A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2816126 in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma, Transformed Follicular Lymphoma, Other Non-Hodgkin's Lymphomas, Solid Tumors and Multiple Myeloma
Condition: Cancer; Neoplasms
MeSH terms: Lymphoma; Multiple Myeloma; Neoplasms, Plasma Cell; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: GSK2816126
Intervention description: GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Subjects will receive escalating doses of GSK2816126 in Part 1 of the study. Subjects enrolled in Part 2 will receive recommended Phase II dose (RP2D) based on Part 1 of the study.
Masking: None (Open Label)
Masking description: This will be an open-label study. Hence, there will be no masking.
Enrollment: 41.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Refractory; Phase I study, dose escalation study; diffuse large B cell lymphoma; Relapsed; Solid tumors; transformed follicular lymphoma; Multiple myeloma; GSK2816126; Non-Hodgkin's lymphoma

Summary:

      This is an open-label, multicenter, 2-part study to determine the recommended Phase 2 dose
      (RP2D) for GSK2816126 given twice weekly by intravenous (IV) infusion. Part 1 will be
      conducted in adult subjects with relapsed/refractory diffuse large B cell lymphoma (DLBCL),
      transformed follicular lymphoma (tFL), other Non-Hodgkin's lymphomas (NHL), solid tumors
      (including castrate resistant prostate cancer) and multiple myeloma (MM) to determine the
      safety and tolerability of GSK2816126. Expansion cohorts (Part 2) are planned to further
      explore clinical activity of GSK2816126 at the RP2D in subjects with Enhancer of Zeste 2
      (EZH2) wild type and EZH2 mutant positive germinal center B-cell like diffuse large B cell
      lymphoma (GCB-DLBCL), tFL and MM.
    

Eligibility criteria:

        Part 1 Inclusion Criteria

          -  Provided signed written informed consent

          -  Males and females >=18 years of age (at the time consent is obtained).

          -  Tumor type criteria: relapsed/refractory non-Hodgkin's lymphoma (NHL) that meets one
             of the following criteria:

          -  Germinal Center B cell Diffuse large B cell lymphoma (GCB-DLBCL) relapsed or
             refractory to at least one prior regimen (e.g., rituximab, cyclophosphamide,
             doxorubicin, vincristine, prednisone [R-CHOP]) AND not a candidate for standard
             salvage regimens or autologous or allogeneic stem cell transplant. Local confirmation
             of lymphoma subtype (e.g. GCB-DLBCL) is allowed for enrollment but must be confirmed
             through central laboratory testing.

          -  Solid tumors that meet the following criteria: Measurable disease by Response
             Evaluation Criteria In Solid Tumors 1.1 (RECIST) in at least 1 site. For Castrate
             Resistant Prostate Cancer (CRPC) measurable disease can also include Prostate Specific
             Antigen (PSA) level. Disease progression with the last line of therapy and at least
             one prior standard of care regimens, or tumor for which there is no approved therapy,
             or for which standard therapy is unsuitable or refused. Mutation Status: Solid tumor
             types, other than prostate, must have a one of the following EZH2 inhibitor
             sensitizing mutations as determined via local testing: An activating mutation in EZH2
             (Y641F/C/S/H/N, A677V/G, and/or A687V; Loss of a component of the SWI/SNF complex,
             including, but not limited to, ARID1A, SMARCB1 (aka SNF5/INI1/BAF47), SMARCA4 (aka
             BRG1), or PBRM1 (aka PB1) as determined by molecular testing (bi-allelic loss or
             mutation) or immunohistochemistry; Loss of BAP1 (ubiquitin carboxy-terminal hydrolase)
             as determined by molecular testing (bi-allelic loss or mutation) or
             immunohistochemistry

          -  CRPC subjects: Must have measurable disease by either: RECIST1.1 or a minimum PSA of 5
             nanogram/milliliter; Disease progression on last line of therapy and must have
             progressed on abiraterone, enzalutamide, or taxane chemotherapy; Subjects may continue
             GnRH agonists; Small cell prostate cancer is eligible

          -  For all subjects: Availability of archival tissue, or willingness to undergo fresh
             biopsy if archival tissue is not available.

          -  Must have a pre-existing central venous access such as a port, Hickmann catheter or a
             peripherally inserted central catheter (PICC line) or be willing and able to have one
             inserted.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

          -  Men with a female partner of childbearing potential must have either had a prior
             bilateral vasectomy with resultant azoospermia, bilateral orchiectomy, or must agree
             to use one of the contraception methods listed in protocol from the time of the first
             dose of study medication until at least 2 weeks (14 days) after the last dose of study
             treatment due to the long elimination phase of study drug.

          -  A female subject is eligible to participate ifs she is of: Non-child bearing potential
             as described in the protocol; OR Child bearing potential and agrees to use effective
             contraception as described in the protocol, for an appropriate period of time (as
             determined by the product label) prior to the start of dosing to sufficiently minimize
             the risk of pregnancy and for at least 2 weeks (14 days) following the last dose of
             study treatment. Women of childbearing potential must have a negative serum pregnancy
             test within 7 days of first dose of study treatment followed by negative urine or
             serum pregnancy test once every 4 weeks (prior to next dose cycle) thereafter.-
             Adequate organ system function as defined in the protocol.

        Part 2 Inclusion Criteria

          -  In addition to inclusion criteria listed for Part 1, Part 2 will enroll GCB-DLBCL tFL
             and MM subjects only. Relapsed and/or refractory MM or tFL that have failed prior
             standard therapy and for which there is no standard salvage regimen

          -  Lymphoma subjects will be required to undergo EZH2 mutation testing. This will require
             availability of archival tissue, or willingness to undergo fresh biopsy, for central
             testing of EZH2 mutation status.

          -  Based on the results of the mutation test, lymphoma subjects may be enrolled in one of
             four cohorts: GCB-DLBCL EZH2 mutant cohort: Tumors must contain one, or more, of the
             following EZH2 activating mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or
             A687V. GCB-DLBCL EZH2 wild type cohort: Tumors that do not contain one of the above
             mutations; Subjects with tumors harboring EZH2 mutations other than the seven outlined
             above will be enrolled in the EZH2 wild type cohort. tFL EZH2 mutant cohort: Tumors
             must contain one, or more, of the following EZH2 activating mutations: Y641F; Y641N;
             Y641S; Y641H; Y641C; A677G; and/or A687V. tFL EZH2 wild type cohort: Tumors that do
             not contain one of the above mutations; Subjects with tumors harboring EZH2 mutations
             other than the seven outlined above will be enrolled in the EZH2 wild type cohort

        Part 1 and 2 Exclusion Criteria

          -  Receiving any cancer therapy within 2 weeks of first dose (including surgery, and/or
             tumor embolization) Note: the following are allowed: Corticosteroids to control
             systemic or local symptoms, up to a dose of 10 mg prednisone or equivalent daily and
             stable for at least 7 days prior to enrollment. Subjects with prostate cancer may
             remain on GnRH agonists. Other hormonal therapies (e.g., bicalutamide, abiraterone and
             enzlutimide) for prostate cancer must be stopped 4 weeks prior to enrolment.

        Note: the following are NOT allowed: Chemotherapy regimens with delayed toxicity within the
        last 3 weeks. Nitrogen mustards, Melphalan, Monoclonal antibody or Nitrosourea within the
        last 6 weeks.

          -  Received an investigational anti-cancer drug within 6weeks, or within 5 half-lives
             (whichever is shorter) of the first dose of study drug(s). A minimum of 14 days must
             have passed between the last dose of prior investigational agent and the first dose of
             study drug.

          -  Current use of a prohibited medication per protocol or expected to require any of
             these medications during treatment with study drug.

          -  Known Human Immunodeficiency Virus, or serological evidence for Hepatitis B (positive
             hepatitis B surface antigen [HBsAg]), or chronic Hepatitis C infection. For subjects
             who are negative for HBsAg, but Hepatitis B core Antibody [HBcAB] positive, a HBV DNA
             (viral load) test will be performed and if negative are eligible. Subjects with
             positive Hepatitis C antibody serology with a negative HCV ribonucleic acid (RNA) test
             results are eligible.

          -  Concurrent use of therapeutic warfarin is allowed. However, anticoagulants that do not
             have reversal agents available are prohibited.

          -  Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first
             dose of study drug, or palliative radiotherapy to a single symptomatic lesion within
             the 2 weeks prior to first dose of study drugs.

          -  Subjects with prior allogeneic transplant are excluded: however, subjects who have
             previously received an autologous stem cell transplant are allowed if a minimum of 100
             days has elapsed from the time of transplant and the subject has recovered from
             transplant-associated toxicities prior to the first dose of GSK2816126

          -  Unresolved toxicity greater than Grade 1 National Cancer Institute - Common
             Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 from previous
             anti-cancer therapy, with the exception of alopecia and peripheral neuropathy.
             Lymphoma subjects with <= Grade 3 lymphopenia can be enrolled at the discretion of the
             investigator.

          -  Packed red blood cell or platelet transfusion within 7 days of screening laboratory
             tests.

          -  Psychological, familial, sociological or geographical conditions that do not permit
             compliance with the protocol.

          -  Cardiac exclusion criteria: History of acute coronary syndromes (including myocardial
             infarction and unstable angina), coronary angioplasty, or stenting within the past 6
             months prior to first dose of study drug; QTcF> 450 milliseconds (msec); Uncontrolled
             arrhythmias. Subjects with rate controlled atrial fibrillation for >1 month prior to
             first dose of study drug may be eligible; Class II, III or IV heart failure as defined
             by the New York Heart Association (NYHA) functional classification system.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study drug or their excipients.

          -  Pregnant or lactating female.

          -  Unwillingness or inability to follow the procedures outlined in the protocol.

          -  Uncontrolled diabetes or other medical condition that may interfere with assessment of
             toxicity.

          -  Central nervous system (CNS) metastases, with the following exception: Subjects who
             have previously treated CNS metastases, are asymptomatic, and have no requirement for
             steroids at least 14 days prior to first dose of study drug; Subjects with
             carcinomatous meningitis are excluded regardless of clinical stability.

          -  Invasive malignancy or history of invasive malignancy other than disease under study:
             any other invasive malignancy from which the subject has been disease-free for more
             than 2 years and, in the opinion of the principal investigator and GSK Medical
             Monitor, will not affect the evaluation of the effects of this clinical trial
             treatment on currently targeted malignancy, can be included in this clinical trial;
             Curatively treated non-melanoma skin cancer and any carcinoma-in-situ.