First Time in Humans (FTIH) Study of GSK3368715 in Participants With Solid Tumors and Diffuse Large B-cell Lymphoma (DLBCL)
Condition: Neoplasms
Intervention: GSK3368715; GSK3368715
Intervention description: 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 .
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
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.
Enrollment: 31.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Dose-escalation; First time in humans; Solid tumors; GSK3368715; Diffuse Large B-Cell Lymphoma

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.