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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

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ClinicalTrials.gov Identifier: NCT02082977
Recruitment Status : Terminated (The maximal dose and schedule attained with GSK2816126 has shown insufficient evidence of clinical activity, and does not justify further clinical investigation)
First Posted : March 11, 2014
Last Update Posted : June 4, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief 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.

Condition or disease Intervention/treatment Phase
Cancer Drug: GSK2816126 Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 24, 2014
Actual Primary Completion Date : June 20, 2017
Actual Study Completion Date : June 20, 2017


Arm Intervention/treatment
Experimental: Part 1
Subject 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)].
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Experimental: Part 2
After 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.
Drug: GSK2816126
GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.




Primary Outcome Measures :
  1. Part 1: Number of participants with serious adverse events (SAEs) and non-serious adverse events (Non-SAEs) [ Time Frame: Up to 3.2 years ]
    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.

  2. Part 1: Number of participants with dose limiting toxicities (DLT) [ Time Frame: Up to 4 weeks ]
    An event was considered a DLT if it occurs within first 4 weeks (28 days) of treatment, and meets the criteria's for hematologic , non-hematologic, infusion reactions and other toxicities, unless it can be clearly established that the event is unrelated to treatment.

  3. Part 1: Number of participants withdrawn due to AEs [ Time Frame: Up to 3.2 years ]
    A participant was considered to have completed the study after they have completed their end of study visit or if the participant died or was still in follow-up at the time the study was closed or terminated. Participants were monitored from start of the study till the development of toxicity. The data for number of participants withdrawn due to AEs have been presented.

  4. Part 1: Number of participants with dose interruptions [ Time Frame: Up to 3.2 years ]
    The number of participants who had any dose interruptions have been presented.

  5. Part 1: Number of participants with dose reductions [ Time Frame: Up to 3.2 years ]
    The number of participants who had any dose reductions have been presented.

  6. Part 1: Number of participants with worst case change from Baseline in clinical chemistry parameters [ Time Frame: Baseline and up to 3.2 years ]
    Blood samples were collected for evaluation of clinical chemistry parameters including direct bilirubin, chloride, lactate dehydrogenase (LDH), total protein, urea/blood urea nitrogen (BUN) and uric acid. Baseline value was defined as the most recent, non-missing value from a local laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are not gradable by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).


Secondary Outcome Measures :
  1. Part 2: Characterize the metabolic profile of GSK2816126 after repeat-dosing [ Time Frame: Days 1, 5 and 15 of first treatment period ]
    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.

  2. 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 ]
    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.

  3. 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 ]
    Dose interruptions and reduction will be assessed as a measure of safety and tolerability.

  4. Part 2: Number of subjects with DLT [ Time Frame: Up to first 28 days of treatment ]
    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.

  5. Part 2: Changes from Baseline in clinical laboratory parameters [ Time Frame: Up to18 months ]
    Laboratory testing includes hematology, clinical chemistry and urinalysis.

  6. Part 2: Changes from Baseline in vital signs [ Time Frame: Up to 18 months ]
    Vital sign measurements include systolic and diastolic BP, temperature, respiration rate and pulse rate.

  7. Part 2: Changes from Baseline in cardiac parameters [ Time Frame: Up to 18 months ]
    Cardiac parameters include electrocardiogram and Holter monitoring

  8. 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 ]
    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).

  9. 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 ]
    Blood samples will be collected and concentration of GSK2816126 will be determined

  10. Part 2: Samples to characterize the metabolites in blood, bile and/or urine [ Time Frame: Days 1 and 15 ]
    Blood, bile, and/or urine samples will be collected

  11. 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 ]
    Urine samples will be collected

  12. Part 2: Duration of response (DoR) [ Time Frame: Up to 18 months ]
    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).

  13. Part 2: Progression-free survival (PFS) [ Time Frame: Up to 18 months ]
    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.

  14. 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 ]
    4beta- hydroxycholesterol is a potential in vivo marker of cytochrome P450 (CYP) 3A4 enzyme activity

  15. 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 ]
    Blood samples will be collected and concentration of GSK2816126 will be determined



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02082977


Locations
United States, Illinois
GSK Investigational Site
Chicago, Illinois, United States, 60611
United States, New York
GSK Investigational Site
New York, New York, United States, 10021
France
GSK Investigational Site
Villejuif cedex, France, 94805
United Kingdom
GSK Investigational Site
Sutton, Surrey, United Kingdom, SM2 5PT
GSK Investigational Site
Southampton, United Kingdom, SO16 6YD
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Statistical Analysis Plan  [PDF] March 1, 2018
Study Protocol  [PDF] March 20, 2017


Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02082977     History of Changes
Other Study ID Numbers: 117208
First Posted: March 11, 2014    Key Record Dates
Last Update Posted: June 4, 2018
Last Verified: May 2018

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

Keywords provided by GlaxoSmithKline:
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

Additional relevant MeSH terms:
Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders