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In 2017, GSK2820151 was terminated due to development of another BET Inhibitor (GSK525762) with a better understanding of the risk benefit profile.
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The study drug, GSK2820151, is a Bromodomain (BRD) and Extra-Terminal (BET) inhibitor arising from a distinct structural class. GSK2820151 potently inhibits tumor growth in vitro and in vivo in animal models. This first time in human (FTIH), open-label, dose escalation study is to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK2820151 in subjects with advanced or recurrent solid tumors. The objective is to determine the safety, tolerability and maximum tolerated dose (MTD) of GSK2820151 in subjects 18 years or older with advanced or recurrent solid tumors. Eligible subjects with advanced or recurrent solid tumors will be enrolled in the dosing cohorts until MTD is established. All subjects will receive study drug. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, or withdrawal of consent. The duration of study will depend on recruitment rates and the timing of subjects' duration on study (withdrawal rates due to toxicity or progression). It is anticipated that approximately 30 to 50 subjects will be enrolled.
GSK has decided to discontinue further development of GSK2820151 due to challenges in recruitment.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GSK2820151 arm | Experimental | An accelerated dose escalation phase will be utilized in order to minimize sub-optimal drug exposures, followed by a conventional 3+3 dose escalation phase to achieve MTD. Initially, one subject per dose cohort will be recruited (accelerated dose escalation phase) until the first instance of a >=Grade 2 drug related toxicity or dose-limiting toxicity (DLT). Further cohorts will be recruited in blocks of three subjects (3+3 dose escalation phase). Projected dose levels are 3 mg, 6 mg, 12 mg, 20 mg, 40 mg, 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg. Additional subjects may be enrolled at previously cleared dose levels in order to obtain further data for PK and/or PD analysis. Once MTD is determined, additional subjects (18 subjects total at MTD) may be enrolled to collect additional safety data. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GSK2820151 | Drug | GSK2820151 is provided as capsules containing 1 mg, 5 mg, 10 mg, 50 mg, or 100 mg of GSK2820151 as free base equivalent to be administered orally. The dosing regimen is as follows: Week 1 - once daily on days 1, 3, 4, and 5; Week 2 - once daily on days 1, 2, 3, 4, 5; and Weeks 3 and beyond - once daily continuously. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or suspected transmission of an infectious agent via the study drug were categorized as SAE. | 2 years 8 months |
| Number of Participants With Dose Delays and Reduction | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. | 2 years 8 months |
| Number of Participants Withdrawn Due to Toxicities | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Withdrawals due to toxicities were evaluated. | 2 years 8 months |
| Number of Participants With Clinically Significant Abnormalities for Clinical Chemistry Parameters | Blood samples were collected at indicated time-points for the analysis of clinical chemistry parameters like total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total protein, albumin, sodium, potassium, calcium, blood urea nitrogen (BUN), creatinine, chloride, fasting glucose, ionized calcium, gamma-glutamyltransferase, total carbon dioxide , uric acid, and magnesium. | 2 years 8 months |
| Number of Participants With Clinically Significant Abnormalities for Hematology Parameters |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLT) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. DLTs included Grade 4 neutropenia, Febrile neutropenia, Grade 4 anemia, Grade 3 thrombocytopenia, Alanine aminotransferase (ALT) >3 times upper limit of normal (ULN) plus bilirubin >=2 times ULN (>35 percent direct) or ALT between 3-5 times ULN with bilirubin < 2 times ULN but with hepatitis symptoms or rash, Grade 3 nausea, vomiting or diarrhea, Grade 3 hypertension, Grade 4 hypertension, Grade 3 or greater clinically significant non-hematologic toxicity, Grade 2 troponin B elevation were considered as DLT. |
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Inclusion Criteria:
Exclusion Criteria:
Primary malignancy of the central nervous system or malignancies related to human immunodeficiency virus (HIV) or solid organ transplant.
More than three prior lines of cytotoxic therapy.
Recent prior therapy, defined as follows: 1) Any investigational or Food and Drug Administration (FDA)-approved anti-cancer drug within 14 days or 5 half-lives, whichever is longer, prior to the first dose of GSK2820151. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of GSK2820151. Prior therapy with monoclonal antibodies is permitted so long as 14 days have elapsed since therapy and all therapy-related toxicity has resolved to Grade 1 or less. Note that an investigational drug is defined as a drug without an approved oncologic indication.
2) Any radiotherapy within 14 days or major surgery within 28 days prior to the first dose of GSK2820151.
3) Anti-androgen therapies for prostate cancer, such as bicalutamide, must be stopped 4 weeks prior to enrollment. Second-line hormone therapies such as enzalutamide, abiraterone, or orteronel should be stopped 2 weeks prior to enrolment. Subjects with prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Subjects with prostate cancer may also remain on low-dose prednisone or prednisolone (up to 10 milligrams [mg]/day) and still be eligible for this study.
4) In addition, any therapy-related toxicity must have resolved to Grade 1 or less, with the exception of alopecia (acceptable at any Grade) and peripheral neuropathy (which must be Grade 2 or less prior to enrollment).
Therapeutic anticoagulation (e.g., warfarin, heparin) must be discontinued and coagulation parameters must be normalized prior to the first dose of GSK2820151. Low dose (prophylactic) low molecular weight heparin (LMWH) is permitted. In addition, INR must be monitored in accordance with local institutional practices.
Current use of a prohibited medication or planned use of any forbidden medications during treatment with GSK2820151.
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.
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. NOTE: Subjects previously treated for these conditions that have had stable central nervous system (CNS) disease (verified with consecutive imaging studies) for >1 months, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted. Stability of brain metastases must be confirmed with imaging. Subject treated with gamma knife therapy can be enrolled 2 weeks post-procedure as long as there are no post-procedure complications/stable. In addition, subjects treated or currently taking enzyme-inducing anticonvulsant (EIAC) are allowed on study.
Cardiac abnormalities as evidenced by any of the following: History of or current "untreated" clinically significant uncontrolled arrhythmias, Clinically significant conduction abnormalities or arrhythmias, Presence of cardiac pacemaker, 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.
Any of the following electrocardiogram (ECG) findings: Baseline QTcF >=450 millisecond (msec). NOTE: Any clinically significant ECG assessments should be reviewed by the site cardiologist prior to study entry.
Any of the following liver findings: ALT >2.5xULN, ALT > 5xULN with liver metastases/tumor infiltration, Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%), 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). NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice or cirrhosis
Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. History of known HIV infection. NOTE: Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) polymerase chain reaction (PCR) is obtained.
Any serious known immediate or delayed hypersensitivity reaction(s) to GSK2820151 or idiosyncrasy to drugs chemically related to the investigational drug.
Hemoptysis >1 teaspoon in 24 hours within the last 28 days.
History of major gastrointestinal bleeding within the last 6 months.
Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Detroit | Michigan | 48201 | United States | ||
| GSK Investigational Site |
The study was terminated due to development of another bromodomain and extra-terminal(BET) Inhibitor with a better understanding of the risk benefit profile.
This was a single-agent open-label dose escalation study to determine the Maximum tolerated dose (MTD)
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| ID | Title | Description |
|---|---|---|
| FG000 | GSK2820151 3 mg | Participants received GSK2820151 capsules at a dose of 3 milligram (mg) once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 3 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| FG001 | GSK2820151 6 mg | Participants received GSK2820151 capsules at a dose of 6 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 6 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| FG002 | GSK2820151 12 mg | Participants received GSK2820151 capsules at a dose of 12 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 12 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| FG003 | GSK2820151 20 mg | Participants received GSK2820151 capsules at a dose of 20 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 20 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | GSK2820151 3 mg | Participants received GSK2820151 capsules at a dose of 3 milligram (mg) once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 3 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or suspected transmission of an infectious agent via the study drug were categorized as SAE. | All Treated Population included all participants who received at least one dose of GSK2820151. | Posted | Count of Participants | Participants | 2 years 8 months |
|
Non-serious AEs and SAEs were collected from the start of study treatment up to 2 years 8 months.
Non-serious AEs and SAEs were reported for the All Treated Population which comprised of all participants who received at least 1 dose of GSK2820151.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | GSK2820151 3 mg | Participants received GSK2820151 capsules at a dose of 3 milligram (mg) once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 3 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| GSK Response Center | GlaxoSmithKline | 866-435-7343 | 1 | GSKClinicalSupportHD@gsk.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 8, 2017 | Dec 10, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 8, 2019 | Dec 10, 2019 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D009369 | Neoplasms |
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Blood samples were collected at indicated time-points for the analysis of hematology parameters like hemoglobin (HGB), platelet count, red blood cell (RBC) count, white blood cell (WBC) count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. |
| 2 years 8 months |
| Number of Participants With Clinically Significant Abnormalities for Urinalysis Parameters | Urine samples were collected at indicated time-points for the analysis of urinalysis parameters like potential of hydrogen (pH), microscopic examination, specific gravity, ketones, protein, glucose, and blood. | 2 years 8 months |
| Number of Participants With Clinically Significant Abnormalities for Gastrointestinal Parameters | Blood samples were collected at indicated time-points for the analysis of gastrointestinal parameters like cytokines and C-peptide. | 2 years 8 months |
| Number of Participants With Clinically Significant Abnormalities for Vital Signs Parameters | Vital signs included systolic blood pressure and diastolic blood pressure, heart rate, and temperature. | 2 years 8 months |
| Number of Participants With Clinically Significant Abnormalities for Electrocardiogram (ECG) | Triple 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT and corrected QT using Fridericia's formula (QTcF) intervals. | 2 years 8 months |
| Up to 4 weeks |
| Changes in Cardiac Safety Including Corrected QT Interval (QTc) | Changes in cardiac parameters like QTc, PR Interval, QRS duration, and QT interval were assessed. Baseline is defined as the most recent, non-missing value prior to or on the first study treatment dose date for GSK2820151. Change from baseline was calculated as visit value minus Baseline value. | Baseline and up to 2 years 8 months |
| Changes in Cardiac Safety Including Heart Rate | Change in heart rate was assessed. Baseline is defined as the most recent, non-missing value prior to or on the first study treatment dose date for GSK2820151. Change from baseline was calculated as visit value minus Baseline value. | Baseline and up to 2 years 8 months |
| Overall Response Rate (ORR) | The ORR is defined as the percentage of participants with a confirmed complete response (CR) or a partial response (PR) at any time as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | 2 years 8 months |
| Progression Free Survival (PFS) | PFS is defined as the interval of time (in weeks) between the start date of treatment and the earlier of the date of disease progression and the date of death due to any cause. PFS was censored at the last adequate assessment where visit level response is CR, PR, or stable disease. | 2 years 8 months |
| Protein Biomarker (Cytokines and Acute Phase Proteins) Analysis for Pharmacodynamic (PD) Data | Blood samples were planned to be collected for analysis of protein PD biomarkers like cytokines and acute phase proteins. | 2 years 8 months |
| Messenger Ribonucleic Acid (mRNA) Analysis for PD Data | Blood samples were planned to be collected for analysis of mRNA. | 2 years 8 months |
| Maximum Observed Concentration (Cmax) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Cmax. The average Standard Deviation (SD) for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. Pharmacokinetic (PK) parameters were conducted by non-compartmental methods using Phoenix WinNonlin. PK Population consisted of all subjects from the All Treated Population for whom a PK sample is obtained and analyzed | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Time to Cmax (Tmax) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Tmax. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Area Under the Plasma Concentration-time Curve From Zero to Time (AUC[0-t]) of GSK2820151 | Blood samples were collected at indicated time-points for analysis of AUC(0-t). The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC[0-inf]) | Blood samples were collected at indicated timepoints for analysis of AUC(0-inf). The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters was conducted by non-compartmental methods using Phoenix WinNonlin. | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Area Under the Plasma Concentration-time Curve From Zero to Tau (AUC[0-tau]) of GSK2820151 | Blood samples were collected at indicated time-points for analysis of AUC(0-tau). The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Apparent Terminal Phase Half-life (t1/2) of GSK2820151 | Blood samples were collected at indicated time-points for analysis of t1/2. The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Trough Concentration (Ctau) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Ctau. The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Accumulation Ratio (Ro) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Ro. Ro was calculated as the ratio of AUC(0-tau) on Week 3 Day 4 divided by AUC(0-tau) on Week 1 Day 1. The ratio was calculated from AUC(0-tau) on Week 3 Day 4 and AUC(0-tau) on Week 1 Day 1 parameters for each participant. | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Time Invariance of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of time invariance. Time invariance was calculated as the ratio of AUC(0-tau) on Week 3 Day 4 divided by AUC(0-inf) on Week 1 Day 1. The ratio for SD was calculated from AUC(0-tau) on Week 3 Day 4 and AUC(0-inf) on Week 1 Day 1 parameters for each participant. | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Clearance (CL/F) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of CL/F. The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Volume of Distribution (Vz/F) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Vz/F. The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
| Nashville |
| Tennessee |
| 37232 |
| United States |
| GSK2820151 6 mg |
Participants received GSK2820151 capsules at a dose of 6 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 6 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| BG002 | GSK2820151 12 mg | Participants received GSK2820151 capsules at a dose of 12 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 12 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| BG003 | GSK2820151 20 mg | Participants received GSK2820151 capsules at a dose of 20 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 20 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| BG004 | Total | Total of all reporting groups |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| OG001 | GSK2820151 6 mg | Participants received GSK2820151 capsules at a dose of 6 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 6 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| OG002 | GSK2820151 12 mg | Participants received GSK2820151 capsules at a dose of 12 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 12 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
| OG003 | GSK2820151 20 mg | Participants received GSK2820151 capsules at a dose of 20 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 20 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. |
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| Primary | Number of Participants With Dose Delays and Reduction | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. | All Treated Population | Posted | Count of Participants | Participants | 2 years 8 months |
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| Primary | Number of Participants Withdrawn Due to Toxicities | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Withdrawals due to toxicities were evaluated. | All Treated Population | Posted | Count of Participants | Participants | 2 years 8 months |
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| Primary | Number of Participants With Clinically Significant Abnormalities for Clinical Chemistry Parameters | Blood samples were collected at indicated time-points for the analysis of clinical chemistry parameters like total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total protein, albumin, sodium, potassium, calcium, blood urea nitrogen (BUN), creatinine, chloride, fasting glucose, ionized calcium, gamma-glutamyltransferase, total carbon dioxide , uric acid, and magnesium. | All Treated Population | Posted | Count of Participants | Participants | 2 years 8 months |
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| Primary | Number of Participants With Clinically Significant Abnormalities for Hematology Parameters | Blood samples were collected at indicated time-points for the analysis of hematology parameters like hemoglobin (HGB), platelet count, red blood cell (RBC) count, white blood cell (WBC) count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. | All Treated Population | Posted | Count of Participants | Participants | 2 years 8 months |
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| Primary | Number of Participants With Clinically Significant Abnormalities for Urinalysis Parameters | Urine samples were collected at indicated time-points for the analysis of urinalysis parameters like potential of hydrogen (pH), microscopic examination, specific gravity, ketones, protein, glucose, and blood. | All Treated Population | Posted | Count of Participants | Participants | 2 years 8 months |
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| Primary | Number of Participants With Clinically Significant Abnormalities for Gastrointestinal Parameters | Blood samples were collected at indicated time-points for the analysis of gastrointestinal parameters like cytokines and C-peptide. | All Treated Population | Posted | Count of Participants | Participants | 2 years 8 months |
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| Primary | Number of Participants With Clinically Significant Abnormalities for Vital Signs Parameters | Vital signs included systolic blood pressure and diastolic blood pressure, heart rate, and temperature. | All Treated Population | Posted | Count of Participants | Participants | 2 years 8 months |
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| Primary | Number of Participants With Clinically Significant Abnormalities for Electrocardiogram (ECG) | Triple 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT and corrected QT using Fridericia's formula (QTcF) intervals. | All Treated Population | Posted | Count of Participants | Participants | 2 years 8 months |
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| Secondary | Number of Participants With Dose-limiting Toxicities (DLT) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. DLTs included Grade 4 neutropenia, Febrile neutropenia, Grade 4 anemia, Grade 3 thrombocytopenia, Alanine aminotransferase (ALT) >3 times upper limit of normal (ULN) plus bilirubin >=2 times ULN (>35 percent direct) or ALT between 3-5 times ULN with bilirubin < 2 times ULN but with hepatitis symptoms or rash, Grade 3 nausea, vomiting or diarrhea, Grade 3 hypertension, Grade 4 hypertension, Grade 3 or greater clinically significant non-hematologic toxicity, Grade 2 troponin B elevation were considered as DLT. | All Treated Population | Posted | Count of Participants | Participants | Up to 4 weeks |
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| Secondary | Changes in Cardiac Safety Including Corrected QT Interval (QTc) | Changes in cardiac parameters like QTc, PR Interval, QRS duration, and QT interval were assessed. Baseline is defined as the most recent, non-missing value prior to or on the first study treatment dose date for GSK2820151. Change from baseline was calculated as visit value minus Baseline value. | All Treated Population | Posted | Mean | Standard Deviation | Milliseconds | Baseline and up to 2 years 8 months |
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| Secondary | Changes in Cardiac Safety Including Heart Rate | Change in heart rate was assessed. Baseline is defined as the most recent, non-missing value prior to or on the first study treatment dose date for GSK2820151. Change from baseline was calculated as visit value minus Baseline value. | All Treated Population | Posted | Mean | Standard Deviation | Beats per minute | Baseline and up to 2 years 8 months |
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| Secondary | Overall Response Rate (ORR) | The ORR is defined as the percentage of participants with a confirmed complete response (CR) or a partial response (PR) at any time as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | All Treated Population | Posted | Number | Percentage of participants | 2 years 8 months |
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| Secondary | Progression Free Survival (PFS) | PFS is defined as the interval of time (in weeks) between the start date of treatment and the earlier of the date of disease progression and the date of death due to any cause. PFS was censored at the last adequate assessment where visit level response is CR, PR, or stable disease. | All Treated Population | Posted | Number | Weeks | 2 years 8 months |
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| Secondary | Protein Biomarker (Cytokines and Acute Phase Proteins) Analysis for Pharmacodynamic (PD) Data | Blood samples were planned to be collected for analysis of protein PD biomarkers like cytokines and acute phase proteins. | PK Population. Data was not collected for this endpoint as the study was terminated. | Posted | 2 years 8 months |
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| Secondary | Messenger Ribonucleic Acid (mRNA) Analysis for PD Data | Blood samples were planned to be collected for analysis of mRNA. | PK Population. Data was not collected for this endpoint as the study was terminated. | Posted | 2 years 8 months |
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| Secondary | Maximum Observed Concentration (Cmax) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Cmax. The average Standard Deviation (SD) for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. Pharmacokinetic (PK) parameters were conducted by non-compartmental methods using Phoenix WinNonlin. PK Population consisted of all subjects from the All Treated Population for whom a PK sample is obtained and analyzed | PK Population | Posted | Mean | Standard Deviation | Nanograms per milliliter | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Time to Cmax (Tmax) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Tmax. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | PK Population | Posted | Median | Full Range | Hours | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Area Under the Plasma Concentration-time Curve From Zero to Time (AUC[0-t]) of GSK2820151 | Blood samples were collected at indicated time-points for analysis of AUC(0-t). The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin | PK Population | Posted | Mean | Standard Deviation | Hours* nanogram per milliliter | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC[0-inf]) | Blood samples were collected at indicated timepoints for analysis of AUC(0-inf). The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters was conducted by non-compartmental methods using Phoenix WinNonlin. | PK Population | Posted | Mean | Standard Deviation | Hours* nanogram per milliliter | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Area Under the Plasma Concentration-time Curve From Zero to Tau (AUC[0-tau]) of GSK2820151 | Blood samples were collected at indicated time-points for analysis of AUC(0-tau). The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | PK Population | Posted | Mean | Standard Deviation | Hours* nanogram per milliliter | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Apparent Terminal Phase Half-life (t1/2) of GSK2820151 | Blood samples were collected at indicated time-points for analysis of t1/2. The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | PK Population | Posted | Mean | Standard Deviation | Hours | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Trough Concentration (Ctau) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Ctau. The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | PK Population | Posted | Mean | Standard Deviation | Nanograms per milliliter | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Accumulation Ratio (Ro) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Ro. Ro was calculated as the ratio of AUC(0-tau) on Week 3 Day 4 divided by AUC(0-tau) on Week 1 Day 1. The ratio was calculated from AUC(0-tau) on Week 3 Day 4 and AUC(0-tau) on Week 1 Day 1 parameters for each participant. | PK Population | Posted | Mean | Standard Deviation | Ratio | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Time Invariance of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of time invariance. Time invariance was calculated as the ratio of AUC(0-tau) on Week 3 Day 4 divided by AUC(0-inf) on Week 1 Day 1. The ratio for SD was calculated from AUC(0-tau) on Week 3 Day 4 and AUC(0-inf) on Week 1 Day 1 parameters for each participant. | PK Population. | Posted | Mean | Standard Deviation | Ratio | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Clearance (CL/F) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of CL/F. The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | PK Population | Posted | Mean | Standard Deviation | Liters per hour | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| Secondary | Volume of Distribution (Vz/F) of GSK2820151 | Blood samples were collected at indicated timepoints for analysis of Vz/F. The average SD for each participant was calculated over indicated time points Week 1, Day 1and Week 3, Day 4. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. | PK Population | Posted | Mean | Standard Deviation | Liters | Week 1, Day 1 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 33 hours post-dose); Week 3, Day 4 (Pre-dose, 15 and 30 minutes, 1, 2, 4, 8, 16, 24 and 48 hours) |
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| EG001 | GSK2820151 6 mg | Participants received GSK2820151 capsules at a dose of 6 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 6 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. | 1 | 1 | 1 | 1 | 1 | 1 |
| EG002 | GSK2820151 12 mg | Participants received GSK2820151 capsules at a dose of 12 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 12 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. | 0 | 1 | 0 | 1 | 1 | 1 |
| EG003 | GSK2820151 20 mg | Participants received GSK2820151 capsules at a dose of 20 mg once daily on days 1, 3, 4 and 5 on Week 1, during Week 2 once daily on days 1, 2, 3, 4, and 5. Participants received GSK2820151 20 mg once daily from Week 3 onwards every 4 weeks, until the end of the treatment. | 1 | 1 | 0 | 1 | 1 | 1 |
| Vomiting | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
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| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Electrocardiogram QT prolonged | Investigations | MedDRA 22.0 | Systematic Assessment |
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| Lymphoedema | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
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| Abdominal distension | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Dehydration | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 22.0 | Systematic Assessment |
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| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
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| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
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| Deep vein thrombosis | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
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| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
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| Brain natriuretic peptide increased | Investigations | MedDRA 22.0 | Systematic Assessment |
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| Tachycardia | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA 22.0 | Systematic Assessment |
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| Oedema peripheral | General disorders | MedDRA 22.0 | Systematic Assessment |
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| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Urine abnormality | Investigations | MedDRA 22.0 | Systematic Assessment |
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| Dysuria | Renal and urinary disorders | MedDRA 22.0 | Systematic Assessment |
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| Urine odour abnormal | Renal and urinary disorders | MedDRA 22.0 | Systematic Assessment |
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| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
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| Blood creatinine increased | Investigations | MedDRA 22.0 | Systematic Assessment |
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| Painful respiration | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Ascites | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Haemoglobin decreased | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
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| Squamous cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 22.0 | Systematic Assessment |
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| Lymphocyte count decreased | Investigations | MedDRA 22.0 | Systematic Assessment |
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| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
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| Hyperaesthesia | Injury, poisoning and procedural complications | MedDRA 22.0 | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA 22.0 | Systematic Assessment |
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| Flank pain | Renal and urinary disorders | MedDRA 22.0 | Systematic Assessment |
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| Transaminases increased | Investigations | MedDRA 22.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
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| Dyspnoea exertional | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Hyperbilirubinaemia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
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| Orthostatic hypotension | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
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| Malaise | General disorders | MedDRA 22.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
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| Joint stiffness | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
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GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
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