Clinical trial NCT03666988: First Time in Humans (FTIH) Study of GSK3368715 in Participants With Solid Tumors and Diffuse Large B-cell Lymphoma (DLBCL)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Neoplasms
Keywords: Dose-escalation
First time in humans
Solid tumors
GSK3368715
Diffuse Large B-Cell Lymphoma
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2018-09-12
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 21 days
measure: Part 1: Number of Participants With Non-Serious Adverse Events (Non-SAEs) and SAEs
timeFrame: Up to 28 months
measure: Part 1: Number of Participants With AEs by Severity Grades
timeFrame: Up to 28 months
measure: Part 2: Percentage of Participants Achieving Objective Response Rate (ORR)
timeFrame: Up to 48 months
Secondary outcomes:
measure: Part 1: Percentage of Participants Achieving Best Overall Response Rate
timeFrame: Up to 28 months
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) Following Administration of GSK3368715
timeFrame: 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
measure: Part 1: Time to Reach Cmax (Tmax) Following Administration of GSK3368715
timeFrame: 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
measure: Part 1: Area Under the Concentration Time Curve From Time Zero to Last Time of Quantifiable Concentration (AUC [0-t]) Following Administration of GSK3368715
timeFrame: 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
measure: Part 1: AUC From Time Zero Extrapolated to Infinite Time (AUC [0-infinity]) Following Administration of GSK3368715
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1
measure: 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
timeFrame: Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
measure: Part 1: Trough (Pre-dose) Concentration (Ctau) Following Administration of GSK3368715
timeFrame: Pre-dose on Day 1 and Day 15
measure: Part 1: Time Invariance Ratio Following Administration of GSK3368715
timeFrame: 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
measure: Part 1: Accumulation Ratio Following Administration of GSK3368715
timeFrame: 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
measure: Part 1: Food Effect Cohorts: Cmax Following Administration of GSK3368715
timeFrame: 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
measure: Part 1: Food Effect Cohorts: Tmax Following Administration of GSK3368715
timeFrame: 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
measure: Part 1: Food Effect Cohorts: AUC (0-t) Following Administration of GSK3368715
timeFrame: 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
measure: Part 1: Food Effect Cohorts: AUC (0-infinity) Following Administration of GSK3368715
timeFrame: 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
measure: Part 1: Food Effect Cohorts: AUC (0-tau) Following Administration of GSK3368715
timeFrame: 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
measure: Part 2: Number of Participants With Non-SAEs and SAEs
timeFrame: Up to 48 months
measure: Part 2: Number of Participants With AEs by Severity Grades
timeFrame: Up to 48 months
measure: Part 2: Progression-free Survival (PFS)
timeFrame: Up to 48 months
measure: Part 2: Cmax Following Administration of GSK3368715
timeFrame: 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
measure: Part 2: Tmax Following Administration of GSK3368715
timeFrame: 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
measure: Part 2: AUC (0-t) Following Administration of GSK3368715
timeFrame: 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
measure: Part 2: AUC (0-infinity) Following Administration of GSK3368715
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1
measure: Part 2: AUC (0-tau) Following Administration of GSK3368715
timeFrame: Pre-dose, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
measure: Part 2: Ctau Following Administration of GSK3368715
timeFrame: Pre-dose on Day 1 and Day 15
measure: Part 2: Time Invariance Ratio Following Administration of GSK3368715
timeFrame: 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
measure: Part 2: Accumulation Ratio Following Administration of GSK3368715
timeFrame: 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
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Newport Beach
country: United States
facility: GSK Investigational Site
state: California
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: