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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

NCT02082977

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Multiple Myeloma
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: A Phase I Open-label, Dose Escalation 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

Clinical Trial IDs

  • ORG STUDY ID: 117208
  • NCT ID: NCT02082977

Conditions

  • Cancer

Interventions

DrugSynonymsArms
GSK2816126Part 2

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part 1ExperimentalSubject will be administered with a 50 milligram (mg) starting dose of GSK2816126 intravenous infusion over 2 - 4 hours, initially twice-weekly 3 weeks on / 1 week off in each 28-day cycle. Dose escalation will continue until an RP2D is determined or until an maximum tolerated dose (MTD) or a dose of 3000 mg twice-weekly is reached [Maximum Feasible Dose (MFD)].
  • GSK2816126
Part 2ExperimentalAfter the RP2D (or MTD/MFD) has been determined in Part 1, Part 2 expansion cohorts will be opened. In Part 2, subjects will be assigned to one of five cohorts based on disease and EZH2 mutation status and cancer type.
  • GSK2816126

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Number of participants with serious adverse events (SAEs) and non-serious adverse events (Non-SAEs)
Time Frame:Up to 3.2 years
Safety Issue:
Description:An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/ incapacity, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function. The analysis was performed on All Subjects Population which included all participants who received at least one dose of study treatment.

Secondary Outcome Measures

Measure:Part 2: Characterize the metabolic profile of GSK2816126 after repeat-dosing
Time Frame:Days 1, 5 and 15 of first treatment period
Safety Issue:
Description:Blood, bile and urine samples for analysis of GSK2816126 and its metabolites will be collected for at least 4 subjects participating in the Part 1 PK/PD expansion cohort.
Measure:Part 2: Number of subjects with Adverse Events (AES), and Serious Adverse Events (SAEs), withdrawals due to AES, dose interruptions and reductions
Time Frame:From the first dose of study treatment until 30 days following discontinuation of study treatment
Safety Issue:
Description:Any AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.
Measure:Part 2: Number of subjects with withdrawals due to AEs, dose interruptions and reductions
Time Frame:From the first dose of study treatment until discontinuation of study treatment
Safety Issue:
Description:Dose interruptions and reduction will be assessed as a measure of safety and tolerability.
Measure:Part 2: Number of subjects with DLT
Time Frame:Up to first 28 days of treatment
Safety Issue:
Description:An event will be considered a DLT if it occurs within the first 4 weeks (28 days) of treatment, and meets the criteria listed in protocol.
Measure:Part 2: Changes from Baseline in clinical laboratory parameters
Time Frame:Up to18 months
Safety Issue:
Description:Laboratory testing includes hematology, clinical chemistry and urinalysis.
Measure:Part 2: Changes from Baseline in vital signs
Time Frame:Up to 18 months
Safety Issue:
Description:Vital sign measurements include systolic and diastolic BP, temperature, respiration rate and pulse rate.
Measure:Part 2: Changes from Baseline in cardiac parameters
Time Frame:Up to 18 months
Safety Issue:
Description:Cardiac parameters include electrocardiogram and Holter monitoring
Measure:Part 2: Population PK parameters for GSK2816126
Time Frame:Days1, 4, 8, 11, 15, and 18 of first treatment period and between Day 4 and Day 24 of Cycle 2, 4, 6 and 12
Safety Issue:
Description:Population PK parameters for GSK2816126 includes clearance (CL), and volume of distribution (Vd) and relevant covariates which may influence exposure (e.g. age, weight, or disease related covariates).
Measure:Part 2: Relationship between GSK2816126 exposure markers (dose, concentration, CMAX or AUC) and PD (pharmacodynamic) responses. PD responses assessed by change from baseline in tri-methylation of histone H3K27 (H3K7ME3)
Time Frame:Days1, 4, 8, 11, 15, 18 and 21 of first treatment period
Safety Issue:
Description:Blood samples will be collected and concentration of GSK2816126 will be determined
Measure:Part 2: Samples to characterize the metabolites in blood, bile and/or urine
Time Frame:Days 1 and 15
Safety Issue:
Description:Blood, bile, and/or urine samples will be collected
Measure:Part 2: Concentration of GSK2816126 in urine measured with an investigational bioanalytical method and extrapolated to total amount excreted in urine over time using urine volume
Time Frame:Days 1 and 15
Safety Issue:
Description:Urine samples will be collected
Measure:Part 2: Duration of response (DoR)
Time Frame:Up to 18 months
Safety Issue:
Description:DoR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among subjects who achieve an overall response (i.e., unconfirmed or confirmed CR or PR).
Measure:Part 2: Progression-free survival (PFS)
Time Frame:Up to 18 months
Safety Issue:
Description:PFS is defined as time from the date of first dose to the date of disease progression according to clinical or radiological assessment or death due to any causes, whichever occurs earliest.
Measure:Part 2: To assess potential change in 4Beta-hydroxycholesterol to cholesterol ratio in plasma following repeat dosing of GSK2816126
Time Frame:Up to 18 months
Safety Issue:
Description:4beta- hydroxycholesterol is a potential in vivo marker of cytochrome P450 (CYP) 3A4 enzyme activity
Measure:Part 2: Relationship between GSK2816126 exposure markers (dose, concentration, CMAX or AUC) and safety/efficacy/ responses
Time Frame:Days 1, 4, 8, 11, 15, 18 and 21 of first treatment period
Safety Issue:
Description:Blood samples will be collected and concentration of GSK2816126 will be determined

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:GlaxoSmithKline

Trial 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

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