Arginine methylation mediated by protein arginine methyl-transferases (PRMTs) is an important post-translational modification of proteins involved in a diverse range of cellular processes. Misregulation and overexpression of PRMT1 (a type I PRMT) has been associated with a number of solid and hematopoietic cancers. GSK3368715 leads to inhibition of tumor cell growth across tumor types with cytotoxic response observed in lymphoma, acute myeloid leukemia (AML) and a subset of solid tumor cell lines. This study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), food effect and preliminary clinical activity of GSK33368715 in participants with relapsed/refractory DLBCL and selected solid tumors with frequent methyl-thioadenosine phosphorylase (MTAP)-deficiency. The study will consist of two parts. In Part 1 (Dose Escalation) escalating doses of GSK3368715 will be evaluated and recommended phase 2 dose (RP2D) will be established in participants with selected solid relapsed/refractory tumors. Once a RP2D is identified, a food effect sub-study will be initiated to determine the effect of a high-fat, high calorie meal on the bioavailability of GSK3368715. In Part 2 (Dose Expansion), this RP2D will be further investigated in two expansion cohorts; participants with DLBCL (Expansion Cohort 2A) and relapsed/refractory solid tumors including pancreatic, bladder, and non-small cell lung cancer (NSCLC)(Expansion Cohort 2B). The study includes a screening period, an intervention period and follow up.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
31
GSK3368715 will be available with dosing strengths of 25 mg, 100 mg and 250 mg to be administered once daily as an oral capsule.
GSK3368715 will be available in Immediate release (IR) white film coated tablet with dosing strengths of 50 mg, 100 mg and 250 mg to be administered orally once daily .
GSK Investigational Site
Los Angeles, California, United States
GSK Investigational Site
Newport Beach, California, United States
GSK Investigational Site
Philadelphia, Pennsylvania, United States
GSK Investigational Site
Houston, Texas, United States
GSK Investigational Site
Salt Lake City, Utah, United States
GSK Investigational Site
Melbourne, Victoria, Australia
GSK Investigational Site
Toronto, Ontario, Canada
GSK Investigational Site
Barcelona, Spain
GSK Investigational Site
Madrid, Spain
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
A DLT is considered by the investigator to be clinically relevant,attributed event during the first 21days of intervention meeting the following criteria:Non-hematologic toxicity:Aspartate Aminotransferase(AST)/Alanine Aminotransferase(ALT) Grade 3/4,ALT\>=5 times Upper limit of Normal(ULN),ALT\>=3times ULN(\>=4 weeks),ALT\>=3 times ULN plus(+)bilirubin\>=2 times ULN,ALT \>= 3 times ULN+liver symptoms or International Normalization Ratio(INR)\>1.5.Nausea:Grade 3;Vomiting or diarrhea:Grade3/4(\>3days);Fatigue:Grade 3(\>5days).Hypertension:Uncontrolled Grade 3/4.Electrocardiogram(ECG)-change:\>20 milliseconds(msec) QRS extension.Lab abnormality:uncontrolled Grade3(\>3days)/Grade4.Hematologic toxicity:Neutropenia:uncontrolled Grade3(\>3days)/febrile neutropenia/Grade 4.Thrombocytopenia:uncontrolled Grade 3(\>3days)/Grade 3(clinically significant Hemorrhage)/Grade 4.Venous thromboembolism (VTE):Grade2 needing systemic anticoagulation/Grade\>=3 during the first 8 weeks or if sooner,study discontinuation
Time frame: Up to 21 days
Part 1: Number of Participants With Non-Serious Adverse Events (Non-SAEs) and SAEs
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Any untoward event resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.
Time frame: Up to 28 months
Part 1: Number of Participants With AEs by Severity Grades
All adverse events were analyzed using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Graded from Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL), Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE. Higher grade indicates more severe condition. Number of participants with maximum severity grades are presented.
Time frame: Up to 28 months
Part 2: Percentage of Participants Achieving Objective Response Rate (ORR)
ORR is defined as the percentage of participants with a confirmed complete response (CR) or a partial response (PR). Participants with solid tumor were planned to be assessed per Response Criteria for Solid Tumors (RECIST) 1.1 and DLBCL participants were planned to be assessed per Lugano Criteria. This analysis was planned but not performed for Part 2 as the study was terminated during Part 1.
Time frame: Up to 48 months
Part 1: Percentage of Participants Achieving Best Overall Response Rate
Overall response rate is defined as the percentage of participants with a confirmed complete response (CR) or a partial response (PR). Participants with solid tumor were assessed per Response Criteria for Solid Tumors (RECIST) 1.1 and DLBCL participants were assessed per Lugano Criteria. The best ORR was recorded from the start of the intervention until disease progression/recurrence and was determined based on the investigator's assessment of response at each time point. The percentage of participants achieving best overall response rate have been presented.
Time frame: Up to 28 months
Part 1: Maximum Observed Plasma Concentration (Cmax) Following Administration of GSK3368715
Blood samples were collected at indicated time points. The pharmacokinetic (PK) parameters were calculated by non-compartmental analysis. PK Population included all participants in the All-Treated population from whom at least one PK sample was obtained, analyzed, and was measurable.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2 ,3 ,4 ,6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: Time to Reach Cmax (Tmax) Following Administration of GSK3368715
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: Area Under the Concentration Time Curve From Time Zero to Last Time of Quantifiable Concentration (AUC [0-t]) Following Administration of GSK3368715
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: AUC From Time Zero Extrapolated to Infinite Time (AUC [0-infinity]) Following Administration of GSK3368715
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1
Part 1: Area Under the Concentration-time Curve From Time Zero to the Predose of the Next Dose [AUC (0-tau)] Following Administration of GSK3368715
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
Time frame: Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: Trough (Pre-dose) Concentration (Ctau) Following Administration of GSK3368715
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. Not applicable (NA) indicates that data could not be calculated as these were derivate values which were below the lower limit of quantification.
Time frame: Pre-dose on Day 1 and Day 15
Part 1: Time Invariance Ratio Following Administration of GSK3368715
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. Time invariance was calculated as the ratio of AUC(0-24) on Day 15 / AUC (0-infinity) on Day 1 for GSK3368715.
Time frame: Pre-dose, 15, 30 minutes, 1 ,1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose, 30 minutes,1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: Accumulation Ratio Following Administration of GSK3368715
Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. Accumulation ratio (AR) was calculated as the ratio of AUC(0-24) on Day 15/Day 1 for GSK3368715.
Time frame: Pre-dose, 15, 30 minutes, 1 ,1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: Food Effect Cohorts: Cmax Following Administration of GSK3368715
Blood samples were planned to be collected at indicated time points in food effect cohorts (fasted followed by fed state and fed followed by fasted state). Samples were not collected due to early termination of study during Part 1; therefore, no analysis could be performed.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose, 1 and 4 hours post dose on Day 8, Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: Food Effect Cohorts: Tmax Following Administration of GSK3368715
Blood samples were planned to be collected at indicated time points in food effect cohorts (fasted followed by fed state and fed followed by fasted state). Samples were not collected due to early termination of the study during Part 1; therefore, no analysis could be performed.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose, 1 and 4 hours post dose on Day 8, Pre-dose, 30 minutes, 1 ,2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: Food Effect Cohorts: AUC (0-t) Following Administration of GSK3368715
Blood samples were planned to be collected at indicated time points in food effect cohorts (fasted followed by fed state and fed followed by fasted state). Samples were not collected due to early termination of the study during Part 1; therefore, no analysis could be performed.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose, 1 and 4 hours post dose on Day 8, Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: Food Effect Cohorts: AUC (0-infinity) Following Administration of GSK3368715
Blood samples were planned to be collected at indicated time points in food effect cohorts (fasted followed by fed state and fed followed by fasted state). Samples were not collected due to early termination of the study during Part 1; therefore, no analysis could be performed.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose, 1 and 4 hours post dose on Day 8, Pre-dose,30 minutes,1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 1: Food Effect Cohorts: AUC (0-tau) Following Administration of GSK3368715
Blood samples were planned to be collected at indicated time points in food effect cohorts (fasted followed by fed state and fed followed by fasted state). Samples were not collected due to early termination of the study during Part 1; therefore, no analysis could be performed.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose, 1 and 4 hours post dose on Day 8, Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 2: Number of Participants With Non-SAEs and SAEs
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Any untoward event resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as serious adverse event (SAE). This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Up to 48 months
Part 2: Number of Participants With AEs by Severity Grades
All adverse events were analyzed using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Graded from Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL), Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE. Higher grade indicates more severe condition. Number of participants with maximum severity grades were presented. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Up to 48 months
Part 2: Progression-free Survival (PFS)
PFS is defined as the time from the first dose of study intervention to disease progression or death due to any cause, whichever occurs earlier. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Up to 48 months
Part 2: Cmax Following Administration of GSK3368715
Blood samples were planned to be collected for PK analysis of GSK3368715. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5 ,2 ,3 ,4 ,6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 2: Tmax Following Administration of GSK3368715
Blood samples were planned to be collected for PK analysis of GSK3368715. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 2: AUC (0-t) Following Administration of GSK3368715
Blood samples were planned to be collected for PK analysis of GSK3368715. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 2: AUC (0-infinity) Following Administration of GSK3368715
Blood samples were planned to be collected for PK analysis of GSK3368715 . This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1
Part 2: AUC (0-tau) Following Administration of GSK3368715
Blood samples were planned to be collected for PK analysis of GSK3368715. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 2: Ctau Following Administration of GSK3368715
Blood samples were planned to be collected for pharmacokinetic analysis of GSK3368715. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Pre-dose on Day 1 and Day 15
Part 2: Time Invariance Ratio Following Administration of GSK3368715
Blood samples were planned to be collected for pharmacokinetic analysis of GSK3368715. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Pre-dose, 15, 30 minutes, 1 ,1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose, 30 minutes,1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
Part 2: Accumulation Ratio Following Administration of GSK3368715
Blood samples were planned to be collected for PK analysis of GSK3368715. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.
Time frame: Pre-dose, 15, 30 minutes, 1 ,1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15