First Time in Humans (FTIH) Study of GSK3368715 in Participants With Solid Tumors and Diffuse Large B-cell Lymphoma (DLBCL)

• ClinicalTrials.gov Identifier: NCT03666988
• Recruitment Status: Terminated
• First Posted: September 12, 2018
• Results First Posted: May 20, 2022
• Last Update Posted: May 20, 2022
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Neoplasms	Drug: GSK3368715	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Eligible participants will receive sequential doses of GSK3368715, administered orally once daily in Part 1 of the study and in Part 2, participants will receive RP2D determined in Part 1.
• Masking: None (Open Label)
• Masking Description: This will be an open-label study. Hence, masking will not be performed.
• Primary Purpose: Treatment
• Official Title: A Phase I, Open-label, Dose-escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK3368715 in Participants With Solid Tumors and DLBCL
• Actual Study Start Date: October 22, 2018
• Actual Primary Completion Date: March 4, 2021
• Actual Study Completion Date: March 4, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: GSK3368715 dose escalation; Eligible participants with solid relapsed/refractory tumors will receive escalating doses of GSK3368715 at a starting dose of 50 mg, administered orally once daily.	Drug: GSK3368715; GSK3368715 will be available with dosing strengths of 25 mg, 100 mg and 250 mg to be administered once daily as an oral capsule.
Experimental: Part 1: GSK3368715 PK/PD/Metabolite/Biomarker; Additional participants in Part 1, treated at or close to the expected the maximum tolerated dose (MTD)/RP2D, will be evaluated for metabolic and biomarker profiling. Participants may be enrolled into this cohort(s) even after MTD/RP2D has been identified and Part 2 has been initiated.	Drug: GSK3368715; GSK3368715 will be available with dosing strengths of 25 mg, 100 mg and 250 mg to be administered once daily as an oral capsule.
Experimental: Part 1: GSK3368715 Food effect; Eligible participants will receive single dose of GSK3368715 at starting dose of 50 mg tablet orally in fasted state followed by fed state in Period 1 and Fed followed by fasted state in Period 2.	Drug: GSK3368715; 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 .
Experimental: Part 2:GSK3368715 dose expansion - DLBCL participants; Eligible participants with relapsed/refractory DLBCL will receive RP2D of GSK3368715 established during Part 1, administered orally once daily.	Drug: GSK3368715; GSK3368715 will be available with dosing strengths of 25 mg, 100 mg and 250 mg to be administered once daily as an oral capsule.
Experimental: Part 2:GSK3368715 dose expansion-solid tumor participants; Eligible participants with relapsed/refractory solid tumors (pancreas cancer, NSCLC, and bladder cancer) will receive RP2D of GSK3368715 established during Part 1, administered orally once daily.	Drug: GSK3368715; GSK3368715 will be available with dosing strengths of 25 mg, 100 mg and 250 mg to be administered once daily as an oral capsule.

Outcome Measures

Primary Outcome Measures :

1. Part 1: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Up to 21 days ]
   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
2. Part 1: Number of Participants With Non-Serious Adverse Events (Non-SAEs) and SAEs [ Time Frame: Up to 28 months ]
   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.
3. Part 1: Number of Participants With AEs by Severity Grades [ Time Frame: Up to 28 months ]
   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.
4. Part 2: Percentage of Participants Achieving Objective Response Rate (ORR) [ Time Frame: Up to 48 months ]
   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.

Secondary Outcome Measures :

1. Part 1: Percentage of Participants Achieving Best Overall Response Rate [ Time Frame: Up to 28 months ]
   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.
2. Part 1: Maximum Observed Plasma Concentration (Cmax) Following Administration of 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 ]
   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.
3. Part 1: Time to Reach Cmax (Tmax) Following Administration of 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 ]
   Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
4. Part 1: Area Under the Concentration Time Curve From Time Zero to Last Time of Quantifiable Concentration (AUC [0-t]) Following Administration of 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 ]
   Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
5. Part 1: AUC From Time Zero Extrapolated to Infinite Time (AUC [0-infinity]) Following Administration of 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 ]
   Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
6. 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 [ Time Frame: Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15 ]
   Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.
7. Part 1: Trough (Pre-dose) Concentration (Ctau) Following Administration of GSK3368715 [ Time Frame: Pre-dose on Day 1 and Day 15 ]
   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.
8. Part 1: Time Invariance Ratio Following Administration of 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 ]
   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.
9. Part 1: Accumulation Ratio Following Administration of 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 ]
   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.
10. Part 1: Food Effect Cohorts: Cmax Following Administration of 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, 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 ]
    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.
11. Part 1: Food Effect Cohorts: Tmax Following Administration of 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, 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 ]
    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.
12. Part 1: Food Effect Cohorts: AUC (0-t) Following Administration of 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, 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 ]
    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.
13. Part 1: Food Effect Cohorts: AUC (0-infinity) Following Administration of 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, 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 ]
    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.
14. Part 1: Food Effect Cohorts: AUC (0-tau) Following Administration of 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, 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 ]
    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.
15. Part 2: Number of Participants With Non-SAEs and SAEs [ Time Frame: Up to 48 months ]
    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.
16. Part 2: Number of Participants With AEs by Severity Grades [ Time Frame: Up to 48 months ]
    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.
17. Part 2: Progression-free Survival (PFS) [ Time Frame: Up to 48 months ]
    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.
18. Part 2: Cmax Following Administration of 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 ]
    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.
19. Part 2: Tmax Following Administration of 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 ]
    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.
20. Part 2: AUC (0-t) Following Administration of 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 ]
    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.
21. Part 2: AUC (0-infinity) Following Administration of 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 ]
    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.
22. Part 2: AUC (0-tau) Following Administration of GSK3368715 [ Time Frame: Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15 ]
    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.
23. Part 2: Ctau Following Administration of GSK3368715 [ Time Frame: Pre-dose on Day 1 and Day 15 ]
    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.
24. Part 2: Time Invariance Ratio Following Administration of 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 ]
    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.
25. Part 2: Accumulation Ratio Following Administration of 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 ]
    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.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Participant must be >=18 to years of age inclusive, at the time of signing the informed consent.
• Diagnosis of one of the following; Part 1 (Dose Escalation and food effect): Histologically- or cytological-confirmed diagnosis of solid tumor malignancy that is metastatic or non-resectable; have received all standard treatment options or are no longer eligible for additional standard treatment options. Evaluable disease that may be measured directly by the size of the tumor or can be evaluated by other methods. Availability of a biopsy of the tumor tissue obtained at any time from the initial diagnosis to study entry. Although a fresh biopsy, which is obtained during screening, is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a fresh biopsy. For participants in the PK/PD cohort, a fresh biopsy and consent for one on treatment biopsy are required for enrollment. Part 2 (Dose Expansion): Cohort 2A & 2B: The availability of archival tumor tissue, or willingness to undergo a fresh biopsy to determine MTAP status (any archival tumor specimen must have been obtained within 6 months prior to starting study drug unless approved by the study Medical Monitor). Local MTAP or Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) results are acceptable for enrollment, but must be confirmed through central laboratory testing. Cohort 2A: Histologically- or cytological-confirmed diagnosis of DLBCL; relapse or refractory disease after at least 1 but not more than 4 lines of prior therapy; at least 1 measurable site of disease according to the Lugano Classification. The site of disease must be greater than 1.5 centimeter (cm) in the long axis regardless of short axis measurement or greater than 1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions. Cohort 2B: Pancreatic Cancer: Histologically or cytologically confirmed adenocarcinoma of the pancreas; unresectable, locally advanced (Stage III), or metastatic (Stage IV) disease; relapsed or refractory disease after at least 1 prior line of approved, systemic therapy; at least 1 measurable tumor lesion per RECIST 1.1. NSCLC: histologically or cytologically confirmed NSCLC; stage IV disease; tested for presence of echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase (EML4-ALK) rearrangement; received at least 2 prior lines of approved, systemic therapy, of which 1 therapy has to be a platinum containing regimen or failed a first-line platinum-containing regimen in combination with an anti- progressive disease (PD1) monocloncal antibody and refused a second-line regimen despite being informed about the different therapeutic options and their specific clinical benefit by the investigator; the content of this informed consent discussion including the therapeutic options reviewed by the investigator need to be documented and the participant needs to sign a specific consent form; at least 1 measurable tumor lesion per RECIST 1.1. Transitional cell carcinoma of the Urothelium: histologically or cytologically confirmed transitional cell carcinoma (TCC) of the urothelium (urinary bladder, urethra, ureter or renal pelvis) including mixed pathology with predominantly (that is [i.e.], > 50 percent of the histopathology sample) TCC with the exception of neuroendocrine or small cell carcinoma; unresectable, locally advanced (T4b) or metastatic (lymph node or visceral) disease; relapsed or refractory disease after at least 1 prior line of approved systemic therapy; at least 1 measurable tumor lesion per RECIST 1.1.
• Adequate organ function as defined by: Absolute neutrophil count (ANC) with a laboratory value of >=1.5 times 10^9 per liter (L); Hemoglobin with a laboratory value of >=9 grams per deciliter (g/dL) for solid malignancy and >=8 g/dL for Non-Hodgkin's lymphoma; Platelets with a laboratory value of >=100 times 10^9/ L; prothrombin time/ International Normalization Ratio (PT/INR) and partial thromboplastin time (PTT) with a laboratory value of <=1.5 times upper limit of normal (ULN), unless participant is receiving systemic anticoagulation (Hematologic); Albumin with a laboratory value of >=2 g/dL, total bilirubin with a laboratory value of <=1.5 times ULN, alanine aminotransferase (ALT) with a laboratory value of <=2.5 times ULN (Part 1 and 2) or <5 times ULN (Part 2 only) is acceptable for participants with documented liver metastases/tumor infiltration (Hepatic); calculated creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or measured from 24 h urine with a laboratory value of >= 50 milliliters per min (mL/min) (Renal); Ejection fraction with a laboratory value of >=Lower limit of normal (LLN) by echocardiogram (minimum of 50 percent)/ multigated (radionuclide) angiogram (MUGA), Electrocardiogram (ECG): corrected QT (QTc) interval using Fridericia's formula (QTcF) with a laboratory value of <450 milliseconds (msec) (Cardiac).
• Eastern cooperative oncology group (ECOG) performance status of 0 or 1.
• Able to swallow and retain orally-administered medication.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies; is not a woman of childbearing potential (WOCBP) or is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1 percent, during the intervention period and for at least 120 days, corresponding to the time needed to eliminate any study intervention(s) (example given [e.g.], 5 terminal half-lives) after the last dose of study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive pregnancy test (urine as required by local regulations) within 7 days before the first dose of study intervention. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 100 days, corresponding to time needed to eliminate study intervention(s) (e.g., 5 terminal half-lives) plus 90 days after the last dose of study intervention: Refrain from donating sperm plus either: Be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception/barrier as detailed below; agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant; agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person.
• Capable of giving signed informed consent.

Exclusion Criteria:

• History of malignancy other than the disease under study. Participants who have been disease-free for 5 years, or participants with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Participants with second malignancies that are indolent or definitively treated may be enrolled even if less than 5 years have elapsed since treatment.
• Primary central nervous system (CNS) tumors, Glioblastoma multiforme (GBM), symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Participants previously treated for these conditions that have had stable CNS disease (verified with consecutive imaging studies) for >1 months, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted. Stability of brain metastases must be confirmed with imaging. Participants treated with gamma knife therapy can be enrolled 2 weeks post-procedure as long as there are no post-procedure complications/they are stable.
• Any severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes, or active infection).
• Any serious and/or unstable pre-existing medical, 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 to first dose of study intervention.
• Any of the following cardiac abnormalities: Uncontrolled high blood pressure; any history of coronary artery disease, including acute coronary syndromes, myocardial infarction, unstable angina, and history of coronary angioplasty, or stenting; presence of a cardiac pacemaker or implanted defibrillator; atrioventricular (AV)-block (asymptomatic 2nd degree Type II or 3rd degree and any degree AV block if related to heart disease or if symptomatic), right bundle branch block (RBBB), left bundle branch block (LBBB), and any fasicular hemiblocks; A QRS interval at Screening or Baseline >110 msec; participants with any symptomatic or sustained arrhythmias (past or present), including but not limited to: Atrial fibrillation, Atrial flutter, Ventricular tachycardia, Ventricular fibrillation, Supraventricular tachycardia; Current or past congestive heart failure; Evidence of a left ventricular ejection fraction below the institutional lower limit of normal on Screening echocardiogram; Evidence of significant structural heart disease on echocardiography at Screening (including any valvular disease greater than "mild" in severity); Cardiac troponin > upper limit of the reference range at Screening.
• Treatment with any local or systemic anti-neoplastic therapy or investigational anticancer agent within 14 days or 4 half-lives, whichever is longer, up to a maximum wash-out period of 28 days prior to initiation of study drug administration. Anti-androgen therapies for prostate cancer, such as bicalutamide, must be stopped 28 days prior to first dose of GSK3368715. Second-line hormone therapies such as enzalutamide or abiraterone should be stopped 14 days prior to enrolment. Participants with prostate cancer may remain on luteinizing hormone-releasing hormone (LHRH) agonists or antagonists and/or low-dose prednisone or prednisolone (up to 10 milligrams per day [mg/day]). Nitrosureas and mitomycin C must be stopped within 42 days prior to first dose of GSK3368715.
• Allogeneic hematopoietic stem-cell transplantation.
• Toxicities from previous anti-cancer therapies have not resolved to Baseline or National Cancer Institute (NCI) CTCAE V5.0. <=Grade 1 (except fatigue and alopecia [permissible at any grade] and peripheral neuropathy [which must be <= Grade 2]) at the time of starting study intervention.
• Major surgery (i.e. requiring general anesthesia) within 3 weeks before screening, or not fully recovered from major surgery, or major surgery planned during study participation. Planned surgical procedures to be conducted under local anesthesia are allowed.
• Prior organ transplantation.
• Concurrent anti-coagulation therapy. Treatment with low-molecular heparin is allowed.
• Current use of a prohibited medication or planned use of any forbidden medications during intervention with GSK3368715.
• 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.
• Participant is considered high-risk for VTE as defined by either Khorana Score of greater than or equal to 3 or prior medical history of VTE.

Contacts and Locations

Locations

United States, California

GSK Investigational Site

Los Angeles, California, United States, 90033

GSK Investigational Site

Newport Beach, California, United States, 92663

United States, Pennsylvania

GSK Investigational Site

Philadelphia, Pennsylvania, United States, 19104-4206

United States, Texas

GSK Investigational Site

Houston, Texas, United States, 77030

United States, Utah

GSK Investigational Site

Salt Lake City, Utah, United States, 84112

Australia, Victoria

GSK Investigational Site

Melbourne, Victoria, Australia, 3000

Canada, Ontario

GSK Investigational Site

Toronto, Ontario, Canada, M5G 1X5

Spain

GSK Investigational Site

Barcelona, Spain, 08035

GSK Investigational Site

Madrid, Spain, 28050

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:

Study Protocol  [PDF] December 5, 2019

Statistical Analysis Plan  [PDF] March 5, 2021

More Information

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03666988
• Other Study ID Numbers: 207675; 2018-001629-20 ( EudraCT Number )
• First Posted: September 12, 2018
• Results First Posted: May 20, 2022
• Last Update Posted: May 20, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• 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; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:

Dose-escalation; First time in humans; Solid tumors; GSK3368715; Diffuse Large B-Cell Lymphoma