Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Trametinib

Antimetabolites

Protein Kinase Inhibitors

Enzyme Inhibitors

Dose escalation to maximum tolerated dose of GSK1120212 and Gemcitabine.

Continuous daily oral dosing while on study or disease progression (cycle = 28 days).

GSK1120212

Dosing once weekly for 3 weeks in a 28 day cycle until disease progression.

GSK Clinical Trials

MEK112111 is a dose-escalation, Phase IB, open-label, single-arm, multi-center study. The primary objective of the study is to determine the recommended dose and regimen for the orally administered MEK inhibitor GSK1120212 dosed in combination with gemcitabine in subjects with solid tumors.

Subjects will be enrolled using a dose-escalation procedure in which the initial cohort receives a fraction of the GSK1120212 dose that achieved a dose limiting toxicity in a previous study and the recommended dose of gemcitabine. Escalation will proceed until the maximum tolerated doses are identified. These doses will be selected based on emerging safety data. Confirmation of the tolerability of the Recommended Phase II Dose (RP2D) will be explored in approximately 12 subjects. Subjects will continue on treatment until treatment discontinuation criteria are met (disease progression, intercurrent illness, adverse event or consent withdrawal).

Combination Study of GSK1120212 With Gemcitabine in Subjects With Solid Tumors

A Phase IB Combination Study of MEK Inhibitor GSK1120212 With Gemcitabine in Subjects With Solid Tumors

GlaxoSmithKline

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Dermatologic Agents

Tretinoin

The safety and PK/PD data will be reviewed prior to the dose decision, and the dose escalation will be guided by the Neuenschwander -continuous reassessment method (N-CRM).The dose escalation will complete when RP2D is determined. The RP2D will be the MTD or a lower dose that provides adequate PK exposure and biologic activity with superior tolerability.

Once the MTD and/or RP2D has been determined in Part 1, an expansion cohort of up to 30 subjects will be enrolled in order to characterize the clinical activity and safety profile of the RP2D. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, or withdrawal of consent.

GSK2879552 capsules contain 0.25 mg, 0.5 mg, 2 mg or 5 mg of GSK2879552 as parent. The initial dosing regimen will be continuous oral daily dosing.

GSK2879552

ATRA (Tretinoin) will be supplied as a 10 mg capsule for oral administration. The initial dosing regimen will be continuous oral twice daily dosing

ATRA

This study is a phase I, open-label study to determine recommended phase 2 dose (RP2D) and regimen for the orally administered lysine specific demethylase 1 (LSD1) inhibitor GSK2879552, alone or in combination with All-Trans Retinoic Acid (ATRA). The recommended dose and regimen will be selected based on the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles observed after the treatment of subjects with relapsed/refractory AML. The study consists of two parts. Part 1 will identify the maximum tolerated dose (MTD) and/or RP2D using a dose-escalation procedure. Dose escalations will be guided by the Neuenschwander-continual reassessment method (N-CRM). PK/PD expansion cohorts will also be included in Part 1 to characterize the range of biologically effective doses by assessing PD markers and obtain additional PK data. Part 2 will explore further the safety, tolerability, and clinical activity of GSK2879552, alone or in combination with ATRA, at the RP2D in subjects with AML.

A Phase I Dose Escalation Study of GSK2879552 in Subjects With Acute Myeloid Leukemia (AML)

A Phase I Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2879552 Given Orally in Subjects With Relapsed/Refractory Acute Myeloid Leukemia

IPD for this study will be made available via the Clinical Study Data Request site.

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function.

An event was considered a DLT if it occursed within the first 28 days of treatment, and meets one of the following criteria unless it can be clearly established that the event was unrelated to treatment: hematologic DLT included myelosuppression, Grade \>=3 non-hematologic toxicity that is considered clinically significant and lasts \>72 hours, Grade 2 toxicity that in the judgment of the investigator and GSK Medical Monitor is dose-limiting and treatment delay of \>=42 days due to unresolved toxicity.

The number of participants who had any dose reduction or delay have been presented.

Participants were monitored from start of the study till the development of toxicity. The data for number of participants withdrawn due to toxicities has been presented.

Blood samples were collected to assess clinical chemistry parameters like urea/blood urea nitrogen (BUN), calcium, potassium, aspartate aminotransferase (AST), total bilirubin, direct bilirubin, creatinine, chloride, alanine aminotransferase (ALT), uric acid, glucose, total carbon dioxide (CO2), gamma glutamyl transferase (GGT), albumin, sodium, alkaline phosphatase, total protein, phosphate, lactate dehydrogenase (LDH). Laboratory values were as per local labs per site with own normal ranges. Values above range were reported as high and values below range as low. Data for worst case post Baseline is reported.

Blood samples were collected for analysis of clinical chemistry parameters based on common terminology criteria for adverse events (CTCAE) version 4.0, where Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life threatening consequences. Data for any increase in grade of worst-case on-therapy has been provided.

Blood samples were collected to assess hematology parameters like mean corpuscle hemoglobin concentration (MCHC), mean corpuscle hemoglobin (MCH), mean corpuscle volume (MCV) mean platelet volume (MPV), basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, platelet count, Red blood cell (RBC) count, reticulocytes, White Blood Cell (WBC) count. Laboratory values were as per local labs per site with own normal ranges. Values above range were reported as high and values below range as low. Data for worst post Baseline were reported. NA indicates that data were not available as standard deviation could not be calculated for a single participant.

Blood samples were collected for analysis of hematology parameters based on common terminology criteria for adverse events (CTCAE) version 4.0, where Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life threatening consequences. Data for any grade increase worst-case on-therapy has been provided.

SBP and DBP were measured after resting for 5 minutes in semi-supine position. Vital signs were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4. An increase is defined as an increase in CTCAE grade relative to Baseline grade. For SBP Grade 0 (\<120 millimeters of mercury \[mmHg\]), Grade 1 (120-139 mmHg), Grade 2 (140-159 mmHg), Grade 3 (\>=160 mmHg). For DBP Grade 0 (\<80 mmHg), Grade 1 (80-89 mmHg), Grade 2 (90-99 mmHg), Grade 3 (\>=100 mmHg). Data for worst-case post Baseline is reported.

Heart rate was measured after restings for 5 minutes in semi-supine position. Data for participants with heart rate decreased to \< 60 beats per minute (bpm), normal or no change, increase to \> 100 bpm. Data for worst post Baseline were reported.

Temperature was measured after resting for 5 minutes in semi-supine position. Data for participants with temperature decreased to \<=35 Celsius, normal or no change, increase to \>=38 Celsius at worst-case post Baseline is reported.

Respiration rate was measured after resting for 5 minutes in semi-supine position. Data for worst case post-Baseline has been reported. Number of participants with respiratory rate decrease to \<12 and increase to \>25 has been reported.

A single 12-lead ECG was performed in semi-recumbent or supine position after 5 minutes of rest for the participant. An ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT intervals was used. Number of participants with any visit post-Baseline abnormal clinically significant findings and abnormal not clinically significant findings in ECG results has been reported.

Data for participants with abnormal physical examinations parameters was planned to be recorded.

Objective response rate defined as the percentage of participants who achievied complete remission (CR), partial remission (PR), CRp (as per CR but platelet count \<100 x 10\^9/L) and morphologic leukemia free state per response criteria. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Blood samples were collected at indicated time points. The Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis. NA indicates that data were not available as geometric co-efficient of variation could not be calculated for a single participant.

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. NA indicates that data were not available as geometric co-efficient could not be calculated for a single participant.

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. NA indicates that data were not available as geometric coefficient of variation could not be calculated for a single participant.

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. NA indicates that data were not available as standard deviation could not be calculated for a single participant.

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. Accumulation ratio was determined dividing AUC (0-tau) on Day 15 by AUC (0-tau) on Day 1. The ratio of accumulation of GSK2879552 was estimated by calculating the ratio of the geometric least squares (GLS) means of the AUC(0-tau) between Day 15 and Day 1 for all dose levels and the corresponding 90 percent confidence interval (CI) for each ratio.

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. The time invariance of GSK2879552 was estimated by calculating the ratio of the GLS means of the AUC (0-tau) between Day 15 and Day 1 for all dose levels and the corresponding 90 percent CI for each ratio.

Objective response rate is defined as the percentage of participants who achieved CR, PR, as per CR but platelet count \<100 x 10\^9/L and morphologic leukemia free state per response criteria.

Blood samples were collected at indicated time points. The Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis.

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

The number of participants who had any dose reduction or delay have been presented. All dose reductions were due to AEs. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Participants were monitored from start of the study till the development of toxicity. The data for number of participants withdrawn due to toxicities has been presented. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Data was not collected for Part 2 as the study was terminated early during Part 1.

This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

All Treated Subjects Population was used to collect adverse events. AEs and SAEs were not collected in Part 2 of the study as no participants were enrolled due to early termination during Part 1.

Participants received GSK2879552 1 mg orally QD in fasted condition with approximately 200 mL of water.

Part 1:GSK2879552 1mg QD

Participants received GSK2879552 2 mg orally once daily in fasted condition with approximately 200 mL of water.

Part 1: GSK2879552 2mg QD

Participants received GSK2879552 4 mg orally once daily in fasted condition with approximately 200 mL of water.

Part 1: GSK2879552 4mg QD

Participants received GSK2879552 8 mg orally once daily in fasted condition with approximately 200 mL of water.

Part 1: GSK2879552 8mg QD

Participants received GSK2879552 12 mg orally once daily in fasted condition with approximately 200 mL of water.

Part 1: GSK2879552 12mg QD

Participants received GSK2879552 20 mg orally once daily in fasted condition with approximately 200 mL of water.

Part 1: GSK2879552 20mg QD

Participants received GSK2879552 2 mg capsule orally once daily in fasted condition with approximately 200 mL of water in combination with ATRA at a dose of 45 mg/m\^2/day.

Part 1: GSK2879552 2mg QD/ATRA 45mg/m^2/Day

Participants received GSK2879552 20 mg capsule orally once daily in fasted condition with approximately 200 mL of water in PK/PD Expansion cohort to collect adequate data on safety, PK or PD.

Part 1: GSK2879552 20mg QD PK/PD Expansion

In Part 2, participants were planned to receive the recommended Phase 2 dose of GSK2879552 orally once daily in fasted condition with approximately 200 mL of water alone or in combination with ATRA.

Part 2: Expansion Cohort

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Baseline data was not collected for Part 2, as no participants were enrolled in Part 2.

GSK Response Center

All AEs

All SAEs

All Treated Subjects Population comprised of all participants who received at least one dose of study treatment.

Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

Part 1: Number of Participants With Dose Limiting Toxicities (DLT)

AEs leading to dose reduction

AEs leading to dose interruption/delay

Part 1: Number of Participants With AE Leading to Dose Reductions or Delays

Part 1: Number of Participants With Withdrawals Due to Toxicities

Direct Bilirubin,to Low,n=1,2,7,5,6,4,10,6

Direct Bilirubin,to High,n=1,2,7,5,6,4,10,6

Chloride,to Low,n=1,2,7,5,6,4,10,6

Chloride,to High,n=1,2,7,5,6,4,10,6

CO2/Bicarbonate,to Low,n=1,2,7,5,6,4,10,6

CO2/Bicarbonate,to High,n=1,2,7,5,6,4,10,6

Lactate Dehydrogenase,to Low,n=1,2,7,5,6,4,10,6

Lactate Dehydrogenase,to High,n=1,2,7,5,6,4,10,6

Total Protein,to Low,n=1,2,7,4,6,4,10,6

Total Protein,to High,n=1,2,7,4,6,4,10,6

Urea/BUN,to Low,n=1,2,7,5,6,4,10,6

Urea/BUN,to High,n=1,2,7,5,6,4,10,6

All Treated Subjects Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Number of Participants With Clinical Chemistry Parameters Changes From Baseline With Respect to the Normal Range

Albumin, n=1,2,7,5,6,4,10,6

ALP, n=1,2,7,5,6,4, 10, 6

ALT, n=1,2,7,5,6,4,10,6

AST, n=1,2,7,5,6,4,10,6

Total bilirubin, n=1,2,7,5,6,4,10,6

Hypercalcemia, n=1,2,7,5,6,4,10,6

Hypoglycemia,n= 1,2,7,5,6,4,10,6

Creatinine,n=1,2,7,5,6,4,10,6

GGT,n=1,2,7,5,3,1,8,3

Hyperglycemia,n= 0,1,7,5,6,4,9,6

Hypoglycemia,n=0,1,7,5,6,4,9,6

Hyperkalemia,n=1,2,7,5,6,4,10,6

Hypokalemia,n=1,2,7,5,6,4,10,6

Hypernatremia, n=1,2,7,5,6,4,10,6

Hyponatremia, n=1,2,7,5,6,4,10,6

Phosphorus, n=1,2,7,5,6,4,10,6

Number of Participants With Clinical Chemistry Toxicity Grade Changes From Baseline

Basophils, to Low,n=1,2,7,4,2,2,9,5

Basophils, to High,n=1,2,7,4,2,2,9,5

Eosinophils, to Low,n=1,2,7,4,2,2,8,5

Eosinophils, to High,n=1,2,7,4,2,2,8,5

Hemoglobin, to Low,n=0,0,0,0,2,0,0,1

Hemoglobin, to High,n=0,0,0,0,2,0,0,1

Hematocrit, to Low,n=1,2,7,5,6,4,10,6

Hematocrit, to High,n=1,2,7,5,6,4,10,6

MCHC, to Low,n=1,2,7,5,3,2,10,6

MCHC, to High,n=1,2,7,5,3,2,10,6

MCH, to Low,n=1,2,7,5,3,2,10,6

MCH, to High,n=1,2,7,5,3,2,10,6

MCV, to Low,n=1,2,7,5,6,4,10,6

MCV, to High,n=1,2,7,5,6,4,10,6

Monocytes, to Low,n=1,2,7,4,2,2,10,6

Monocytes, to High,n=1,2,7,4,2,2,10,6

MPV, to Low,n=0,0,0,3,6,3,7,6

MPV, to High,n=0,0,0,3,6,3,7,6

Nucleated RBC, to Low,n=0,0,0,1,1,0,1,0

Nucleated RBC, to High,n=0,0,0,1,1,0,1,0

RBC, to Low,n=1,2,7,5,6,4,10,6

RBC, to High,n=1,2,7,5,6,4,10,6

Reticulocytes, to Low,n=1,2,7,4,2,2,7,5

Reticulocytes, to High,n=1,2,7,4,2,2,7,5

Number of Participants With Hematology Parameters Change From Baseline With Respect to the Normal Range

Hg increase,n=1,2,7,5,6,4,10,6

Hg anemia,n=1,2,7,5,6,4,10,6

Lymph increase,n=1,2,7,4,2,2,10,6

Lymph decrease,n=1,2,7,4,2,2,10,6

Total Neu,n=1,2,7,4,2,2,10,6

Platelet,n=1,2,7,5,6,4,10,6

WBC,n=1,2,7,5,6,4,10,6

Number of Participants With Hematology Toxicity Grade Changes From Baseline

SBP,Any Grade Increase; n=1, 1, 3, 4, 6, 2, 5, 3

SBP,Increase to Grade 2;n=1, 1, 3, 4, 6, 2, 5, 3

SBP,Increase to Grade 3;n=1, 1, 3, 4, 6, 2, 5, 3

DBP,Any Grade Increase;n=1, 2, 3, 2, 4, 1, 3, 2

DBP,Increase to Grade 2;n=1, 2, 3, 2, 4, 1, 3, 2

DBP,Increase to Grade 3;n=1, 2, 3, 2, 4, 1, 3, 2

All Treated Subjects Population. Only those participants with available data at the specified time points were analyzed (represented by n=X in category titles).

Part 1: Number of Participants With Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Decrease to <60

Change to Normal or No Change

Increase to >100

All Treated Subjects Population. Only those participants with available data at the specified time points were analyzed.

Part 1: Number of Participants With Change From Baseline in Heart Rate

Decrease to <=35

Increase to >=38

Part 1: Number of Participants With Change From Baseline in Temperature

Decrease to <12

Increase to >25

Part 1: Number of Participants With Change From Baseline in Respiratory Rate

Abnormal - not clinically significant

Abnormal - clinically significant

Part 1: Number of Participants With Abnormal Electrocardiograms (ECGs) Findings

All Treated Subjects Population. The data was not collected as it was not captured within the case report form (CRF).

Part 1: Number of Participants With Abnormal Physical Examinations

All Treated Subjects Population. Data for this endpoint was not collected as this study was terminated early during Part 1 as the risk benefit in relapsed/refractory AML did not favor continuation of the study

Part 2: Objective Response Rate of Participants

AUC(0-t) n=1, 2, 7, 5, 6,4, 9,5

AUC(0-inf); n=1, 2, 7, 5, 6,4, 8,5

PK Population comprised of all treated participants for whom a PK sample was obtained and analyzed. Only those participants with available data at the specified time points were analyzed (represented by n=X in category titles).

Part 1: Area Under the Plasma Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration [AUC(0-t)] and From Time Zero (Pre-dose) Extrapolated to Infinite Time [(AUC(0-inf)] After Single Dose Administration

PK Population. Only those participants with available data at the specified time points were analyzed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination Study of GSK1120212 With Gemcitabine in Subjects With Solid Tumors	NCT01428427	Leukaemia, Myel...	GSK1120212 Gemcitabine	18 Years -	GlaxoSmithKline
A Phase I Dose Escalation Study of GSK2879552 in Subjects With Acute Myeloid Leukemia (AML)	NCT02177812	Leukaemia, Myel...	GSK2879552 ATRA	18 Years -	GlaxoSmithKline
Evaluation of a New Anti-cancer Immunotherapy After Chemotherapy in Adult Patients With Acute Myeloid Leukemia (AML)	NCT00725283	Leukaemia, Myel...	GSK Biologicals...	18 Years -	GlaxoSmithKline

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