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
Overview
- Phase
- Phase 1
- Intervention
- GSK2816126
- Conditions
- Cancer
- Sponsor
- GlaxoSmithKline
- Enrollment
- 41
- Locations
- 1
- Primary Endpoint
- Part 1: Number of Participants With Dose Reductions
- Status
- Terminated
- Last Updated
- 6 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Part 1:GSK2816126 50 mg twice-weekly
Eligible subjects will receive GSK2816126 with a starting dose of 50 milligrams (mg) twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off).
Intervention: GSK2816126
Part 1:GSK2816126 100 mg twice-weekly
Eligible subjects will receive GSK2816126 with a dose of 100 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off).
Intervention: GSK2816126
Part 1:GSK2816126 200 mg twice-weekly
Eligible subjects will receive GSK2816126 with a dose of 200 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off).
Intervention: GSK2816126
Part 1:GSK2816126 400 mg twice-weekly
Eligible subjects will receive GSK2816126 with a dose of 400 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off).
Intervention: GSK2816126
Part 1:GSK2816126 800 mg twice-weekly
Eligible subjects will receive GSK2816126 with a dose of 800 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off).
Intervention: GSK2816126
Part 1:GSK2816126 1200 mg twice-weekly
Eligible subjects will receive GSK2816126 with a dose of 1200 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off).
Intervention: GSK2816126
Part 1:GSK2816126 1800 mg twice-weekly
Eligible subjects will receive GSK2816126 with a dose of 1800 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off).
Intervention: GSK2816126
Part 1:GSK2816126 2400 mg twice-weekly
Eligible subjects will receive GSK2816126 with a dose of 2400 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off).
Intervention: GSK2816126
Part 1:GSK2816126 3000 mg twice-weekly
Eligible subjects will receive GSK2816126 with a dose of 3000 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off).
Intervention: GSK2816126
Part 2: All subjects
Subjects with Germinal Center B-cell-like Diffuse Large B-cell Lymphoma (GCB-DLBCL)-mutant and wild type, Transformed Follicular Lymphoma (TFL)-mutant and wild type as well as with multiple myeloma (MM) will be enrolled in Part 2 of the study. Subjects enrolled in Part 2 will receive recommended Phase II dose (RP2D).
Intervention: GSK2816126
Outcomes
Primary Outcomes
Part 1: Number of Participants With Dose Reductions
Time Frame: Up to 3.2 years
The number of participants who had any dose reductions have been presented.
Part 1: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters
Time Frame: Baseline and up to 3.2 years
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).
Part 1: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)
Time Frame: Up to 3.2 years
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.
Part 1: Number of Participants With Dose Limiting Toxicities (DLT)
Time Frame: Up to 4 weeks
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.
Part 1: Number of Participants Withdrawn Due to AEs
Time Frame: Up to 3.2 years
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.
Part 1: Number of Participants With Dose Interruptions
Time Frame: Up to 3.2 years
The number of participants who had any dose interruptions have been presented.
Part 2: Percentage of Participants Achieving Overall Response Rate
Time Frame: Up to 3.2 years
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.
Part 1: Number of Participants With Worst Case Change From Baseline in Hematology Parameters
Time Frame: Baseline and up to 3.2 years
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).
Part 1:Number of Participants With Abnormal Values for Vital Signs
Time Frame: Up to 3.2 years
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.
Part 1: Number of Participants With Abnormal Findings for Electrocardiogram (ECG) Parameters
Time Frame: Up to 3.2 years
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.
Secondary Outcomes
- 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(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))
- 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(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))
- Part 1: Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Repeat Dose Administration of GSK2816126(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))
- Part 1: Trough (Pre-dose) Concentration at the End of Dosing Interval on the Specified Days (Ctau) Following Administration of GSK2816126(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))
- Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2816126(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))
- Part 1: Time to Reach Cmax (Tmax) Following Single and Repeat Dose Administration of GSK2816126(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))
- Part 1: Apparent Terminal Phase Elimination Rate Constant (Lambda z) Following Single and Repeat Dose Administration of GSK2816126(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))
- Part 1: Apparent Terminal Phase Half-life (T1/2) Following Single and Repeat Dose Administration of GSK2816126(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))
- Part 1: Accumulation Ratio Following Administration of GSK2816126(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))
- Part 1: Time Invariance Ratio Following Administration of GSK2816126(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))
- Part 1: Exposure Producing 50 Percent of the Maximum Effect (EC50) of GSK2816126 With Respect to Exposure Markers(Up to 3.2 years)
- Part 1: Maximum Effect (Emax) of GSK2816126 With Respect to Exposure Markers(Up to 3.2 years)
- Part 1: Number of Participants With Overall Change in Tri-methylated Histone H3 Lysine 27 (H3K27me3) Ratios Compared to Baseline(Baseline and up to 3.2 years)
- Part 1: Percentage of Participants With Solid Tumors Achieving Best Overall Response Rate(Up to 3.2 years)
- Part 1: Percentage of Participants With Lymphoma Achieving Best Overall Response Rate(Up to 3.2 years)
- Part 1: Concentration of GSK2816126 and Its Metabolites in Blood(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))
- Part 1: Concentration of GSK2816126 and Its Metabolites in Bile(Day 15)
- Part 1: Concentration of GSK2816126 and Its Metabolites in Urine(Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15)
- Part 1:Concentration of GSK2816126 in Urine After Dosing at Steady State(Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15)
- Part 2: Number of Participants With SAEs and Non-SAEs(Up to 3.2 years)
- Part 2: Number of Participants With DLTs(Up to 4 weeks)
- Part 2: Number of Participants Withdrawn Due to AEs(Up to 3.2 years)
- Part 2: Number of Participants With Dose Interruptions(Up to 3.2 years)
- Part 2: Number of Participants With Dose Reductions(Up to 3.2 years)
- Part 2: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters(Baseline and up to 3.2 years)
- Part 2: Number of Participants With Worst Case Changes From Baseline in Hematology Parameters(Baseline and up to 3.2 years)
- Part 2: Number of Participants With Abnormal Values for Vital Signs(Up to 3.2 years)
- Part 2: Concentration of GSK2816126 and Its Metabolites in Bile(Day 15)
- Part 2: Concentration of GSK2816126 and Its Metabolites in Urine(Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15)
- Part 2:Concentration of GSK2816126 in Urine After Dosing at Steady State(Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15)
- Part 2: Number of Participants With Abnormal Findings for ECG Parameters(Up to 3.2 years)
- Part 2: Clearance Following Administration of GSK2816126(Up to 3.2 years)
- Part 2: Volume of Distribution Following Administration of GSK2816126(Up to 3.2 years)
- Part 2:EC50 of GSK2816126 With Respect to Exposure Markers(Up to 3.2 years)
- Part 2:Emax of GSK2816126 With Respect to Exposure Markers(Up to 3.2 years)
- Part 2: Number of Participants With Change in H3K27me3 Ratios Compared to Baseline(Baseline and up to 3.2 years)
- Part 2: Concentration of GSK2816126 and Its Metabolites in Blood(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))
- Part 2: Change in 4-beta-hydroxy Cholesterol to Cholesterol Ratio From Baseline Following Repeat Dosing of GSK2816126(Baseline and up to 21 days)
- Part 2: Duration of Response(Up to 3.2 years)
- Part 2: Number of Participants With Progression Free Survival(Up to 3.2 years)