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Report for Mutation Y641N

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There is one clinical trial.

Clinical Trials


1 A Phase I Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2816126 in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma, Transformed Follicular Lymphoma, Other Non-Hodgkin's Lymphomas, Solid Tumors and Multiple Myeloma

This is an open-label, multicenter, 2-part study to determine the recommended Phase 2 dose (RP2D) for GSK2816126 given twice weekly by intravenous (IV) infusion. Part 1 will be conducted in adult subjects with relapsed/refractory diffuse large B cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), other Non-Hodgkin's lymphomas (NHL), solid tumors (including castrate resistant prostate cancer) and multiple myeloma (MM) to determine the safety and tolerability of GSK2816126. Expansion cohorts (Part 2) are planned to further explore clinical activity of GSK2816126 at the RP2D in subjects with Enhancer of Zeste 2 (EZH2) wild type and EZH2 mutant positive germinal center B-cell like diffuse large B cell lymphoma (GCB-DLBCL), tFL and MM.

NCT02082977 Cancer Neoplasms Drug: GSK2816126
MeSH: Lymphoma Multiple Myeloma Neoplasms, Plasma Cell Lymphoma, Follicular Lymphoma, Non-Hodgkin Lymphoma, B-Cell Lymphoma, Large B-Cell, Diffuse
HPO: B-cell lymphoma Lymphoma Multiple myeloma Non-Hodgkin lymphoma

- Based on the results of the mutation test, lymphoma subjects may be enrolled in one of four cohorts: GCB-DLBCL EZH2 mutant cohort: Tumors must contain one, or more, of the following EZH2 activating mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or A687V. --- Y641F --- --- Y641N ---

tFL EZH2 mutant cohort: Tumors must contain one, or more, of the following EZH2 activating mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or A687V. --- Y641F --- --- Y641N ---

Primary Outcomes

Description: An AE is any untoward medical occurrence in a participant or 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/ incapacity, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function. The analysis was performed on All Subjects Population which included all participants who received at least one dose of study treatment.

Measure: Part 1: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)

Time: Up to 3.2 years

Description: An event was considered a DLT if it occurred within first 4 weeks (28 days) of treatment, and met the criteria's for hematologic , non-hematologic, infusion reactions and other toxicities, unless it can be clearly established that the event is unrelated to treatment.

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

Time: Up to 4 weeks

Description: A participant was considered to have completed the study if they have completed their end of study visit or if the participant died or was still in follow-up at the time the study was closed or terminated. Participants were monitored from start of the study till the development of toxicity. The data for number of participants withdrawn due to AEs have been presented.

Measure: Part 1: Number of Participants Withdrawn Due to AEs

Time: Up to 3.2 years

Description: The number of participants who had any dose interruptions have been presented.

Measure: Part 1: Number of Participants With Dose Interruptions

Time: Up to 3.2 years

Description: The number of participants who had any dose reductions have been presented.

Measure: Part 1: Number of Participants With Dose Reductions

Time: Up to 3.2 years

Description: Blood samples were collected for evaluation of clinical chemistry parameters including direct bilirubin, chloride, lactate dehydrogenase (LDH), total protein, urea/blood urea nitrogen (BUN) and uric acid. Baseline value was defined as the most recent, non-missing value from a local laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are not gradable by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Measure: Part 1: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters

Time: Baseline and up to 3.2 years

Description: Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, hematocrit, mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), monocytes, segmented (seg) neutrophils, red blood cell (RBC) count and reticulocytes. Baseline value was defined as the most recent, non-missing value from a local laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are not gradable by CTCAE version 4.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Measure: Part 1: Number of Participants With Worst Case Change From Baseline in Hematology Parameters

Time: Baseline and up to 3.2 years

Description: Vital sign measurements includes systolic blood pressure (SBP), diastolic blood pressure (DBP), body temperature and heart rate. Vital signs were measured after resting for at least 5 minutes in a semi-supine position. The number of participants with abnormal findings for vital signs have been presented.

Measure: Part 1:Number of Participants With Abnormal Values for Vital Signs

Time: Up to 3.2 years

Description: Single measurements of 12-lead ECGs were obtained a semi-recumbent or semi-supine position after at least a 5 minutes rest using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and corrected QT (QTc) intervals. The number of participants with abnormal, abnormal-not clinically significant (NCS), and abnormal-clinically significant (CS) worst case Post Baseline findings have been presented.

Measure: Part 1: Number of Participants With Abnormal Findings for Electrocardiogram (ECG) Parameters

Time: Up to 3.2 years

Description: Overall response rate is defined as percentage of participants achieving complete response and partial response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Percentage of Participants Achieving Overall Response Rate

Time: Up to 3.2 years

Secondary Outcomes

Description: Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-t) following single (Day 1) and repeat dose (Day 15) administration of GSK2816126. Pharmacokinetic analysis of GSK2816126 in Part 1 was conducted by non-compartmental methods. The analysis was performed on Pharmacokinetic Population which included all participants in the All Subject population for whom a blood sample for pharmacokinetics was analyzed and at least 1 non-missing values was obtained. NA indicates data was not available since geometric coefficient of variation could not be calculated for single participant. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Measure: Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0-t]) Following Single and Repeat Dose Administration of GSK2816126

Time: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)

Description: Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-infinity) following single (Day 1) dose administration of GSK2816126. Pharmacokinetic analysis of GSK2816126 in Part 1 was conducted by non-compartmental methods. NA indicates data was not available since geometric coefficient of variation could not be calculated for single participant. Pharmacokinetic parameter derivation for some participants did not strictly conform to the prescribed acceptance criteria and hence data was not available for those participants.

Measure: Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) Following Single Dose Administration of GSK2816126

Time: Pre-dose, 0.5, 1, 2, 12, 18 , 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 (Each cycle was of 28 days)

Description: Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-tau) following repeat (Day 15) dose administration of GSK2816126. Pharmacokinetic analysis of GSK2816126 in Part 1 was conducted by non-compartmental methods. NA indicates data was not available since geometric coefficient of variation could not be calculated for single participant.

Measure: Part 1: Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Repeat Dose Administration of GSK2816126

Time: Pre-dose, 0.5, 1, 2, 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 15 (Each cycle was of 28 days)

Description: Blood samples were collected from participants for pharmacokinetic analysis including Ctau following specified days (Days 8 and 15) administration of GSK2816126. Pharmacokinetic analysis of GSK2816126 in Part 1 was conducted by non-compartmental methods. NA indicates data was not available as data could not be calculated due to limited number of participants at specified data point. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Measure: Part 1: Trough (Pre-dose) Concentration at the End of Dosing Interval on the Specified Days (Ctau) Following Administration of GSK2816126

Time: Pre-dose from start of infusion till end of infusion on Cycle 1 of Day 8; Pre-dose, 0.5, 1, 2, 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 15 (Each cycle was of 28 days)

Description: Blood samples were collected from participants for pharmacokinetic analysis including Cmax following single (Day 1) and repeat dose (Day 15) administration of GSK2816126. Pharmacokinetic analysis of GSK2816126 in Part 1 was conducted by non-compartmental methods. NA indicates data was not available since geometric coefficient of variation could not be calculated for single participant. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Measure: Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2816126

Time: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)

Description: Blood samples were collected from participants for pharmacokinetic analysis including Tmax following single (Day 1) and repeat dose (Day 15) administration of GSK2816126. Tmax is the time to reach Cmax, determined directly from the concentration-time data. Pharmacokinetic analysis of GSK2816126 in Part 1 was conducted by non-compartmental methods. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Measure: Part 1: Time to Reach Cmax (Tmax) Following Single and Repeat Dose Administration of GSK2816126

Time: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)

Description: Blood samples were collected from participants for pharmacokinetic analysis including lambda z following single (Day 1) and repeat dose (Day 15) administration of GSK2816126. Pharmacokinetic analysis of GSK2816126 in Part 1 was conducted by non-compartmental methods. Pharmacokinetic parameter derivation for some participants did not strictly conform to the prescribed acceptance criteria and hence data was not available for those participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Measure: Part 1: Apparent Terminal Phase Elimination Rate Constant (Lambda z) Following Single and Repeat Dose Administration of GSK2816126

Time: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)

Description: Blood samples were collected from participants for pharmacokinetic analysis including T1/2 following single (Day 1) and repeat dose (Day 15) administration of GSK2816126. Pharmacokinetic analysis of GSK2816126 in Part 1 was conducted by non-compartmental methods. Pharmacokinetic parameter derivation for some participants did not strictly conform to the prescribed acceptance criteria and hence data was not available for those participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Measure: Part 1: Apparent Terminal Phase Half-life (T1/2) Following Single and Repeat Dose Administration of GSK2816126

Time: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)

Description: Accumulation ratio was determined from the ratio of AUC (0-tau) on Cycle 1 Day 15/AUC (0-tau) on Cycle 1 Day 1 by dose cohort. Only those participants with data available at the specified data points were analyzed. To assess accumulation ratio for a dose level based on ANOVA method, it was required that at least 2 participants had derived PK parameter AUC(0- tau) on both Cycle 1 Day 1 and Cycle 1 Day 15. For dose 100mg, 200mg and 400mg, only 1 participant received treatment. For dose 50mg, 2 participants received treatment but there was one participant whose AUC(0- tau) on Cycle 1 Day 15 could not be derived due to discontinuation of treatment before Day 15. Hence, accumulation ratio could not be calculated for these 4 arms. Accumulation ratio of GSK2816126 was estimated by calculating the ratio of geometric least squares (GLS) means of the AUC between Day 15 and Day 1 for all dose levels and corresponding 90 percent (%) confidence interval (CI) for each ratio.

Measure: Part 1: Accumulation Ratio Following Administration of GSK2816126

Time: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)

Description: Ratio of AUC(0-tau) on Day15/Day1 AUC(0-inf) was calculated to assess time invariance. Only those participants with data available at specified data points were analyzed. To assess time invariance based on ANOVA method, it is required that at least 2 participants in a dose level had AUC(0-inf) on Cycle1 Day1 and AUC(0-tau) on Cycle1 Day15. For dose 100mg, 200mg and 400mg, only 1 participant received treatment. For 50mg, 2 participants received treatment but there was one participant whose AUC(0-tau) on Cycle1 Day15 could not be derived due to discontinuation of treatment before Day15, so time invariance could not be calculated. For 1200mg, 4 participants received treatment, however, AUC(0-inf) derivation on Cycle1 Day1 for 3 out of 4 participants did not strictly conform to the prescribed acceptance criteria. Time invariance ratio of GSK2816126 was estimated by calculating ratio of GLS means of AUC between Day15 and Day1 for all dose levels and corresponding 90% CI for each ratio.

Measure: Part 1: Time Invariance Ratio Following Administration of GSK2816126

Time: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)

Description: The pharmacokinetic/pharmacodynamic relationship between GSK2816126 exposure markers (dose, concentration, Cmax or AUC) was planned to be characterized by linear and/or non-linear mixed effect models. This analysis was planned to be based on Pharmacodynamic Population which consists of participants in the All Subjects population for whom a pharmacodynamics/biomarkers sample was obtained and analyzed. This analysis was planned but not performed as the pharmacodynamic response was not observed and therefore a relationship between pharmacokinetic and pharmacodynamic parameters could not be determined.

Measure: Part 1: Exposure Producing 50 Percent of the Maximum Effect (EC50) of GSK2816126 With Respect to Exposure Markers

Time: Up to 3.2 years

Description: The pharmacokinetic/pharmacodynamic relationship between GSK2816126 exposure markers (dose, concentration, Cmax or AUC) was characterized by linear and/or non-linear mixed effect models. This analysis was planned but not performed as the pharmacodynamic response was not observed and therefore a relationship between pharmacokinetic and pharmacodynamic parameters could not be determined.

Measure: Part 1: Maximum Effect (Emax) of GSK2816126 With Respect to Exposure Markers

Time: Up to 3.2 years

Description: The pre and post-treatment samples for tumor or surrogate tissue/body fluid (e.g. Peripheral blood mononuclear cell [PBMCs], blood, skin or hair) were collected for the analysis of H3K27me3. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was defined as any visit value minus Baseline value.

Measure: Part 1: Number of Participants With Overall Change in Tri-methylated Histone H3 Lysine 27 (H3K27me3) Ratios Compared to Baseline

Time: Baseline and up to 3.2 years

Description: Overall response rate is defined as percentage of participants achieving complete response and partial response per RECIST version 1.1. Complete Response is the disappearance of all target/non-target lesions. Partial Response is at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence. The percentage of participants with solid tumors (including prostate) achieving best overall response rate have been presented. No participants with solid tumors were treated at doses below 800mg (i.e. 50mg, 100mg, 200mg, 400mg). Hence data could not be calculated for these 4 arms.

Measure: Part 1: Percentage of Participants With Solid Tumors Achieving Best Overall Response Rate

Time: Up to 3.2 years

Description: Overall response rate is defined as percentage of participants achieving complete response and partial response per RECIST version 1.1. Complete Response is the disappearance of all target/non-target lesions. Partial Response is at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence. The percentage of participants with lymphoma achieving best overall response rate have been presented.

Measure: Part 1: Percentage of Participants With Lymphoma Achieving Best Overall Response Rate

Time: Up to 3.2 years

Description: Blood samples were planned to be collected from participants in the pharmacokinetic/pharmacodynamic expansion cohort for analysis of GSK2816126 and its metabolites. Samples were not collected due to early termination of the study; therefore, no analysis could be performed.

Measure: Part 1: Concentration of GSK2816126 and Its Metabolites in Blood

Time: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)

Description: Bile samples were planned to be collected from participants in the pharmacokinetic/pharmacodynamic expansion cohort for analysis of GSK2816126 and its metabolites via the Entero-Test. Samples were not collected due to early termination of the study; therefore, no analysis could be performed.

Measure: Part 1: Concentration of GSK2816126 and Its Metabolites in Bile

Time: Day 15

Description: Urine samples were planned to be collected from participants in the pharmacokinetic/pharmacodynamic expansion cohort for analysis of GSK2816126 and its metabolites. Samples were not collected due to early termination of the study; therefore, no analysis could be performed.

Measure: Part 1: Concentration of GSK2816126 and Its Metabolites in Urine

Time: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15

Description: The amount of GSK2816126 excreted in urine after dosing at steady state was determined. The concentration of GSK2816126 in urine was planned to be measured with an investigational bio-analytical method and extrapolated to total amount excreted in urine over time using urine volume. Samples were not collected due to early termination of the study; therefore, no analysis could be performed.

Measure: Part 1:Concentration of GSK2816126 in Urine After Dosing at Steady State

Time: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15

Description: An AE is any untoward medical occurrence in a participant or 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/ incapacity, 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.

Measure: Part 2: Number of Participants With SAEs and Non-SAEs

Time: Up to 3.2 years

Description: An event was considered a DLT if it occurred within first 4 weeks (28 days) of treatment, and met the criteria's for hematologic , non-hematologic, infusion reactions and other toxicities, unless it can be clearly established that the event is unrelated to treatment. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants With DLTs

Time: Up to 4 weeks

Description: A participant was considered to have completed the study if they have completed their end of study visit or if the participant died or was still in follow-up at the time the study was closed or terminated. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants Withdrawn Due to AEs

Time: Up to 3.2 years

Description: The number of participants who had any dose interruptions were planned to be analyzed. However, this analysis was not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants With Dose Interruptions

Time: Up to 3.2 years

Description: The number of participants who had any dose reduction or delay were planned to be analyzed. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants With Dose Reductions

Time: Up to 3.2 years

Description: Blood samples were planned to be collected for evaluation of clinical chemistry parameters including direct bilirubin, chloride, LDH, total protein, urea/BUN and uric acid. Baseline value was defined as the most recent, non-missing value from a local laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters

Time: Baseline and up to 3.2 years

Description: Blood samples were planned to be collected for the analysis of hematology parameters including basophils, eosinophils, hematocrit, MCHC, MCH, MCV, monocytes, seg neutrophils, RBC count and reticulocytes. Baseline value was defined as the most recent, non-missing value from a local laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants With Worst Case Changes From Baseline in Hematology Parameters

Time: Baseline and up to 3.2 years

Description: Vital sign measurements includes SBP, DBP, body temperature and heart rate. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants With Abnormal Values for Vital Signs

Time: Up to 3.2 years

Description: Single measurements of 12-lead ECGs were planned to be obtained a semi-recumbent or semi-supine position after at least a 5 minutes rest using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants With Abnormal Findings for ECG Parameters

Time: Up to 3.2 years

Description: Blood samples were planned to be collected at Pre-dose, single draw between 0.5 and 1.9 hours from start of infusion, single draw between 3-6 hours following end of infusion on Day 1 and Day 11; Pre-dose on Day 4; Day 8, Day 11; Pre-dose on Day 15 for Cycle 1 and Cycles 2, 4, 6 and 12 pre-dose and within 5 minutes prior to end of infusion on Day 4 for population pharmacokinetic analysis of GSK2816126 including clearance. Each cycle was of 28 days. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Clearance Following Administration of GSK2816126

Time: Up to 3.2 years

Description: Blood samples were planned to be collected on Pre-dose, single draw between 0.5 and 1.9 hours from start of infusion, single draw between 3-6 hours following end of infusion on Day 1 and Day 11; Pre-dose on Day 4; Day 8,Day 11; Pre-dose on Day 15 for Cycle 1 and Cycle 2, 4, 6 and 12 pre-dose and within 5 minutes prior to end of infusion on Day 4 for population pharmacokinetic analysis of GSK2816126 including clearance. Each cycle was of 28 days. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Volume of Distribution Following Administration of GSK2816126

Time: Up to 3.2 years

Description: The pharmacokinetic/pharmacodynamic relationship between GSK2816126 exposure markers (dose, concentration, Cmax or AUC) was planned to be characterized by linear and/or non-linear mixed effect models. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2:EC50 of GSK2816126 With Respect to Exposure Markers

Time: Up to 3.2 years

Description: The pharmacokinetic/pharmacodynamic relationship between GSK2816126 exposure markers (dose, concentration, Cmax or AUC) was planned to be characterized by linear and/or non-linear mixed effect models. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2:Emax of GSK2816126 With Respect to Exposure Markers

Time: Up to 3.2 years

Description: The pre and post-treatment samples for tumor or surrogate tissue/body fluid (e.g. PBMCs, blood, skin or hair) were planned to be collected for the analysis of H3K27me3. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was defined as any visit value minus Baseline value. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants With Change in H3K27me3 Ratios Compared to Baseline

Time: Baseline and up to 3.2 years

Description: Blood samples were planned to be collected from participants in the pharmacokinetic/pharmacodynamic expansion cohort for analysis of GSK2816126 and its metabolites. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Concentration of GSK2816126 and Its Metabolites in Blood

Time: Pre-dose, single draw between 0.5 and 1.9 hours from start of infusion, single draw between 3-6 hours following end of infusion on Day 1; Pre-dose on Day 15 for Cycle 1 and Cycles 2, 4, 6 and 12 (Each cycle was of 28 days)

Description: Bile samples were planned to be collected from participants in the pharmacokinetic/pharmacodynamic expansion cohort for analysis of GSK2816126 and its metabolites via the Entero-Test. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Concentration of GSK2816126 and Its Metabolites in Bile

Time: Day 15

Description: Urine samples were planned to be collected from participants in the pharmacokinetic/pharmacodynamic expansion cohort for analysis of GSK2816126 and its metabolites. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Concentration of GSK2816126 and Its Metabolites in Urine

Time: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15

Description: The amount of GSK2816126 excreted in urine after dosing at steady state was planned to be determined. The concentration of GSK2816126 in urine was planned to be measured with an investigational bio-analytical method and extrapolated to total amount excreted in urine over time using urine volume. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2:Concentration of GSK2816126 in Urine After Dosing at Steady State

Time: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15

Description: Plasma analysis for 4-beta-hydroxycholesterol and cholesterol was planned to be conducted. Baseline value was defined as the most recent, non-missing value from a local laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Change in 4-beta-hydroxy Cholesterol to Cholesterol Ratio From Baseline Following Repeat Dosing of GSK2816126

Time: Baseline and up to 21 days

Description: Duration of response for participants is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Duration of Response

Time: Up to 3.2 years

Description: PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Measure: Part 2: Number of Participants With Progression Free Survival

Time: Up to 3.2 years


HPO Nodes


Non-Hodgkin lymphoma
Genes 32
ATM FAS CASP10 CTLA4 FAS BCL10 CD28 BIRC3 FOXP1 TNFRSF1B MYC CCND1 ASXL1 ATM MALT1 CTLA4 CD28 SRSF2 KIT POLE IGH ADA TET2 FASLG PIK3R1 NTHL1 RASGRP1 TNFRSF1B PRKCD NBN RHOH IGH
B-cell lymphoma
Genes 17
IGH FAS CASP10 ADA FAS FASLG BCL10 PIK3R1 BIRC3 FOXP1 RASGRP1 CCND1 ATM PRKCD MALT1 NBN IGH
Multiple myeloma
Genes 3
LIG4 CCND1 GBA
Lymphoma
Genes 133
ATM KRAS CD19 IGH DDX41 BCL10 BIRC3 FOXP1 MS4A1 TP63 RAG1 LIG4 NFKB2 MSH6 TERC RECQL4 NTHL1 WIPF1 CTC1 LYST NOP10 RASGRP1 TNFRSF1B XRCC4 PRKCD NHP2 MAGT1 TNFRSF13B IGH RMRP RUNX1 CTLA4 DCLRE1C FAS ICOS RNF43 NSUN2 XIAP IL7R CASP10 BCL6 CDKN2A ATM IL2RG RTEL1 PARN NBN KIT TNFRSF13C TCF4 ICOS TNFSF12 CHEK2 USB1 CD19 CR2 NRAS MSH2 WAS BCL10 CASP10 MYD88 COL14A1 PRKCD TNFRSF13B MYC MDM2 SH2D1A CCND1 BCL10 CFTR CD27 PGM3 TCF4 CHD7 IGH LIG4 BLM BCL2 TET2 HLA-DRB1 PRSS1 NPM1 KIF11 ITK WRAP53 RAD54B TINF2 FAS DKC1 APC CD81 LIG4 BLM CD28 DKC1 AAGAB RAG2 TNFRSF1B MLH1 TNFRSF13C DNASE1L3 NFKB1 PMS2 ASXL1 IL2RG PRF1 PTEN MALT1 RAD54L CTLA4 CD28 PNP SRSF2 TNFSF12 STAT3 POLE ADA CR2 ADA FASLG PIK3R1 TP53 CTRC ZAP70 MYD88 RB1 RMRP SPINK1 TERT KLHDC8B NBN RHOH