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A 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

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ClinicalTrials.gov Identifier: NCT02082977
Recruitment Status : Terminated (The maximal dose and schedule attained with GSK2816126 has shown insufficient evidence of clinical activity, and does not justify further clinical investigation)
First Posted : March 11, 2014
Results First Posted : June 28, 2019
Last Update Posted : June 28, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Cancer Neoplasms Drug: GSK2816126 Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Subjects will receive escalating doses of GSK2816126 in Part 1 of the study. Subjects enrolled in Part 2 will receive recommended Phase II dose (RP2D) based on Part 1 of the study.
Masking: None (Open Label)
Masking Description: This will be an open-label study. Hence, there will be no masking.
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 24, 2014
Actual Primary Completion Date : June 20, 2017
Actual Study Completion Date : June 20, 2017


Arm Intervention/treatment
Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: 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).
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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).

  7. 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).

  8. 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.

  9. 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.

  10. 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.


Secondary Outcome Measures :
  1. 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 Frame: 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) ]
    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).

  2. 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 Frame: 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) ]
    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.

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

  4. Part 1: Trough (Pre-dose) Concentration at the End of Dosing Interval on the Specified Days (Ctau) Following Administration of GSK2816126 [ Time Frame: 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) ]
    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).

  5. Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2816126 [ Time Frame: 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) ]
    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).

  6. Part 1: Time to Reach Cmax (Tmax) Following Single and Repeat Dose Administration of GSK2816126 [ Time Frame: 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) ]
    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).

  7. Part 1: Apparent Terminal Phase Elimination Rate Constant (Lambda z) Following Single and Repeat Dose Administration of GSK2816126 [ Time Frame: 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) ]
    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).

  8. Part 1: Apparent Terminal Phase Half-life (T1/2) Following Single and Repeat Dose Administration of GSK2816126 [ Time Frame: 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) ]
    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).

  9. Part 1: Accumulation Ratio Following Administration of GSK2816126 [ Time Frame: 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) ]
    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.

  10. Part 1: Time Invariance Ratio Following Administration of GSK2816126 [ Time Frame: 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) ]
    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.

  11. Part 1: Exposure Producing 50 Percent of the Maximum Effect (EC50) of GSK2816126 With Respect to Exposure Markers [ Time Frame: Up to 3.2 years ]
    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.

  12. Part 1: Maximum Effect (Emax) of GSK2816126 With Respect to Exposure Markers [ Time Frame: Up to 3.2 years ]
    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.

  13. Part 1: Number of Participants With Overall Change in Tri-methylated Histone H3 Lysine 27 (H3K27me3) Ratios Compared to Baseline [ Time Frame: Baseline and up to 3.2 years ]
    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.

  14. Part 1: Percentage of Participants With Solid Tumors Achieving Best 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 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.

  15. Part 1: Percentage of Participants With Lymphoma Achieving Best 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 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.

  16. Part 1: Concentration of GSK2816126 and Its Metabolites in Blood [ Time Frame: 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) ]
    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.

  17. Part 1: Concentration of GSK2816126 and Its Metabolites in Bile [ Time Frame: Day 15 ]
    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.

  18. Part 1: Concentration of GSK2816126 and Its Metabolites in Urine [ Time Frame: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15 ]
    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.

  19. Part 1:Concentration of GSK2816126 in Urine After Dosing at Steady State [ Time Frame: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15 ]
    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.

  20. Part 2: Number of Participants With SAEs and 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. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

  21. Part 2: Number of Participants With DLTs [ 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. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

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

  23. Part 2: Number of Participants With Dose Interruptions [ Time Frame: Up to 3.2 years ]
    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.

  24. Part 2: Number of Participants With Dose Reductions [ Time Frame: Up to 3.2 years ]
    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.

  25. Part 2: 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 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.

  26. Part 2: Number of Participants With Worst Case Changes From Baseline in Hematology Parameters [ Time Frame: Baseline and up to 3.2 years ]
    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.

  27. Part 2: Number of Participants With Abnormal Values for Vital Signs [ Time Frame: Up to 3.2 years ]
    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.

  28. Part 2: Number of Participants With Abnormal Findings for ECG Parameters [ Time Frame: Up to 3.2 years ]
    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.

  29. Part 2: Clearance Following Administration of GSK2816126 [ Time Frame: Up to 3.2 years ]
    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.

  30. Part 2: Volume of Distribution Following Administration of GSK2816126 [ Time Frame: Up to 3.2 years ]
    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.

  31. Part 2:EC50 of GSK2816126 With Respect to Exposure Markers [ Time Frame: Up to 3.2 years ]
    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.

  32. Part 2:Emax of GSK2816126 With Respect to Exposure Markers [ Time Frame: Up to 3.2 years ]
    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.

  33. Part 2: Number of Participants With Change in H3K27me3 Ratios Compared to Baseline [ Time Frame: Baseline and up to 3.2 years ]
    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.

  34. Part 2: Concentration of GSK2816126 and Its Metabolites in Blood [ Time Frame: 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) ]
    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.

  35. Part 2: Concentration of GSK2816126 and Its Metabolites in Bile [ Time Frame: Day 15 ]
    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.

  36. Part 2: Concentration of GSK2816126 and Its Metabolites in Urine [ Time Frame: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15 ]
    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.

  37. Part 2:Concentration of GSK2816126 in Urine After Dosing at Steady State [ Time Frame: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15 ]
    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.

  38. Part 2: Change in 4-beta-hydroxy Cholesterol to Cholesterol Ratio From Baseline Following Repeat Dosing of GSK2816126 [ Time Frame: Baseline and up to 21 days ]
    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.

  39. Part 2: Duration of Response [ Time Frame: Up to 3.2 years ]
    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.

  40. Part 2: Number of Participants With Progression Free Survival [ Time Frame: Up to 3.2 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Part 1 Inclusion Criteria

  • Provided signed written informed consent
  • Males and females >=18 years of age (at the time consent is obtained).
  • Tumor type criteria: relapsed/refractory non-Hodgkin's lymphoma (NHL) that meets one of the following criteria:
  • Germinal Center B cell Diffuse large B cell lymphoma (GCB-DLBCL) relapsed or refractory to at least one prior regimen (e.g., rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]) AND not a candidate for standard salvage regimens or autologous or allogeneic stem cell transplant. Local confirmation of lymphoma subtype (e.g. GCB-DLBCL) is allowed for enrollment but must be confirmed through central laboratory testing.
  • Solid tumors that meet the following criteria: Measurable disease by Response Evaluation Criteria In Solid Tumors 1.1 (RECIST) in at least 1 site. For Castrate Resistant Prostate Cancer (CRPC) measurable disease can also include Prostate Specific Antigen (PSA) level. Disease progression with the last line of therapy and at least one prior standard of care regimens, or tumor for which there is no approved therapy, or for which standard therapy is unsuitable or refused. Mutation Status: Solid tumor types, other than prostate, must have a one of the following EZH2 inhibitor sensitizing mutations as determined via local testing: An activating mutation in EZH2 (Y641F/C/S/H/N, A677V/G, and/or A687V; Loss of a component of the SWI/SNF complex, including, but not limited to, ARID1A, SMARCB1 (aka SNF5/INI1/BAF47), SMARCA4 (aka BRG1), or PBRM1 (aka PB1) as determined by molecular testing (bi-allelic loss or mutation) or immunohistochemistry; Loss of BAP1 (ubiquitin carboxy-terminal hydrolase) as determined by molecular testing (bi-allelic loss or mutation) or immunohistochemistry
  • CRPC subjects: Must have measurable disease by either: RECIST1.1 or a minimum PSA of 5 nanogram/milliliter; Disease progression on last line of therapy and must have progressed on abiraterone, enzalutamide, or taxane chemotherapy; Subjects may continue GnRH agonists; Small cell prostate cancer is eligible
  • For all subjects: Availability of archival tissue, or willingness to undergo fresh biopsy if archival tissue is not available.
  • Must have a pre-existing central venous access such as a port, Hickmann catheter or a peripherally inserted central catheter (PICC line) or be willing and able to have one inserted.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  • Men with a female partner of childbearing potential must have either had a prior bilateral vasectomy with resultant azoospermia, bilateral orchiectomy, or must agree to use one of the contraception methods listed in protocol from the time of the first dose of study medication until at least 2 weeks (14 days) after the last dose of study treatment due to the long elimination phase of study drug.
  • A female subject is eligible to participate ifs she is of: Non-child bearing potential as described in the protocol; OR Child bearing potential and agrees to use effective contraception as described in the protocol, for an appropriate period of time (as determined by the product label) prior to the start of dosing to sufficiently minimize the risk of pregnancy and for at least 2 weeks (14 days) following the last dose of study treatment. Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment followed by negative urine or serum pregnancy test once every 4 weeks (prior to next dose cycle) thereafter.- Adequate organ system function as defined in the protocol.

Part 2 Inclusion Criteria

  • In addition to inclusion criteria listed for Part 1, Part 2 will enroll GCB-DLBCL tFL and MM subjects only. Relapsed and/or refractory MM or tFL that have failed prior standard therapy and for which there is no standard salvage regimen
  • Lymphoma subjects will be required to undergo EZH2 mutation testing. This will require availability of archival tissue, or willingness to undergo fresh biopsy, for central testing of EZH2 mutation status.
  • 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. GCB-DLBCL EZH2 wild type cohort: Tumors that do not contain one of the above mutations; Subjects with tumors harboring EZH2 mutations other than the seven outlined above will be enrolled in the EZH2 wild type cohort. 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. tFL EZH2 wild type cohort: Tumors that do not contain one of the above mutations; Subjects with tumors harboring EZH2 mutations other than the seven outlined above will be enrolled in the EZH2 wild type cohort

Part 1 and 2 Exclusion Criteria

  • Receiving any cancer therapy within 2 weeks of first dose (including surgery, and/or tumor embolization) Note: the following are allowed: Corticosteroids to control systemic or local symptoms, up to a dose of 10 mg prednisone or equivalent daily and stable for at least 7 days prior to enrollment. Subjects with prostate cancer may remain on GnRH agonists. Other hormonal therapies (e.g., bicalutamide, abiraterone and enzlutimide) for prostate cancer must be stopped 4 weeks prior to enrolment.

Note: the following are NOT allowed: Chemotherapy regimens with delayed toxicity within the last 3 weeks. Nitrogen mustards, Melphalan, Monoclonal antibody or Nitrosourea within the last 6 weeks.

  • Received an investigational anti-cancer drug within 6weeks, or within 5 half-lives (whichever is shorter) of the first dose of study drug(s). A minimum of 14 days must have passed between the last dose of prior investigational agent and the first dose of study drug.
  • Current use of a prohibited medication per protocol or expected to require any of these medications during treatment with study drug.
  • Known Human Immunodeficiency Virus, or serological evidence for Hepatitis B (positive hepatitis B surface antigen [HBsAg]), or chronic Hepatitis C infection. For subjects who are negative for HBsAg, but Hepatitis B core Antibody [HBcAB] positive, a HBV DNA (viral load) test will be performed and if negative are eligible. Subjects with positive Hepatitis C antibody serology with a negative HCV ribonucleic acid (RNA) test results are eligible.
  • Concurrent use of therapeutic warfarin is allowed. However, anticoagulants that do not have reversal agents available are prohibited.
  • Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first dose of study drug, or palliative radiotherapy to a single symptomatic lesion within the 2 weeks prior to first dose of study drugs.
  • Subjects with prior allogeneic transplant are excluded: however, subjects who have previously received an autologous stem cell transplant are allowed if a minimum of 100 days has elapsed from the time of transplant and the subject has recovered from transplant-associated toxicities prior to the first dose of GSK2816126
  • Unresolved toxicity greater than Grade 1 National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 from previous anti-cancer therapy, with the exception of alopecia and peripheral neuropathy. Lymphoma subjects with <= Grade 3 lymphopenia can be enrolled at the discretion of the investigator.
  • Packed red blood cell or platelet transfusion within 7 days of screening laboratory tests.
  • Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol.
  • Cardiac exclusion criteria: History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 6 months prior to first dose of study drug; QTcF> 450 milliseconds (msec); Uncontrolled arrhythmias. Subjects with rate controlled atrial fibrillation for >1 month prior to first dose of study drug may be eligible; Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug or their excipients.
  • Pregnant or lactating female.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Uncontrolled diabetes or other medical condition that may interfere with assessment of toxicity.
  • Central nervous system (CNS) metastases, with the following exception: Subjects who have previously treated CNS metastases, are asymptomatic, and have no requirement for steroids at least 14 days prior to first dose of study drug; Subjects with carcinomatous meningitis are excluded regardless of clinical stability.
  • Invasive malignancy or history of invasive malignancy other than disease under study: any other invasive malignancy from which the subject has been disease-free for more than 2 years and, in the opinion of the principal investigator and GSK Medical Monitor, will not affect the evaluation of the effects of this clinical trial treatment on currently targeted malignancy, can be included in this clinical trial; Curatively treated non-melanoma skin cancer and any carcinoma-in-situ.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02082977


Locations
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United States, Illinois
GSK Investigational Site
Chicago, Illinois, United States, 60611
United States, New York
GSK Investigational Site
New York, New York, United States, 10021
France
GSK Investigational Site
Villejuif cedex, France, 94805
United Kingdom
GSK Investigational Site
Sutton, Surrey, United Kingdom, SM2 5PT
GSK Investigational Site
Southampton, United Kingdom, SO16 6YD
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Statistical Analysis Plan  [PDF] March 1, 2018
Study Protocol  [PDF] March 20, 2017


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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02082977     History of Changes
Other Study ID Numbers: 117208
2013-001585-42 ( EudraCT Number )
First Posted: March 11, 2014    Key Record Dates
Results First Posted: June 28, 2019
Last Update Posted: June 28, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Refractory
Phase I study, dose escalation study
diffuse large B cell lymphoma
Relapsed
Solid tumors
transformed follicular lymphoma
Multiple myeloma
GSK2816126
Non-Hodgkin's lymphoma
Additional relevant MeSH terms:
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Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders