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.
Name: GSK3326595
Name: Pembrolizumab
Description: 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.
Measure: Part 1: Number of participants with any adverse events (AEs) Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 1: Number of participants with serious adverse events (SAEs) Time: Up to approximately 2 yearsDescription: Number of participants withdrawn due to AEs will be evaluated.
Measure: Part 1: Number of participants withdrawn due to AEs Time: Up to approximately 2 yearsDescription: Number of participants with dose interruptions and with dose reductions will be analyzed.
Measure: Part 1: Number of participants with dose interruptions and with dose reductions Time: Up to approximately 2 yearsDescription: Number of participants withdrawn due to AEs will be evaluated.
Measure: Part 3: Number of participants withdrawn due to AEs Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 3: Number of participants with any AEs Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 3: Number of participants with SAEs Time: Up to approximately 2 yearsDescription: Number of participants with dose interruptions and with dose reductions will be analyzed.
Measure: Part 3: Number of participants with dose interruptions and with dose reductions Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 1: Number of participants with dose limiting toxicity (DLT) Time: Up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 1: Change from Baseline in Hemoglobin (Hb) (Grams per Liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 3: Change from Baseline in Hb (Grams per Liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 1: Change from Baseline in Hematocrit (Proportion of red blood cells in blood) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 3: Change from Baseline in Hematocrit (Proportion of red blood cells in blood) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 1: Change from Baseline in Mean Corpuscle Hemoglobin (MCH) (Picograms) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 3: Change from Baseline in MCH (Picograms) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 1: Change from Baseline in Mean Corpuscle Volume (MCV) (Femtoliters) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 3: Change from Baseline in MCV (Femtoliters) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameters.
Measure: Part 1: Change from Baseline in hematology parameter: red blood cells (RBC) Count and Reticulocytes (Trillion cells per liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameters.
Measure: Part 3: Change from Baseline in hematology parameter: RBC Count and Reticulocytes (Trillion cells per liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameters.
Measure: Part 1: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameters.
Measure: Part 3: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 1: Change from Baseline in Blood urea nitrogen (BUN), Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 3: Change from Baseline in BUN, Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 1: Change from Baseline in Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT), Alkaline phosphatase (International units per Liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 3: Change from Baseline in AST, ALT, Alkaline phosphatase (International units per Liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 1: Change from Baseline in total protein and albumin (grams per day) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 3: Change from Baseline in total protein and albumin (grams per day) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 1: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 3: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter) Time: Baseline and up to approximately 2 yearsDescription: Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.
Measure: Part 1: Change from Baseline in temperature (Degrees Celsius) Time: Baseline and up to approximately 2 yearsDescription: Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.
Measure: Part 3: Change from Baseline in temperature (Degrees Celsius) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of specific gravity.
Measure: Part 1: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of specific gravity.
Measure: Part 3: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio) Time: Baseline and up to approximately 2 yearsDescription: 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).
Measure: Part 1: Change from Baseline in Urinalysis Parameters- Urine potential of hydrogen (pH) Time: Baseline and up to approximately 2 yearsDescription: 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).
Measure: Part 3: Change from Baseline in Urinalysis Parameters- Urine pH Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary glucose.
Measure: Part 1: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary glucose.
Measure: Part 3: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary ketones.
Measure: Part 1: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary ketones.
Measure: Part 3: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary occult blood.
Measure: Part 1: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary occult blood.
Measure: Part 3: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary protein.
Measure: Part 1: Change from Baseline in urinalysis parameter: Protein Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary protein.
Measure: Part 3: Change from Baseline in urinalysis parameter: Protein Time: Baseline and up to approximately 2 yearsDescription: Change from Baseline pulse rate will be assessed in a seated or semi-supine position.
Measure: Part 1: Change from Baseline in Pulse rate (Beats per minute) Time: Baseline and up to approximately 2 yearsDescription: Change from Baseline pulse rate will be assessed in a seated or semi-supine position.
Measure: Part 3: Change from Baseline in Pulse rate (Beats per minute) Time: Baseline and up to approximately 2 yearsDescription: 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.
Measure: 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: Baseline and up to approximately 2 yearsDescription: 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.
Measure: Part 3: Change from Baseline in ECG Parameters: PR Interval, QRS Interval, QT Interval, QTcF (Milliseconds) Time: Baseline and up to approximately 2 yearsDescription: Change from Baseline in SBP and DBP will be assessed in a seated or semi-supine position with a completely automated device.
Measure: Part 1: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (Millimeter of mercury) Time: Baseline and up to approximately 2 yearsDescription: Change from Baseline in SBP and DBP will be assessed in a seated or semi-supine position with a completely automated device.
Measure: Part 3: Change from Baseline in SBP and DBP (Millimeter of mercury) Time: Baseline and up to approximately 2 yearsDescription: Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
Measure: Part 1: Number of participants with clinically significant change in respiratory rate Time: Up to approximately 2 yearsDescription: Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
Measure: Part 3: Number of participants with clinically significant change in respiratory rate Time: Up to approximately 2 yearsDescription: Organ-specific evaluations will be done for abnormal values.
Measure: Part 1: Number of participants with clinically significant change in organ-specific parameters Time: Up to approximately 2 yearsDescription: 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
Measure: Part 2: Solid tumor cohorts (non-GBM): Overall response rate (ORR) of participants Time: Up to approximately 2 yearsDescription: ORR is defined as the percentage of participants achieving CR or PR based on Lugano criteria.
Measure: Part 2: NHL cohort(s): ORR of participants Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 2: GMB cohort: Progression free survival (PFS) rate of participants Time: Up to approximately 2 yearsDescription: Organ-specific evaluations will be done for abnormal values.
Measure: Part 3: Number of participants with clinically significant change in organ-specific parameters Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 1: Number of participants with abnormality in physical examinations Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 3: Number of participants with abnormality in physical examinations Time: Up to approximately 2 yearsDescription: Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.
Measure: Part 1:Change from Baseline in symmetrical arginine dimethylation (SDMA) as a PD measure Time: Baseline and up to approximately 2 yearsDescription: Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.
Measure: Part 2:Change from Baseline in SDMA as a PD measure Time: Baseline and up to approximately 2 yearsDescription: Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.
Measure: Part 3:Change from Baseline in SDMA as a PD measure Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.
Measure: Part 1: Maximum observed plasma concentration (Cmax) in plasma following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 1: Cmax in plasma following repeat-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: 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: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 1: AUC (0-inf) following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood samples will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.
Measure: Part 1: AUC from time zero to the last quantifiable concentration after dosing (AUC[0-t]) following single-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 1: AUC(0-t) following repeat-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 1: AUC over the dosing interval tau (AUC[0-tau]) following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 1: AUC(0-tau) following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 1: Terminal phase half-life (t½) following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 1: t½ following repeat-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 1: Oral clearance (CL/F) following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 1: CL/F following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 1: Accumulation ratio (AR) following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 1: AR following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 1: Time invariance (TI) following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 1: TI following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 1: Time to Cmax (tmax) following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 1: tmax following repeat-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: ORR is defined as the percentage of participants achieving a confirmed CR or PR based on RECIST 1.1 criteria
Measure: Part 1: ORR of participants Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 3: AUC(0-inf) following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 3: AUC(0-t) following single-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 3: AUC(0-t) following repeat-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 3: AUC(0-tau) following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 3: AUC(0-tau) following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 3: AUC[0-inf] following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 3: tmax following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 3: tmax following repeat-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 3: t½ following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 3: t½ following repeat-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 3: CL/F following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 3: CL/F following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 3: AR following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 3: AR following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 3: Cmax in plasma following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 3: Cmax in plasma following repeat-dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure: Part 3: TI following single dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure: Part 3: TI following repeat dose administration of GSK3326595 Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 3: ORR of participants Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.
Measure: Part 1: Cmax following single-dose administration of GSK3326595 tablets in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: Tmax following single-dose administration of GSK3326595 tablets in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: t½ following single-dose administration of GSK3326595 tablets in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: AUC (0-t) following single-dose administration of GSK3326595 tablets in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: AUC (0-inf) following single-dose administration of GSK3326595 tablets in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: AUC (0-tau) following single-dose administration of GSK3326595 tablets in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: CL/F following single-dose administration of GSK3326595 tablets in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: TI following single-dose administration of GSK3326595 tablets in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: AR following single-dose administration of GSK3326595 tablets in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: Cmax following single-dose administration of GSK3326595 tablets in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: Tmax following single-dose administration of GSK3326595 tablets in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: t½ following single-dose administration of GSK3326595 tablets in fasted condition Time: Up to approximately 2 yearsDescription: Tumor biopsies will be performed to obtain p53 gene data.
Measure: Part 2: Relationship between p53 mutational status and ORR in participants with NHL Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: AUC (0-t) following single-dose administration of GSK3326595 tablets in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: AUC (0-inf) following single-dose administration of GSK3326595 tablets in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: AUC (0-tau) following single-dose administration of GSK3326595 tablets in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: CL/F following single-dose administration of GSK3326595 tablets in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: AR following single-dose administration of GSK3326595 tablets in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: TI following single-dose administration of GSK3326595 tablets in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: Cmax following single-dose administration of GSK3326595 capsules in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: Tmax following single-dose administration of GSK3326595 capsules in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: AUC (0-inf) following single-dose administration of GSK3326595 capsules in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: AUC (0-t) following single-dose administration of GSK3326595 capsules in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: AUC (0-tau) following single-dose administration of GSK3326595 capsules in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: CL/F following single-dose administration of GSK3326595 capsules in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: TI following single-dose administration of GSK3326595 capsules in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: AR following single-dose administration of GSK3326595 capsules in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure: Part 1: t½ following single-dose administration of GSK3326595 capsules in fasted condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: Cmax following single-dose administration of GSK3326595 capsules in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: Tmax following single-dose administration of GSK3326595 capsules in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: AUC (0-inf) following single-dose administration of GSK3326595 capsules in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: AUC (0-t) following single-dose administration of GSK3326595 capsules in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: AUC (0-tau) following single-dose administration of GSK3326595 capsules in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: CL/F following single-dose administration of GSK3326595 capsules in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: TI following single-dose administration of GSK3326595 capsules in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: AR following single-dose administration of GSK3326595 capsules in fed condition Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure: Part 1: t½ following single-dose administration of GSK3326595 capsules in fed condition Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 2: Number of participants with any AEs Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 2: Number of participants with SAEs Time: Up to approximately 2 yearsDescription: Number of participants withdrawn due to AEs will be evaluated.
Measure: Part 2: Number of participants withdrawn due to AEs Time: Up to approximately 2 yearsDescription: Number of participants with dose interruptions and with dose reductions will be analyzed.
Measure: Part 2: Number of participants with dose interruptions and with dose reductions Time: Up to approximately 2 yearsDescription: PFS defined as time from first dose until radiographic progression per standard criteria, or death due to any cause, whichever is earlier.
Measure: Part 2: PFS of participants Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595.
Measure: Part 2: AUC following administration of GSK3326595 Time: Up to approximately 2 yearsDescription: ORR is defined as CR + PR based on Response Assessment in Neuro-Oncology (RANO) Working Group criteria.
Measure: Part 2: ORR of participants present in GBM cohort Time: Up to approximately 2 yearsDescription: Blood sample will be collected at given time points to study the PK profile of GSK3326595.
Measure: Part 2: Cmax, dose concentration following administration of GSK3326595 Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 2: Duration of Response (DOR) for ACC cohort Time: Up to approximately 2 yearsDescription: ORR is defined as the percentage of participants achieving a confirmed CR or PR based on RECIST 1.1 criteria.
Measure: Part 2: ORR of participants for ACC cohort Time: Up to approximately 2 yearsDescription: OS is defined as time from first dose until death from any cause in ACC participants who are systemic-treatment naïve.
Measure: Part 2: Overall survival (OS) of participants for ACC cohort Time: Up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 2: Change from Baseline in Hb (Grams per Liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 2: Change from Baseline in Hematocrit (Proportion of red blood cells in blood) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 2: Change from Baseline in MCH (Picograms) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure: Part 2: Change from Baseline in MCV (Femtoliters) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameters.
Measure: Part 2: Change from Baseline in hematology parameter: RBC Count and Reticulocytes (Trillion cells per liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of hematology parameters.
Measure: Part 2: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 2: Change from Baseline in BUN, Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 2: Change from Baseline in AST, ALT, Alkaline phosphatase (International units per Liter) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 2: Change from Baseline in total protein and albumin (grams per day) Time: Baseline and up to approximately 2 yearsDescription: Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure: Part 2: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter) Time: Baseline and up to approximately 2 yearsDescription: Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.
Measure: Part 2: Change from Baseline in temperature (Degrees Celsius) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of specific gravity.
Measure: Part 2: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio) Time: Baseline and up to approximately 2 yearsDescription: 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).
Measure: Part 2: Change from Baseline in Urinalysis Parameters- Urine pH Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary glucose.
Measure: Part 2: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary ketones.
Measure: Part 2: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary occult blood.
Measure: Part 2: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter) Time: Baseline and up to approximately 2 yearsDescription: Urine samples will be collected at indicated time points for the assessment of urinary protein.
Measure: Part 2: Change from Baseline in urinalysis parameter: Protein Time: Baseline and up to approximately 2 yearsDescription: Change from Baseline pulse rate will be assessed in a semi-supine position.
Measure: Part 2: Change from Baseline in Pulse rate (Beats per minute) Time: Baseline and up to approximately 2 yearsDescription: Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
Measure: Part 2: Number of participants with clinically significant change in respiratory rate Time: Up to approximately 2 yearsDescription: Temperature measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
Measure: Part 2: Number of participants with clinically significant change in temperature Time: Up to approximately 2 yearsDescription: 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.
Measure: Part 2: Change from Baseline in ECG Parameters: PR Interval, QRS Interval, QT Interval, QTcF (Milliseconds) Time: Baseline and up to approximately 2 yearsDescription: Change from Baseline in SBP and DBP will be assessed in a semi-supine position with a completely automated device.
Measure: Part 2: Change from Baseline in SBP and DBP (Millimeter of mercury) Time: Baseline and up to approximately 2 yearsDescription: 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.
Measure: Part 2: Number of participants with abnormality in physical examinations Time: Up to approximately 2 yearsDescription: Organ-specific evaluations will be done for abnormal values.
Measure: Part 2: Number of participants with clinically significant change in organ-specific parameters Time: Up to approximately 2 yearsAllocation: Non-Randomized
Parallel Assignment
There is one SNP
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. --- V600E ---