of this end point: PHASE I - Safety profile: AE/SAE review continuous from signing informed consent; ECG (screening, week 1 days 1 and 4, weeks 2-5 day 1, every 4 weeks after week 9 until week 49, every 12 weeks from week 49 to EoT and at final study visit), ECHO/MUGA (screening, week 5 day 1, beginning at week 13 and every 12 weeks to | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I - AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, electrocardiogram (ECG), cardiotoxicity, gastrointestinal, etc.) - Disease control rate ([DCR], defined as CR plus PR plus stable disease [SD] rate), duration of response, and progression-free survival [PFS] - Concentrations of GSK525762, GSK525762 relevant metabolites and fulvestrant following administration in combination Phase II - Overall survival [OS] - ORR, DCR - GSK525762 and metabolites concentration following administration in combination with fulvestrant - Fulvestrant concentrations following administration alone or in combination with GSK525762;Timepoint(s) of evaluation of this end point: PHASE I - AE/SAE review continuous from signing ICF; ECG, ECHO/MUGA and liver chemistry - according to protocol - DCR, PSF: screening + every 8 weeks after week 9 and at the final study visit - PK: week 1 day 1, week 3 day 1, week 5 day 1, every 8 weeks after week 9 (till week 26th) PHASE II - Tumor assessment: screening + every 8 weeks after week 9 and at the final study visit - PK: weeks 1 and 5 day 1, every 8 weeks after week 9 (till week 26th) | — |
Countries
Australia, Canada, France, Korea, Republic of, Spain, United Kingdom, United States
Contacts
Public ContactGSK Clinical Support Help Desk
GlaxoSmithKline Research & Development Limited
Outcome results
None listed