Cancer, Neoplasms
Conditions
Keywords
Cancer, Safety, GSK2820151, Dose escalation, Tolerability, Pharmacodynamics, Pharmacokinetics
Brief summary
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.
Detailed description
GSK has decided to discontinue further development of GSK2820151 due to challenges in recruitment.
Interventions
DRUGGSK2820151
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.
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent provided * Males and females 18 years old and greater * Diagnosis of advanced or recurrent, histologically or cytologically confirmed, solid malignancy that is either metastatic or unresectable. At time of enrollment, subjects either refuse standard curative or palliative therapy, are not candidates for standard curative or palliative therapy, have a disease for which no non-investigational therapy exists, OR have progressed on prior therapy (up to three lines of prior cytotoxic agents are permitted). * Subjects with solid tumors, with the exception of castration-resistant prostate cancer (CRPC), must demonstrate measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. * All prior treatment- related toxicities must be National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 \<=Grade 1 (except alopecia \[permissible at any Grade\] and peripheral neuropathy \[which must be \<= Grade 2\]) at the time of treatment allocation. * Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1. * Adequate organ function defined as follows: System and Laboratory Values: Hematologic - Absolute neutrophil count (ANC) \>=1.5 X 10\^9/liter (L), Hemoglobin \>=9 grams (g)/deciliter (dL) (subjects that required transfusion or growth factor need to demonstrate stable hemoglobin for 7 days of 9 g/dL), Platelets \>=100 X 10\^9/L, prothrombin time (PT)/ international normalized ratio (INR) and partial thromboplastin time (PTT) - \<=1.5 X upper limit of normal (ULN); Hepatic - Albumin \>=2.5 g/dL, Total bilirubin \<=1.5 X ULN (isolated bilirubin \>1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35% or subject has a diagnosis of Gilbert's syndrome), Alanine aminotransferase (ALT) \<=2.5 x ULN OR \<5 x ULN is acceptable for subjects with documented liver metastases/tumor infiltration; Renal - Creatinine \<=1.5 X ULN OR Creatinine clearance \[either directly measured or calculated by Cockcroft-Gault formula\] \>=40 milliliter (mL)/minute (min); Cardiac - Ejection fraction \>=50% by echocardiogram or multigated acquisition scan (MUGA), Troponin (T) \<=ULN, Potassium \>=Lower limit of normal (LLN) and \<=ULN, Magnesium \>=LLN * Able to swallow and retain orally administered medication. * A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, hysterectomy, or documented bilateral tubal oophorectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \>40 units (U)/mL and estradiol \<40 picograms (pg)/mL (\<140 picomoles (pmol)/L) is confirmatory\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. Child-bearing potential and agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception 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 5 half-lives of GSK2820151 or at least 28 days (whichever is longer) following the last dose of study treatment. * Male subjects with female partners of child bearing potential must agree to use one of the methods of contraception specified. This method must be used from the time of the first dose of study medication until 16 weeks after the last dose of study medication. In addition, male subjects whose partners are or become pregnant on study medication must continue to use condoms for 7 days after stopping study medication
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 2 years 8 months | 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. |
| Number of Participants With Dose Delays and Reduction | 2 years 8 months | 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. |
| Number of Participants Withdrawn Due to Toxicities | 2 years 8 months | 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. |
| Number of Participants With Clinically Significant Abnormalities for Clinical Chemistry Parameters | 2 years 8 months | 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. |
| Number of Participants With Clinically Significant Abnormalities for Hematology Parameters | 2 years 8 months | 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. |
| Number of Participants With Clinically Significant Abnormalities for Urinalysis Parameters | 2 years 8 months | 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. |
| Number of Participants With Clinically Significant Abnormalities for Gastrointestinal Parameters | 2 years 8 months | Blood samples were collected at indicated time-points for the analysis of gastrointestinal parameters like cytokines and C-peptide. |
| Number of Participants With Clinically Significant Abnormalities for Vital Signs Parameters | 2 years 8 months | Vital signs included systolic blood pressure and diastolic blood pressure, heart rate, and temperature. |
| Number of Participants With Clinically Significant Abnormalities for Electrocardiogram (ECG) | 2 years 8 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Zero to Time (AUC[0-t]) of GSK2820151 | 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) | 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 |
| Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC[0-inf]) | 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) | 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. |
| Area Under the Plasma Concentration-time Curve From Zero to Tau (AUC[0-tau]) of GSK2820151 | 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) | 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. |
| Apparent Terminal Phase Half-life (t1/2) of GSK2820151 | 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) | 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. |
| Number of Participants With Dose-limiting Toxicities (DLT) | Up to 4 weeks | 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. |
| Accumulation Ratio (Ro) of GSK2820151 | 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) | 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. |
| Time Invariance of GSK2820151 | 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) | 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. |
| Clearance (CL/F) of GSK2820151 | 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) | 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. |
| Volume of Distribution (Vz/F) of GSK2820151 | 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) | 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. |
| Trough Concentration (Ctau) of GSK2820151 | 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) | 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. |
| Changes in Cardiac Safety Including Corrected QT Interval (QTc) | Baseline and up to 2 years 8 months | 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. |
| Changes in Cardiac Safety Including Heart Rate | Baseline and up to 2 years 8 months | 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. |
| Overall Response Rate (ORR) | 2 years 8 months | 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. |
| Progression Free Survival (PFS) | 2 years 8 months | 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. |
| Protein Biomarker (Cytokines and Acute Phase Proteins) Analysis for Pharmacodynamic (PD) Data | 2 years 8 months | Blood samples were planned to be collected for analysis of protein PD biomarkers like cytokines and acute phase proteins. |
| Messenger Ribonucleic Acid (mRNA) Analysis for PD Data | 2 years 8 months | Blood samples were planned to be collected for analysis of mRNA. |
| Maximum Observed Concentration (Cmax) of GSK2820151 | 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) | 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 |
| Time to Cmax (Tmax) of GSK2820151 | 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) | Blood samples were collected at indicated timepoints for analysis of Tmax. PK parameters were conducted by non-compartmental methods using Phoenix WinNonlin. |
Countries
United States
Participant flow
Recruitment details
This was a single-agent open-label dose escalation study to determine the Maximum tolerated dose (MTD)
Pre-assignment details
The study was terminated due to development of another bromodomain and extra-terminal(BET) Inhibitor with a better understanding of the risk benefit profile.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 2 |
| 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 |
| 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. | 1 |
| 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 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | GSK2820151 3 mg | GSK2820151 6 mg | GSK2820151 12 mg | GSK2820151 20 mg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White/Caucasian/European Heritage | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 2 | 1 / 1 | 0 / 1 | 1 / 1 |
| other Total, other adverse events | 2 / 2 | 1 / 1 | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 2 / 2 | 1 / 1 | 0 / 1 | 0 / 1 |
Outcome results
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.
Time frame: 2 years 8 months
Population: All Treated Population included all participants who received at least one dose of GSK2820151.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GSK2820151 3 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 Participants |
| GSK2820151 3 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| GSK2820151 6 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| GSK2820151 6 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 Participants |
| GSK2820151 12 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 Participants |
| GSK2820151 12 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| GSK2820151 20 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 Participants |
| GSK2820151 20 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK2820151 3 mg | Number of Participants With Clinically Significant Abnormalities for Clinical Chemistry Parameters | 0 Participants |
| GSK2820151 6 mg | Number of Participants With Clinically Significant Abnormalities for Clinical Chemistry Parameters | 0 Participants |
| GSK2820151 12 mg | Number of Participants With Clinically Significant Abnormalities for Clinical Chemistry Parameters | 0 Participants |
| GSK2820151 20 mg | Number of Participants With Clinically Significant Abnormalities for Clinical Chemistry Parameters | 0 Participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK2820151 3 mg | Number of Participants With Clinically Significant Abnormalities for Electrocardiogram (ECG) | 0 Participants |
| GSK2820151 6 mg | Number of Participants With Clinically Significant Abnormalities for Electrocardiogram (ECG) | 0 Participants |
| GSK2820151 12 mg | Number of Participants With Clinically Significant Abnormalities for Electrocardiogram (ECG) | 0 Participants |
| GSK2820151 20 mg | Number of Participants With Clinically Significant Abnormalities for Electrocardiogram (ECG) | 0 Participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK2820151 3 mg | Number of Participants With Clinically Significant Abnormalities for Gastrointestinal Parameters | 0 Participants |
| GSK2820151 6 mg | Number of Participants With Clinically Significant Abnormalities for Gastrointestinal Parameters | 0 Participants |
| GSK2820151 12 mg | Number of Participants With Clinically Significant Abnormalities for Gastrointestinal Parameters | 0 Participants |
| GSK2820151 20 mg | Number of Participants With Clinically Significant Abnormalities for Gastrointestinal Parameters | 0 Participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK2820151 3 mg | Number of Participants With Clinically Significant Abnormalities for Hematology Parameters | 0 Participants |
| GSK2820151 6 mg | Number of Participants With Clinically Significant Abnormalities for Hematology Parameters | 0 Participants |
| GSK2820151 12 mg | Number of Participants With Clinically Significant Abnormalities for Hematology Parameters | 0 Participants |
| GSK2820151 20 mg | Number of Participants With Clinically Significant Abnormalities for Hematology Parameters | 0 Participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK2820151 3 mg | Number of Participants With Clinically Significant Abnormalities for Urinalysis Parameters | 0 Participants |
| GSK2820151 6 mg | Number of Participants With Clinically Significant Abnormalities for Urinalysis Parameters | 0 Participants |
| GSK2820151 12 mg | Number of Participants With Clinically Significant Abnormalities for Urinalysis Parameters | 0 Participants |
| GSK2820151 20 mg | Number of Participants With Clinically Significant Abnormalities for Urinalysis Parameters | 0 Participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK2820151 3 mg | Number of Participants With Clinically Significant Abnormalities for Vital Signs Parameters | 0 Participants |
| GSK2820151 6 mg | Number of Participants With Clinically Significant Abnormalities for Vital Signs Parameters | 0 Participants |
| GSK2820151 12 mg | Number of Participants With Clinically Significant Abnormalities for Vital Signs Parameters | 0 Participants |
| GSK2820151 20 mg | Number of Participants With Clinically Significant Abnormalities for Vital Signs Parameters | 0 Participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK2820151 3 mg | Number of Participants With Dose Delays and Reduction | 0 Participants |
| GSK2820151 6 mg | Number of Participants With Dose Delays and Reduction | 0 Participants |
| GSK2820151 12 mg | Number of Participants With Dose Delays and Reduction | 0 Participants |
| GSK2820151 20 mg | Number of Participants With Dose Delays and Reduction | 0 Participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK2820151 3 mg | Number of Participants Withdrawn Due to Toxicities | 0 Participants |
| GSK2820151 6 mg | Number of Participants Withdrawn Due to Toxicities | 0 Participants |
| GSK2820151 12 mg | Number of Participants Withdrawn Due to Toxicities | 0 Participants |
| GSK2820151 20 mg | Number of Participants Withdrawn Due to Toxicities | 0 Participants |
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.
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Accumulation Ratio (Ro) of GSK2820151 | 1.17 Ratio | Standard Deviation 0.999 |
| GSK2820151 6 mg | Accumulation Ratio (Ro) of GSK2820151 | 1.33 Ratio | — |
| GSK2820151 12 mg | Accumulation Ratio (Ro) of GSK2820151 | 0.95 Ratio | — |
| GSK2820151 20 mg | Accumulation Ratio (Ro) of GSK2820151 | 1.26 Ratio | — |
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.
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Apparent Terminal Phase Half-life (t1/2) of GSK2820151 | 11.66 Hours | Standard Deviation 6.3 |
| GSK2820151 6 mg | Apparent Terminal Phase Half-life (t1/2) of GSK2820151 | 10.91 Hours | Standard Deviation 1.153 |
| GSK2820151 12 mg | Apparent Terminal Phase Half-life (t1/2) of GSK2820151 | 4.77 Hours | Standard Deviation 0.336 |
| GSK2820151 20 mg | Apparent Terminal Phase Half-life (t1/2) of GSK2820151 | 10.14 Hours | Standard Deviation 1.379 |
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.
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC[0-inf]) | 488.40 Hours* nanogram per milliliter | Standard Deviation 381.276 |
| GSK2820151 6 mg | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC[0-inf]) | 479.12 Hours* nanogram per milliliter | Standard Deviation 127.755 |
| GSK2820151 12 mg | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC[0-inf]) | 216.65 Hours* nanogram per milliliter | Standard Deviation 18.215 |
| GSK2820151 20 mg | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC[0-inf]) | 1107.74 Hours* nanogram per milliliter | Standard Deviation 147.297 |
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.
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Area Under the Plasma Concentration-time Curve From Zero to Tau (AUC[0-tau]) of GSK2820151 | 328.55 Hours* nanogram per milliliter | Standard Deviation 209.993 |
| GSK2820151 6 mg | Area Under the Plasma Concentration-time Curve From Zero to Tau (AUC[0-tau]) of GSK2820151 | 377.60 Hours* nanogram per milliliter | Standard Deviation 75.413 |
| GSK2820151 12 mg | Area Under the Plasma Concentration-time Curve From Zero to Tau (AUC[0-tau]) of GSK2820151 | 210.32 Hours* nanogram per milliliter | Standard Deviation 16.761 |
| GSK2820151 20 mg | Area Under the Plasma Concentration-time Curve From Zero to Tau (AUC[0-tau]) of GSK2820151 | 918.11 Hours* nanogram per milliliter | Standard Deviation 149.815 |
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
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Area Under the Plasma Concentration-time Curve From Zero to Time (AUC[0-t]) of GSK2820151 | 356.10 Hours* nanogram per milliliter | Standard Deviation 237.739 |
| GSK2820151 6 mg | Area Under the Plasma Concentration-time Curve From Zero to Time (AUC[0-t]) of GSK2820151 | 392.17 Hours* nanogram per milliliter | Standard Deviation 54.801 |
| GSK2820151 12 mg | Area Under the Plasma Concentration-time Curve From Zero to Time (AUC[0-t]) of GSK2820151 | 211.84 Hours* nanogram per milliliter | Standard Deviation 16.349 |
| GSK2820151 20 mg | Area Under the Plasma Concentration-time Curve From Zero to Time (AUC[0-t]) of GSK2820151 | 958.35 Hours* nanogram per milliliter | Standard Deviation 92.9 |
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.
Time frame: Baseline and up to 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Changes in Cardiac Safety Including Corrected QT Interval (QTc) | -5.33 Milliseconds | Standard Deviation 17.272 |
| GSK2820151 6 mg | Changes in Cardiac Safety Including Corrected QT Interval (QTc) | -9.25 Milliseconds | Standard Deviation 13.849 |
| GSK2820151 12 mg | Changes in Cardiac Safety Including Corrected QT Interval (QTc) | 4.91 Milliseconds | Standard Deviation 11.274 |
| GSK2820151 20 mg | Changes in Cardiac Safety Including Corrected QT Interval (QTc) | -24.95 Milliseconds | Standard Deviation 10.4 |
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.
Time frame: Baseline and up to 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Changes in Cardiac Safety Including Heart Rate | -0.44 Beats per minute | Standard Deviation 7.719 |
| GSK2820151 6 mg | Changes in Cardiac Safety Including Heart Rate | 11.51 Beats per minute | Standard Deviation 8.072 |
| GSK2820151 12 mg | Changes in Cardiac Safety Including Heart Rate | 3.41 Beats per minute | Standard Deviation 5.929 |
| GSK2820151 20 mg | Changes in Cardiac Safety Including Heart Rate | 2.03 Beats per minute | Standard Deviation 4.609 |
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.
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Clearance (CL/F) of GSK2820151 | 11.29 Liters per hour | Standard Deviation 8.91 |
| GSK2820151 6 mg | Clearance (CL/F) of GSK2820151 | 12.96 Liters per hour | Standard Deviation 3.373 |
| GSK2820151 12 mg | Clearance (CL/F) of GSK2820151 | 66.92 Liters per hour | Standard Deviation 15.339 |
| GSK2820151 20 mg | Clearance (CL/F) of GSK2820151 | 18.21 Liters per hour | Standard Deviation 2.425 |
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
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Maximum Observed Concentration (Cmax) of GSK2820151 | 31.78 Nanograms per milliliter | Standard Deviation 9.599 |
| GSK2820151 6 mg | Maximum Observed Concentration (Cmax) of GSK2820151 | 35.08 Nanograms per milliliter | Standard Deviation 1.061 |
| GSK2820151 12 mg | Maximum Observed Concentration (Cmax) of GSK2820151 | 36.17 Nanograms per milliliter | Standard Deviation 8.237 |
| GSK2820151 20 mg | Maximum Observed Concentration (Cmax) of GSK2820151 | 148.11 Nanograms per milliliter | Standard Deviation 14.595 |
Secondary
Messenger Ribonucleic Acid (mRNA) Analysis for PD Data
Blood samples were planned to be collected for analysis of mRNA.
Time frame: 2 years 8 months
Population: PK Population. Data was not collected for this endpoint as the study was terminated.
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.
Time frame: Up to 4 weeks
Population: All Treated Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GSK2820151 3 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 0 Participants |
| GSK2820151 6 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 0 Participants |
| GSK2820151 12 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 0 Participants |
| GSK2820151 20 mg | Number of Participants With Dose-limiting Toxicities (DLT) | 0 Participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GSK2820151 3 mg | Overall Response Rate (ORR) | 0 Percentage of participants |
| GSK2820151 6 mg | Overall Response Rate (ORR) | 0 Percentage of participants |
| GSK2820151 12 mg | Overall Response Rate (ORR) | 100 Percentage of participants |
| GSK2820151 20 mg | Overall Response Rate (ORR) | 0 Percentage of participants |
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.
Time frame: 2 years 8 months
Population: All Treated Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK2820151 3 mg | Progression Free Survival (PFS) | Participant 4 | 0 Weeks |
| GSK2820151 3 mg | Progression Free Survival (PFS) | Participant 1 | 5.3 Weeks |
| GSK2820151 3 mg | Progression Free Survival (PFS) | Participant 5 | 0 Weeks |
| GSK2820151 3 mg | Progression Free Survival (PFS) | Participant 3 | 0 Weeks |
| GSK2820151 3 mg | Progression Free Survival (PFS) | Participant 2 | 9.9 Weeks |
| GSK2820151 6 mg | Progression Free Survival (PFS) | Participant 3 | 8.4 Weeks |
| GSK2820151 6 mg | Progression Free Survival (PFS) | Participant 4 | 0 Weeks |
| GSK2820151 6 mg | Progression Free Survival (PFS) | Participant 2 | 0 Weeks |
| GSK2820151 6 mg | Progression Free Survival (PFS) | Participant 5 | 0 Weeks |
| GSK2820151 6 mg | Progression Free Survival (PFS) | Participant 1 | 0 Weeks |
| GSK2820151 12 mg | Progression Free Survival (PFS) | Participant 1 | 0 Weeks |
| GSK2820151 12 mg | Progression Free Survival (PFS) | Participant 2 | 0 Weeks |
| GSK2820151 12 mg | Progression Free Survival (PFS) | Participant 3 | 0 Weeks |
| GSK2820151 12 mg | Progression Free Survival (PFS) | Participant 4 | 72.1 Weeks |
| GSK2820151 12 mg | Progression Free Survival (PFS) | Participant 5 | 0 Weeks |
| GSK2820151 20 mg | Progression Free Survival (PFS) | Participant 4 | 0 Weeks |
| GSK2820151 20 mg | Progression Free Survival (PFS) | Participant 2 | 0 Weeks |
| GSK2820151 20 mg | Progression Free Survival (PFS) | Participant 1 | 0 Weeks |
| GSK2820151 20 mg | Progression Free Survival (PFS) | Participant 3 | 0 Weeks |
| GSK2820151 20 mg | Progression Free Survival (PFS) | Participant 5 | 8.1 Weeks |
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.
Time frame: 2 years 8 months
Population: PK Population. Data was not collected for this endpoint as the study was terminated.
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.
Time frame: 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)
Population: PK Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Time Invariance of GSK2820151 | 0.87 Ratio | Standard Deviation 0.366 |
| GSK2820151 6 mg | Time Invariance of GSK2820151 | 1.10 Ratio | — |
| GSK2820151 12 mg | Time Invariance of GSK2820151 | 0.92 Ratio | — |
| GSK2820151 20 mg | Time Invariance of GSK2820151 | 1.02 Ratio | — |
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.
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK2820151 3 mg | Time to Cmax (Tmax) of GSK2820151 | 1.50 Hours |
| GSK2820151 6 mg | Time to Cmax (Tmax) of GSK2820151 | 2.50 Hours |
| GSK2820151 12 mg | Time to Cmax (Tmax) of GSK2820151 | 1.00 Hours |
| GSK2820151 20 mg | Time to Cmax (Tmax) of GSK2820151 | 0.75 Hours |
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.
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Trough Concentration (Ctau) of GSK2820151 | 7.02 Nanograms per milliliter | Standard Deviation 6.674 |
| GSK2820151 6 mg | Trough Concentration (Ctau) of GSK2820151 | 6.04 Nanograms per milliliter | Standard Deviation 2.871 |
| GSK2820151 12 mg | Trough Concentration (Ctau) of GSK2820151 | 0.91 Nanograms per milliliter | Standard Deviation 0.276 |
| GSK2820151 20 mg | Trough Concentration (Ctau) of GSK2820151 | 12.77 Nanograms per milliliter | Standard Deviation 2.036 |
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.
Time frame: 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)
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK2820151 3 mg | Volume of Distribution (Vz/F) of GSK2820151 | 136.07 Liters | Standard Deviation 63.572 |
| GSK2820151 6 mg | Volume of Distribution (Vz/F) of GSK2820151 | 201.07 Liters | Standard Deviation 31.48 |
| GSK2820151 12 mg | Volume of Distribution (Vz/F) of GSK2820151 | 455.65 Liters | Standard Deviation 72.602 |
| GSK2820151 20 mg | Volume of Distribution (Vz/F) of GSK2820151 | 268.91 Liters | Standard Deviation 71.679 |