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Dose Escalation Study of GSK3326595 in Participants With Solid Tumors and Non-Hodgkin's Lymphoma (NHL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02783300
Recruitment Status : Recruiting
First Posted : May 26, 2016
Last Update Posted : May 27, 2020
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE April 11, 2016
First Posted Date  ICMJE May 26, 2016
Last Update Posted Date May 27, 2020
Actual Study Start Date  ICMJE August 30, 2016
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 22, 2020)
  • Part 1: Number of participants with any adverse events (AEs) [ Time Frame: Up to approximately 2 years ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.
  • Part 1: Number of participants with serious adverse events (SAEs) [ Time Frame: Up to approximately 2 years ]
    An SAE is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement.
  • Part 1: Number of participants withdrawn due to AEs [ Time Frame: Up to approximately 2 years ]
    Number of participants withdrawn due to AEs will be evaluated.
  • Part 1: Number of participants with dose interruptions and with dose reductions [ Time Frame: Up to approximately 2 years ]
    Number of participants with dose interruptions and with dose reductions will be analyzed.
  • Part 3: Number of participants withdrawn due to AEs [ Time Frame: Up to approximately 2 years ]
    Number of participants withdrawn due to AEs will be evaluated.
  • Part 3: Number of participants with any AEs [ Time Frame: Up to approximately 2 years ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.
  • Part 3: Number of participants with SAEs [ Time Frame: Up to approximately 2 years ]
    An SAE is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement.
  • Part 3: Number of participants with dose interruptions and with dose reductions [ Time Frame: Up to approximately 2 years ]
    Number of participants with dose interruptions and with dose reductions will be analyzed.
  • Part 1: Number of participants with dose limiting toxicity (DLT) [ Time Frame: Up to approximately 2 years ]
    An event is considered to be a DLT if the event is attributed (definitely, probably or possibly) to the study treatment during the first 21 days of treatment.
  • Part 1: Change from Baseline in Hemoglobin (Hb) (Grams per Liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 3: Change from Baseline in Hb (Grams per Liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 1: Change from Baseline in Hematocrit (Proportion of red blood cells in blood) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 3: Change from Baseline in Hematocrit (Proportion of red blood cells in blood) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 1: Change from Baseline in Mean Corpuscle Hemoglobin (MCH) (Picograms) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 3: Change from Baseline in MCH (Picograms) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 1: Change from Baseline in Mean Corpuscle Volume (MCV) (Femtoliters) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 3: Change from Baseline in MCV (Femtoliters) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 1: Change from Baseline in hematology parameter: red blood cells (RBC) Count and Reticulocytes (Trillion cells per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameters.
  • Part 3: Change from Baseline in hematology parameter: RBC Count and Reticulocytes (Trillion cells per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameters.
  • Part 1: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameters.
  • Part 3: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameters.
  • Part 1: Change from Baseline in Blood urea nitrogen (BUN), Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 3: Change from Baseline in BUN, Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 1: Change from Baseline in Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT), Alkaline phosphatase (International units per Liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 3: Change from Baseline in AST, ALT, Alkaline phosphatase (International units per Liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 1: Change from Baseline in total protein and albumin (grams per day) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 3: Change from Baseline in total protein and albumin (grams per day) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 1: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 3: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 1: Change from Baseline in temperature (Degrees Celsius) [ Time Frame: Baseline and up to approximately 2 years ]
    Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.
  • Part 3: Change from Baseline in temperature (Degrees Celsius) [ Time Frame: Baseline and up to approximately 2 years ]
    Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.
  • Part 1: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of specific gravity.
  • Part 3: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of specific gravity.
  • Part 1: Change from Baseline in Urinalysis Parameters- Urine potential of hydrogen (pH) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).
  • Part 3: Change from Baseline in Urinalysis Parameters- Urine pH [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).
  • Part 1: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary glucose.
  • Part 3: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary glucose.
  • Part 1: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary ketones.
  • Part 3: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary ketones.
  • Part 1: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary occult blood.
  • Part 3: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary occult blood.
  • Part 1: Change from Baseline in urinalysis parameter: Protein [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary protein.
  • Part 3: Change from Baseline in urinalysis parameter: Protein [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary protein.
  • Part 1: Change from Baseline in Pulse rate (Beats per minute) [ Time Frame: Baseline and up to approximately 2 years ]
    Change from Baseline pulse rate will be assessed in a seated or semi-supine position.
  • Part 3: Change from Baseline in Pulse rate (Beats per minute) [ Time Frame: Baseline and up to approximately 2 years ]
    Change from Baseline pulse rate will be assessed in a seated or semi-supine position.
  • Part 1: Change from Baseline in Electrocardiogram (ECG) Parameters: PR Interval, QRS Interval, QT Interval, Corrected QT interval using the Fridericia formula (QTcF) (Milliseconds) [ Time Frame: Baseline and up to approximately 2 years ]
    12-lead ECGs will be obtained using an ECG machine that automatically calculates and measures PR, QRS, QT, and QTcF intervals. Twelve lead ECG will be measured in a supine or semi supine position after 10 minutes rest.
  • Part 3: Change from Baseline in ECG Parameters: PR Interval, QRS Interval, QT Interval, QTcF (Milliseconds) [ Time Frame: Baseline and up to approximately 2 years ]
    12-lead ECGs will be obtained using an ECG machine that automatically calculates and measures PR, QRS, QT, and QTcF intervals. Twelve lead ECG will be measured in a supine or semi supine position after 10 minutes rest.
  • Part 1: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (Millimeter of mercury) [ Time Frame: Baseline and up to approximately 2 years ]
    Change from Baseline in SBP and DBP will be assessed in a seated or semi-supine position with a completely automated device.
  • Part 3: Change from Baseline in SBP and DBP (Millimeter of mercury) [ Time Frame: Baseline and up to approximately 2 years ]
    Change from Baseline in SBP and DBP will be assessed in a seated or semi-supine position with a completely automated device.
  • Part 1: Number of participants with clinically significant change in respiratory rate [ Time Frame: Up to approximately 2 years ]
    Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
  • Part 3: Number of participants with clinically significant change in respiratory rate [ Time Frame: Up to approximately 2 years ]
    Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
  • Part 1: Number of participants with clinically significant change in organ-specific parameters [ Time Frame: Up to approximately 2 years ]
    Organ-specific evaluations will be done for abnormal values.
  • Part 2: Solid tumor cohorts (non-GBM): Overall response rate (ORR) of participants [ Time Frame: Up to approximately 2 years ]
    ORR is defined as the percentage of participants achieving a confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
  • Part 2: NHL cohort(s): ORR of participants [ Time Frame: Up to approximately 2 years ]
    ORR is defined as the percentage of participants achieving CR or PR based on Lugano criteria.
  • Part 2: GMB cohort: Progression free survival (PFS) rate of participants [ Time Frame: Up to approximately 2 years ]
    PFS is defined as the percentage of participants free from radiographic progression per Response Assessment in Neuro-Oncology (RANO) criteria, or death due to any cause, for six months after starting GSK3326595.
  • Part 3: Number of participants with clinically significant change in organ-specific parameters [ Time Frame: Up to approximately 2 years ]
    Organ-specific evaluations will be done for abnormal values.
  • Part 1: Number of participants with abnormality in physical examinations [ Time Frame: Up to approximately 2 years ]
    A complete physical examination will include, assessments of the head, eyes, ears, nose, throat, Skin, thyroid, Cardiovascular, Respiratory, Gastrointestinal, Neurological systems, lymph nodes and extremities. Brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen.
  • Part 3: Number of participants with abnormality in physical examinations [ Time Frame: Up to approximately 2 years ]
    A complete physical examination will include, assessments of the head, eyes, ears, nose, throat, Skin, thyroid, Cardiovascular, Respiratory, Gastrointestinal, Neurological systems, lymph nodes and extremities. Brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen.
Original Primary Outcome Measures  ICMJE
 (submitted: May 23, 2016)
  • Part 1: Number of subjects with any adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 2 years ]
    AEs and SAEs will be collected from the start of study treatment until 30 days after the last dose of study treatment
  • Part 1: Number of subjects withdrawn due to AEs, with dose interruptions and with dose reductions. [ Time Frame: Up to 2 years ]
  • Part 1: Dose limiting toxicity (DLT) [ Time Frame: Up to 2 years ]
    An event is considered to be a dose-limiting toxicity (DLT) if the event is attributed (definitely, probably or possibly) to the study treatment during the first 21 days of treatment.
  • Part 1: Changes from Baseline in hematology laboratory parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline in clinical chemistry laboratory parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline in urinalysis laboratory parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline in temperature [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline in systolic and diastolic blood pressure [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline in pulse rate [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline in respiratory rate [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline performance status assessment is based on the Eastern cooperative oncology group (ECOG) scale [ Time Frame: Baseline and up to 2 years ]
    Eastern Cooperative Oncology Group (ECOG) scale rating from 0 to 5
  • Part 1: Changes from Baseline in Electrocardiogram (ECG) parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline in Echocardiogram (ECHO) parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline in Troponin [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Solid tumor cohorts: Overall response rate (ORR) [ Time Frame: Up to 2 years ]
    ORR is defined as the percentage of subjects achieving a confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
  • Part 2: Glioblastoma multiforme (GBM) cohort: Overall response rate (ORR) [ Time Frame: Up to 2 years ]
    ORR is defined as CR or PR and is based on Response Assessment in Neuro-Oncology (RANO) Working Group criteria
  • Part 2: Non-Hodgkin's lymphoma (NHL) cohort(s): Overall response rate (ORR) [ Time Frame: Up to 2 years ]
    ORR is defined as the percentage of subjects achieving CR or PR based on International Workshop criteria
  • Part 1: Changes from Baseline in physical examinations parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Changes from Baseline in organ-specific parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 1: Number of pregnancies reported during study period [ Time Frame: Up to 2 years ]
    Details of all pregnancies in female subjects and female partners of male subjects will be collected.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2020)
  • Part 1:Change from Baseline in symmetrical arginine dimethylation (SDMA) as a PD measure [ Time Frame: Baseline and up to approximately 2 years ]
    Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.
  • Part 2:Change from Baseline in SDMA as a PD measure [ Time Frame: Baseline and up to approximately 2 years ]
    Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.
  • Part 3:Change from Baseline in SDMA as a PD measure [ Time Frame: Baseline and up to approximately 2 years ]
    Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.
  • Part 1: Maximum observed plasma concentration (Cmax) in plasma following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood samples will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.
  • Part 1: Cmax in plasma following repeat-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 1: Area under the plasma concentration-time curve (AUC) extrapolated from time zero to infinity (AUC[0-inf]) following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 1: AUC (0-inf) following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 1: AUC from time zero to the last quantifiable concentration after dosing (AUC[0-t]) following single-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood samples will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.
  • Part 1: AUC(0-t) following repeat-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 1: AUC over the dosing interval tau (AUC[0-tau]) following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 1: AUC(0-tau) following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 1: Terminal phase half-life (t½) following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 1: t½ following repeat-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 1: Oral clearance (CL/F) following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 1: CL/F following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 1: Accumulation ratio (AR) following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 1: AR following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 1: Time invariance (TI) following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 1: TI following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 1: Time to Cmax (tmax) following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 1: tmax following repeat-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 1: ORR of participants [ Time Frame: Up to approximately 2 years ]
    ORR is defined as the percentage of participants achieving a confirmed CR or PR based on RECIST 1.1 criteria
  • Part 3: AUC(0-inf) following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 3: AUC(0-t) following single-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 3: AUC(0-t) following repeat-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 3: AUC(0-tau) following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 3: AUC(0-tau) following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 3: AUC[0-inf] following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 3: tmax following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 3: tmax following repeat-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 3: t½ following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 3: t½ following repeat-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 3: CL/F following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 3: CL/F following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 3: AR following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 3: AR following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 3: Cmax in plasma following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 3: Cmax in plasma following repeat-dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 3: TI following single dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
  • Part 3: TI following repeat dose administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
  • Part 3: ORR of participants [ Time Frame: Up to approximately 2 years ]
    ORR is defined as the percentage of participants achieving a confirmed CR or PR based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and based on independent central review (ICR) in ACC cohort administered with tablet formulation.
  • Part 1: Cmax following single-dose administration of GSK3326595 tablets in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.
  • Part 1: Tmax following single-dose administration of GSK3326595 tablets in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: t½ following single-dose administration of GSK3326595 tablets in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: AUC (0-t) following single-dose administration of GSK3326595 tablets in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: AUC (0-inf) following single-dose administration of GSK3326595 tablets in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: AUC (0-tau) following single-dose administration of GSK3326595 tablets in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: CL/F following single-dose administration of GSK3326595 tablets in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: TI following single-dose administration of GSK3326595 tablets in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: AR following single-dose administration of GSK3326595 tablets in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: Cmax following single-dose administration of GSK3326595 tablets in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: Tmax following single-dose administration of GSK3326595 tablets in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: t½ following single-dose administration of GSK3326595 tablets in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 2: Relationship between p53 mutational status and ORR in participants with NHL [ Time Frame: Up to approximately 2 years ]
    Tumor biopsies will be performed to obtain p53 gene data.
  • Part 1: AUC (0-t) following single-dose administration of GSK3326595 tablets in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: AUC (0-inf) following single-dose administration of GSK3326595 tablets in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: AUC (0-tau) following single-dose administration of GSK3326595 tablets in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: CL/F following single-dose administration of GSK3326595 tablets in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: AR following single-dose administration of GSK3326595 tablets in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: TI following single-dose administration of GSK3326595 tablets in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: Cmax following single-dose administration of GSK3326595 capsules in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: Tmax following single-dose administration of GSK3326595 capsules in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: AUC (0-inf) following single-dose administration of GSK3326595 capsules in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: AUC (0-t) following single-dose administration of GSK3326595 capsules in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: AUC (0-tau) following single-dose administration of GSK3326595 capsules in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: CL/F following single-dose administration of GSK3326595 capsules in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: TI following single-dose administration of GSK3326595 capsules in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: AR following single-dose administration of GSK3326595 capsules in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: t½ following single-dose administration of GSK3326595 capsules in fasted condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
  • Part 1: Cmax following single-dose administration of GSK3326595 capsules in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: Tmax following single-dose administration of GSK3326595 capsules in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: AUC (0-inf) following single-dose administration of GSK3326595 capsules in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: AUC (0-t) following single-dose administration of GSK3326595 capsules in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: AUC (0-tau) following single-dose administration of GSK3326595 capsules in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: CL/F following single-dose administration of GSK3326595 capsules in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: TI following single-dose administration of GSK3326595 capsules in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: AR following single-dose administration of GSK3326595 capsules in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 1: t½ following single-dose administration of GSK3326595 capsules in fed condition [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
  • Part 2: Number of participants with any AEs [ Time Frame: Up to approximately 2 years ]
    An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
  • Part 2: Number of participants with SAEs [ Time Frame: Up to approximately 2 years ]
    Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.
  • Part 2: Number of participants withdrawn due to AEs [ Time Frame: Up to approximately 2 years ]
    Number of participants withdrawn due to AEs will be evaluated.
  • Part 2: Number of participants with dose interruptions and with dose reductions [ Time Frame: Up to approximately 2 years ]
    Number of participants with dose interruptions and with dose reductions will be analyzed.
  • Part 2: PFS of participants [ Time Frame: Up to approximately 2 years ]
    PFS defined as time from first dose until radiographic progression per standard criteria, or death due to any cause, whichever is earlier.
  • Part 2: AUC following administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595.
  • Part 2: ORR of participants present in GBM cohort [ Time Frame: Up to approximately 2 years ]
    ORR is defined as CR + PR based on Response Assessment in Neuro-Oncology (RANO) Working Group criteria.
  • Part 2: Cmax, dose concentration following administration of GSK3326595 [ Time Frame: Up to approximately 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595.
  • Part 2: Duration of Response (DOR) for ACC cohort [ Time Frame: Up to approximately 2 years ]
    DOR is defined as time from first evidence of response (CR or PR per Immune Response Evaluation Criteria in Solid Tumors [iRECIST 1.1]) to earlier date of disease progression or death due to any cause.
  • Part 2: ORR of participants for ACC cohort [ Time Frame: Up to approximately 2 years ]
    ORR is defined as the percentage of participants achieving a confirmed CR or PR based on RECIST 1.1 criteria.
  • Part 2: Overall survival (OS) of participants for ACC cohort [ Time Frame: Up to approximately 2 years ]
    OS is defined as time from first dose until death from any cause in ACC participants who are systemic-treatment naïve.
  • Part 2: Change from Baseline in Hb (Grams per Liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 2: Change from Baseline in Hematocrit (Proportion of red blood cells in blood) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 2: Change from Baseline in MCH (Picograms) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 2: Change from Baseline in MCV (Femtoliters) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameter.
  • Part 2: Change from Baseline in hematology parameter: RBC Count and Reticulocytes (Trillion cells per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameters.
  • Part 2: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of hematology parameters.
  • Part 2: Change from Baseline in BUN, Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 2: Change from Baseline in AST, ALT, Alkaline phosphatase (International units per Liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 2: Change from Baseline in total protein and albumin (grams per day) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 2: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Blood samples will be collected at indicated time points for analysis of chemistry parameters.
  • Part 2: Change from Baseline in temperature (Degrees Celsius) [ Time Frame: Baseline and up to approximately 2 years ]
    Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.
  • Part 2: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of specific gravity.
  • Part 2: Change from Baseline in Urinalysis Parameters- Urine pH [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).
  • Part 2: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary glucose.
  • Part 2: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary ketones.
  • Part 2: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter) [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary occult blood.
  • Part 2: Change from Baseline in urinalysis parameter: Protein [ Time Frame: Baseline and up to approximately 2 years ]
    Urine samples will be collected at indicated time points for the assessment of urinary protein.
  • Part 2: Change from Baseline in Pulse rate (Beats per minute) [ Time Frame: Baseline and up to approximately 2 years ]
    Change from Baseline pulse rate will be assessed in a semi-supine position.
  • Part 2: Number of participants with clinically significant change in respiratory rate [ Time Frame: Up to approximately 2 years ]
    Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
  • Part 2: Number of participants with clinically significant change in temperature [ Time Frame: Up to approximately 2 years ]
    Temperature measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
  • Part 2: Change from Baseline in ECG Parameters: PR Interval, QRS Interval, QT Interval, QTcF (Milliseconds) [ Time Frame: Baseline and up to approximately 2 years ]
    12-lead ECGs will be obtained using an ECG machine that automatically calculates and measures PR, QRS, QT, and QTcF intervals. Twelve lead ECG will be measured in a supine or semi supine position after 10 minutes rest.
  • Part 2: Change from Baseline in SBP and DBP (Millimeter of mercury) [ Time Frame: Baseline and up to approximately 2 years ]
    Change from Baseline in SBP and DBP will be assessed in a semi-supine position with a completely automated device.
  • Part 2: Number of participants with abnormality in physical examinations [ Time Frame: Up to approximately 2 years ]
    A complete physical examination will include, assessments of the head, eyes, ears, nose, throat, Skin, thyroid, Cardiovascular, Respiratory, Gastrointestinal, Neurological systems, lymph nodes and extremities. Brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen.
  • Part 2: Number of participants with clinically significant change in organ-specific parameters [ Time Frame: Up to approximately 2 years ]
    Organ-specific evaluations will be done for abnormal values.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 23, 2016)
  • Part 1: Composite of PD data [ Time Frame: Baseline and 2 years ]
    Evaluation of change from baseline in symmetrical arginine dimethylation (SDMA), a pharmacodynamic biomarker of PRMT5 inhibition.
  • Part 1: Maximum observed plasma concentration (Cmax) in plasma following single dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: Cmax in plasma following repeat-dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: Time to Cmax (tmax) following single dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: tmax following repeat-dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: Terminal phase half-life (t½) following single dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: t½ following repeat-dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: Area under the plasma concentration-time curve (AUC) following single dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: AUC following repeat-dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: Oral clearance (CL/F) following administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: Time invariance (TI) following administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 1: Accumulation ratio (AR) following administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 2: Progression Free Survival (PFS) to describe the duration of response to GSK3326595 [ Time Frame: Up to 2 years ]
    PFS defined as time from first dose until radiographic progression as measured by standard measures and defined by standard criteria
  • Part 2: Relationship between p53 mutational status and clinical response in subjects with NHL [ Time Frame: Up to 2 years ]
    Tumor biopsies will be performed to obtain p53 gene data.
  • Part 2: Cmax, dose concentration following administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 2: AUC following administration of GSK3326595 [ Time Frame: Up to 2 years ]
  • Part 2: Number of subjects with any AEs and SAEs [ Time Frame: Up to 2 years ]
    AEs and SAEs will be collected from the start of study treatment until 30 days after the last dose of study treatment
  • Part 2: Number of subjects withdrawn due to AEs, with dose interruptions and with dose reductions [ Time Frame: Up to 2 years ]
  • Part 2: Dose limiting toxicity (DLT) [ Time Frame: Up to 2 years ]
    An event is considered to be a dose-limiting toxicity (DLT) if the event meets at least one of the pre-defined toxicity criteria and is attributed as related to the study treatment during the first 21 days of treatment.
  • Part 2: Changes from Baseline in hematology laboratory parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in clinical chemistry laboratory parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in urinalysis laboratory parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in temperature [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in systolic and diastolic blood pressure [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in pulse rate [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in respiratory rate [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in performance status assessment based on the Eastern Cooperative Oncology Group (ECOG) scale [ Time Frame: Baseline and up to 2 years ]
    Eastern Cooperative Oncology Group (ECOG) scale rating from 0 to 5.
  • Part 2: Changes from Baseline in ECG parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in Echocardiogram (ECHO) parameters [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in Troponin [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Number of pregnancies reported during study period [ Time Frame: Up to 2 years ]
    Details of all pregnancies in female subjects and female partners of male subjects will be collected.
  • Part 1: Disease control rate (DCR) based on RECIST 1.1 criteria [ Time Frame: Up to 2 years ]
    DCR is defined as complete response ([CR)] + partial response ([PR)] + stable disease ([SD]).
  • Part 1: Overall Response Rate (ORR), based on RECIST 1.1 criteria [ Time Frame: Up to 2 years ]
    ORR is defined as CR + PR.
  • Part 2: Change from baseline in SDMA [ Time Frame: Up to 2 years ]
    Pharmacodynamic response assessed by change from baseline in symmetrical arginine dimethylation (SDMA).
  • Part 2: Changes from Baseline in physical examinations [ Time Frame: Baseline and up to 2 years ]
  • Part 2: Changes from Baseline in organ-specific parameters [ Time Frame: Baseline and up to 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose Escalation Study of GSK3326595 in Participants With Solid Tumors and Non-Hodgkin's Lymphoma (NHL)
Official Title  ICMJE A Phase I, Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK3326595 in Subjects With Solid Tumors and Non-Hodgkin's Lymphoma
Brief Summary The study drug, GSK3326595, is an inhibitor of protein arginine methyltransferase 5 (PRMT5) that potently inhibits tumor growth in vitro and in vivo in animal models. This first time in human (FTIH), open-label, dose escalation study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK3326595 in participants with advanced or recurrent solid tumors, as well as clinical activity in participants with a subset of solid tumors and NHL. This is an open-label, repeat-dose, multicenter, three-part study to establish the maximally tolerated dose (MTD)/ recommended phase 2 dose (RP2D) based on safety and tolerability and preliminary clinical efficacy of orally-administered GSK3326595. Part 1 is a dose-escalation phase to identify the MTD/RP2D based on the safety, PK, and PD profiles observed after oral administration of GSK3326595 and to preliminarily identify whether or not there is an effect of fed versus fasted state and of tablet versus capsule formulation on the PK of GSK3326595. This Part will be conducted in adult participants with relapsed and/or refractory solid tumors. It is estimated that up to 66 participants will be enrolled into the dose escalation cohort of the study, including up to 42 participants to identify the MTD and approximately 12 participants in the PK/PD/metabolite/biomarker expansion cohort(s) and approximately 12 participants in the food effect and relative bioavailability sub-study. Disease-specific expansion cohorts (Part 2) are planned to further explore clinical activity of GSK3326595 in participants with selected solid tumors and NHL. It is estimated that up to 316 participants will be enrolled in Part 2. Part 3 will be a dose determination study to evaluate the safety, PK/PD profile, and clinical activity of orally-administered GSK3326595 in combination with intravenous pembrolizumab. Overall, approximately 30 participants will be enrolled in Part 3. The duration of study will depend on recruitment rates and the timing of participant's duration on study (withdrawal rates due to toxicity or progression), with an approximate duration of 6 years.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE
  • Drug: GSK3326595
    The capsules will be opaque white 12.5 mg, 10 mg, 25 mg and 100 mg capsules. The tablets will be white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 milliliter [mL]) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
  • Drug: Pembrolizumab
    The solution will be concentrate solution for infusion at 100 mg/4mL administered intravenously every 3 weeks in combination with GSK3326595.
Study Arms  ICMJE
  • Experimental: Part 1a: Dose Escalation
    In Part 1, participants will receive GSK3326595 12.5 milligram (mg) once daily (QD) and escalate until the maximum tolerated dose (MTD) is reached. Projected daily dose levels are 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg. BID dosing may divide this total daily dose into two equal doses, administered twice daily. Additional doses (either lower than 12.5 mg, higher than 1200 mg, or intermediate doses between those listed above) and schedules may be explored based on emerging safety, PK and PD data. Further enrollment to this cohort is closed.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2a: Disease-Specific TNBC
    This part 2 expansion cohort will enroll participants with triple-negative breast cancer (TNBC). The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2b: Disease-Specific MTCC
    This part 2 expansion cohort will enroll participants with metastatic transitional cell carcinoma (MTCC) of the urinary system. The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2c: Disease-Specific recurrent GBM
    This part 2 expansion cohort will enroll participants with recurrent glioblastoma multiforme (GBM). The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2d: Disease-Specific NHL p53 mutant
    This part 2 expansion cohort will enroll participants with NHL p53 mutant gene. The dose of GSK3326595 was started at 400 mg QD but going forward participants will receive 300 mg QD.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2e: Disease-Specific NHL p53 wildtype
    This part 2 expansion cohort will enroll participants with NHL p53 wild-type gene. The dose of GSK3326595 was started at 400 mg QD but going forward participants will receive 300 mg QD.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2f: Disease-specific ACC (GSK3326595 capsule)
    This part 2 expansion cohort will enroll participants with adenoid cystic carcinoma (ACC) and will receive GSK3326595 capsules. The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2g: Disease-specific ACC (GSK3326595 tablet)
    This part 2 expansion cohort will enroll participants with ACC who have not received any systemic therapy for locally advanced or metastatic disease and will receive GSK3326595 tablets. The dose of GSK3326595 will be 300 mg QD.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2h: Disease specific ER+BC
    This part 2 expansion cohort will enroll participants with hormone receptor-positive adenocarcinoma of the breast (ER+BC). The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2i: Disease-specific HPV
    This part 2 expansion cohort will enroll participants with human papillomavirus (HPV) positive solid tumors of any histology (including cervical cancer and squamous cell carcinoma of the head and neck [HNSCC]). The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
    Intervention: Drug: GSK3326595
  • Experimental: Part 2j: Disease specific p53 wild-type NSCLC
    This part 2 expansion cohort will enroll participants with P53 wild-type non small-cell lung cancer (NSCLC) and will receive GSK3326595. The dose of GSK3326595 will be 300 mg QD.
    Intervention: Drug: GSK3326595
  • Experimental: Part 3: Dose Determination at 100 mg
    The participants with NSCLC, melanoma, mTCC, or HNSCC will receive pembrolizumab at the approved dose (200 mg intravenous [IV] every 3 weeks), in combination with GSK3326595 dosed orally at 100 mg QD.
    Interventions:
    • Drug: GSK3326595
    • Drug: Pembrolizumab
  • Experimental: Part 3: Dose Determination at 200 mg
    The participants with NSCLC, melanoma, mTCC, or HNSCC will receive pembrolizumab at the approved dose (200 mg IV every 3 weeks), in combination with GSK3326595 dosed orally at 200 mg QD.
    Interventions:
    • Drug: GSK3326595
    • Drug: Pembrolizumab
  • Experimental: Part 3: Dose Determination at 300 mg
    The participants with NSCLC, melanoma, mTCC, or HNSCC will receive pembrolizumab at the approved dose (200 mg IV every 3 weeks), in combination with GSK3326595 dosed orally at 300 mg QD.
    Interventions:
    • Drug: GSK3326595
    • Drug: Pembrolizumab
  • Experimental: Part 1b: Food Effect and Relative Bioavailability
    Part 1 will include a sub-study that will be an open-label, randomized, single dose, three period, cross over study to investigate the effect of a high-fat, high-calorie meal on the bioavailability of GSK3326595, and compare two formulations of GSK3326595 (capsule versus tablet). The dose of GSK3326595 will be 300 mg QD.
    Intervention: Drug: GSK3326595
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 22, 2020)
412
Original Estimated Enrollment  ICMJE
 (submitted: May 23, 2016)
208
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Males and females >=18 years of age (at the time consent is obtained). For NHL cohort only, participants must be <=75 years of age at the time consent is obtained.
  • Capable of giving signed informed consent.
  • Able to swallow and retain orally-administered medication.
  • Eastern cooperative oncology group (ECOG) performance status of 0 to 2.
  • Diagnosis of one of the following:
  • Part 1: Histologically- or cytological-confirmed diagnosis of non-resectable or metastatic solid malignancy that has progressed on prior therapy (radiographic documentation of progression is adequate for study participation).
  • Part 2: Histologically- or cytologically-confirmed diagnosis of metastatic or non-resectable disease that has progressed on prior therapy (ACC tablet cohort does not require prior therapy for enrollment i.e. must be systemic therapy naive; for all tumors, (radiographic documentation of progression is adequate for study participation):
  • TNBC (estrogen receptor negative [ER-]/ progesterone receptor [PR-]/Human Epidermal Growth Factor Receptor 2 negative [Her2-], as defined by local laboratory standards);
  • ER+BC (estrogen receptor positive [ER+] or progesterone receptor positive [PR+], Her2-, as defined by local laboratory standards);
  • metastatic or non-resectable transitional cell carcinoma of the bladder, ureter, or renal pelvis;
  • recurrent GBM;
  • ACC requiring systemic therapy. In order to be eligible for enrolment, ACC participants must: have shown progression by local evaluation of scans, as per RECIST 1.1, within the 13 months prior to enrolment and have measurable disease, as confirmed by independent central review of baseline scans prior to first dose.
  • HPV-positive solid tumor of any primary histology.
  • NHL that is not one of the following subtypes, as determined by local laboratory testing: Burkitt's lymphoma or other high-grade lymphoma and double- or triple-hit large B-cell lymphoma.
  • NSCLC, of any histologic sub-type; with local mutational analysis demonstrating wild-type status of TP53 (i.e., p53 wild-type NSCLC).
  • Part 3: Histologically- or cytologically-confirmed diagnosis of metastatic or nonresectable NSCLC (of any histologic sub-type), metastatic transitional cell carcinoma of the urinary system (mTCC), squamous cell carcinoma of the head and neck (HNSCC), or melanoma that failed to respond to prior treatment with Programmed Cell Death-Protein 1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) targeted therapy.
  • Prior therapy: ACC tablet cohort: participants must be systemic therapy-naïve. Prior surgery and/or radiation is permitted. NHL cohort: participants may have received up to 4 prior lines of systemic therapy for disease. Tumors with actionable mutations (e.g., BRAF V600E gene mutation in melanoma; Epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements in NSCLC) must have received prior therapy with targeted agents prior to enrollment. Apart from ACC tablet cohort, participants must have received at least one line of prior systemic therapy (or have a disease for which no approved therapy exists), and have no standard-of-care therapy that would be expected achieve a durable clinical response, or refuse standard therapy, or are not candidates for standard therapy.
  • Evaluable disease: During Part 1, evaluable disease is required; measurable disease per RECIST v1.1 is recommended but not required and Participants enrolled in Part 2 and Part 3 must demonstrate measurable disease per the disease-specific criteria.
  • PK/PD/biomarker/metabolite expansion cohort(s) only: Participants must consent to pre- and post-dose tumor biopsies and additional sample collection procedures.
  • Food effect and relative bioavailability sub-study only: Participants must consent to additional procedures.
  • Part 3 only: Participants must consent to additional procedures (including paired biopsies).
  • All prior treatment-related toxicities must be National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 =<Grade 1 (except alopecia [permissible at any Grade] and peripheral neuropathy [which must be =<Grade 2]) at the time of treatment allocation.
  • Adequate organ function as per Hematologic, Hepatic and Renal Laboratory Values.
  • Reproductive criteria:
  • A male participant with female partner of child bearing potential must agree to use one of the methods of contraception for the duration specified in protocol.
  • A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test), not nursing, and at least one of the following conditions apply: Reproductive potential: participants must agree to follow one of the options and the duration specified in protocol;
  • Non-reproductive potential defined as
  • i) Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy;
  • ii) Postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile or females over 60 years of age. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment.

Exclusion Criteria:

  • Malignancy attributed to prior solid organ transplant.
  • Leptomeningeal disease, spinal cord compression, or brain metastases that require immediate central nervous system (CNS)-specific treatment in the opinion of the Investigator (e.g., for symptomatic disease).
  • Recent prior therapy, defined as
  • 1. Any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is longer, prior to the first dose of GSK3326595. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of GSK3326595. Prior therapy with biologic agents (including monoclonal antibodies) is permitted so long as 28 days have elapsed since therapy and all therapy-related AEs have resolved to =<Grade 1, note that participants with immunotherapy-related endocrinopathies, currently managed with replacement therapy, will be allowed on study.
  • 2. Any radiotherapy within 14 days or major surgery within 28 days prior to the first dose of GSK3326595. For participants in the GBM cohort, participants must have completed radiation therapy at least 28 days prior to the first dose of GSK3326595.
  • 3. Anti-androgen therapies for prostate cancer, such as bicalutamide, must be stopped 4 weeks prior to enrollment. Second-line hormone therapies such as enzalutamide or abiraterone should be stopped 2 weeks prior to enrolment. Participants with prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Participants with prostate cancer may also remain on low-dose prednisone or prednisolone (up to 10 mg/day) and still be eligible for this study.
  • Part 3 only: History of any of the following: Recent history (within the past 2 years) of autoimmune disease or syndrome that required systemic treatment; a diagnosis of immunodeficiency or administration of systemic steroids (>=10 mg oral prednisone or equivalent) or other immunosuppressive agents within 7 days prior to randomization; Receipt of any live vaccine within 30 days prior randomization; Prior allogeneic/autologous bone marrow or solid organ transplantation; Current pneumonitis or history of non-infectious pneumonitis that required steroids or other immunosuppressive agents; Recent history of allergen desensitization therapy within 4 weeks of randomization; History of severe hypersensitivity to monoclonal antibodies.
  • History of a second malignancy, excluding non-melanoma skin cell cancer within the last three years. Participants with second malignancies that were indolent, in situ or definitively treated may be enrolled even if less than three years have elapsed since treatment. Consult the GSK Medical Monitor if second malignancies meet the requirements specified above.
  • Current use of a prohibited medication or planned use of any forbidden medications during treatment with GSK3326595.
  • Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes). Any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric disorder, or other conditions that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator.
  • Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
  • History of known human immunodeficiency virus (HIV) infection or positive HIV test result at screening.
  • Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) polymerase chain reaction (PCR) is obtained.
  • Any of the following cardiac abnormalities: 1. Recent history (within 6 months of first dose of study drug) of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting. 2. Presence of a cardiac pacemaker, 3. Baseline QTcF >=450 millisecond, 4. Uncontrolled arrhythmias. Participants with rate-controlled atrial fibrillation for >1 month prior to first dose of study drugs may be eligible. 5. Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com
Listed Location Countries  ICMJE Canada,   France,   Netherlands,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02783300
Other Study ID Numbers  ICMJE 204653
2016-000278-39 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP