| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ER-positive Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast Cancer with growth promoted by estrogen - female hormone. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10070575 |
| E.1.2 | Term | Estrogen receptor positive breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal 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., clopidogrel, prasugrel) will not be permitted to enroll.
·Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy
12.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).
13.Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening.
14.History of known HIV infection.
15.Any serious known immediate or delayed hypersensitivity reaction(s) to GSK525762 or fulvestrant, or idiosyncrasy to drugs chemically related to the investigational drugs.
16.Hemoptysis >1 teaspoon in 24 hours within the last 28 days.
17. Concurrent use if NSAIDs and high dose aspirin (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).
18. Subjects with history of known bleeding disorder(s) including clinically significant hemorrhage with the past 6 months.
19. Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption.
|
|
| E.5 End points |
| E.5.1 | 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.
|
|
| E.5.1.1 | 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 EoT and at final study visit), liver chemistry (screening, every visit through week 11 and then every 4 weeks starting at week 13 to EoT and final study visit)
- ORR: screening + every 8 weeks after week 9 and at the final study visit
PHASE II
- PFS: screening + every 8 weeks after week 9 and at the final study visit |
|
| E.5.2 | 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 |
|
| E.5.2.1 | 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) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation and expansion study |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase I - dose escalation, expansion; Phase II - randomized, double-blind, placebo-controlled cohort |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| France |
| Korea, Republic of |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will be considered completed for purposes of a final analysis when approximately 70% of subjects enrolled in Phase II have progressed or died. However, the study could be stopped due to toxicity or futility before that when there is enough evidence to conclude as such. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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