Clinical trial NCT02082977: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Cancer
Neoplasms
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
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-03-11
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Part 1: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)
timeFrame: Up to 3.2 years
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLT)
timeFrame: Up to 4 weeks
measure: Part 1: Number of Participants Withdrawn Due to AEs
timeFrame: Up to 3.2 years
measure: Part 1: Number of Participants With Dose Interruptions
timeFrame: Up to 3.2 years
measure: Part 1: Number of Participants With Dose Reductions
timeFrame: Up to 3.2 years
measure: Part 1: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters
timeFrame: Baseline and up to 3.2 years
measure: Part 1: Number of Participants With Worst Case Change From Baseline in Hematology Parameters
timeFrame: Baseline and up to 3.2 years
measure: Part 1:Number of Participants With Abnormal Values for Vital Signs
timeFrame: Up to 3.2 years
measure: Part 1: Number of Participants With Abnormal Findings for Electrocardiogram (ECG) Parameters
timeFrame: Up to 3.2 years
measure: Part 2: Percentage of Participants Achieving Overall Response Rate
timeFrame: Up to 3.2 years
Secondary outcomes:
measure: Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0-t]) Following Single and Repeat Dose Administration of GSK2816126
timeFrame: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)
measure: Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) Following Single Dose Administration of GSK2816126
timeFrame: Pre-dose, 0.5, 1, 2, 12, 18 , 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 (Each cycle was of 28 days)
measure: Part 1: Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Repeat Dose Administration of GSK2816126
timeFrame: Pre-dose, 0.5, 1, 2, 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 15 (Each cycle was of 28 days)
measure: Part 1: Trough (Pre-dose) Concentration at the End of Dosing Interval on the Specified Days (Ctau) Following Administration of GSK2816126
timeFrame: Pre-dose from start of infusion till end of infusion on Cycle 1 of Day 8; Pre-dose, 0.5, 1, 2, 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 15 (Each cycle was of 28 days)
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2816126
timeFrame: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)
measure: Part 1: Time to Reach Cmax (Tmax) Following Single and Repeat Dose Administration of GSK2816126
timeFrame: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)
measure: Part 1: Apparent Terminal Phase Elimination Rate Constant (Lambda z) Following Single and Repeat Dose Administration of GSK2816126
timeFrame: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)
measure: Part 1: Apparent Terminal Phase Half-life (T1/2) Following Single and Repeat Dose Administration of GSK2816126
timeFrame: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)
measure: Part 1: Accumulation Ratio Following Administration of GSK2816126
timeFrame: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)
measure: Part 1: Time Invariance Ratio Following Administration of GSK2816126
timeFrame: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)
measure: Part 1: Exposure Producing 50 Percent of the Maximum Effect (EC50) of GSK2816126 With Respect to Exposure Markers
timeFrame: Up to 3.2 years
measure: Part 1: Maximum Effect (Emax) of GSK2816126 With Respect to Exposure Markers
timeFrame: Up to 3.2 years
measure: Part 1: Number of Participants With Overall Change in Tri-methylated Histone H3 Lysine 27 (H3K27me3) Ratios Compared to Baseline
timeFrame: Baseline and up to 3.2 years
measure: Part 1: Percentage of Participants With Solid Tumors Achieving Best Overall Response Rate
timeFrame: Up to 3.2 years
measure: Part 1: Percentage of Participants With Lymphoma Achieving Best Overall Response Rate
timeFrame: Up to 3.2 years
measure: Part 1: Concentration of GSK2816126 and Its Metabolites in Blood
timeFrame: Pre-dose, 0.5, 1, 2, (12, 18 on Day 1 only), 24, and 96 hours post-dose from start of infusion; 0.5, 1, 2, 4, 6 hours from end of infusion on Cycle 1 of Day 1 and Day 15 (Each cycle was of 28 days)
measure: Part 1: Concentration of GSK2816126 and Its Metabolites in Bile
timeFrame: Day 15
measure: Part 1: Concentration of GSK2816126 and Its Metabolites in Urine
timeFrame: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15
measure: Part 1:Concentration of GSK2816126 in Urine After Dosing at Steady State
timeFrame: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15
measure: Part 2: Number of Participants With SAEs and Non-SAEs
timeFrame: Up to 3.2 years
measure: Part 2: Number of Participants With DLTs
timeFrame: Up to 4 weeks
measure: Part 2: Number of Participants Withdrawn Due to AEs
timeFrame: Up to 3.2 years
measure: Part 2: Number of Participants With Dose Interruptions
timeFrame: Up to 3.2 years
measure: Part 2: Number of Participants With Dose Reductions
timeFrame: Up to 3.2 years
measure: Part 2: Number of Participants With Worst Case Change From Baseline in Clinical Chemistry Parameters
timeFrame: Baseline and up to 3.2 years
measure: Part 2: Number of Participants With Worst Case Changes From Baseline in Hematology Parameters
timeFrame: Baseline and up to 3.2 years
measure: Part 2: Number of Participants With Abnormal Values for Vital Signs
timeFrame: Up to 3.2 years
measure: Part 2: Number of Participants With Abnormal Findings for ECG Parameters
timeFrame: Up to 3.2 years
measure: Part 2: Clearance Following Administration of GSK2816126
timeFrame: Up to 3.2 years
measure: Part 2: Volume of Distribution Following Administration of GSK2816126
timeFrame: Up to 3.2 years
measure: Part 2:EC50 of GSK2816126 With Respect to Exposure Markers
timeFrame: Up to 3.2 years
measure: Part 2:Emax of GSK2816126 With Respect to Exposure Markers
timeFrame: Up to 3.2 years
measure: Part 2: Number of Participants With Change in H3K27me3 Ratios Compared to Baseline
timeFrame: Baseline and up to 3.2 years
measure: Part 2: Concentration of GSK2816126 and Its Metabolites in Blood
timeFrame: Pre-dose, single draw between 0.5 and 1.9 hours from start of infusion, single draw between 3-6 hours following end of infusion on Day 1; Pre-dose on Day 15 for Cycle 1 and Cycles 2, 4, 6 and 12 (Each cycle was of 28 days)
measure: Part 2: Concentration of GSK2816126 and Its Metabolites in Bile
timeFrame: Day 15
measure: Part 2: Concentration of GSK2816126 and Its Metabolites in Urine
timeFrame: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15
measure: Part 2:Concentration of GSK2816126 in Urine After Dosing at Steady State
timeFrame: Pre-dose and 0 to 24 hours post-dose on Day 1; 0 to 8 hours post-dose on Day 15
measure: Part 2: Change in 4-beta-hydroxy Cholesterol to Cholesterol Ratio From Baseline Following Repeat Dosing of GSK2816126
timeFrame: Baseline and up to 21 days
measure: Part 2: Duration of Response
timeFrame: Up to 3.2 years
measure: Part 2: Number of Participants With Progression Free Survival
timeFrame: Up to 3.2 years
Other outcomes:
Locations:
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Villejuif cedex
country: France
facility: GSK Investigational Site
city: Sutton
country: United Kingdom
facility: GSK Investigational Site
state: Surrey
city: Southampton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Yap TA, Winter JN, Giulino-Roth L, Longley J, Lopez J, Michot JM, Leonard JP, Ribrag V, McCabe MT, Creasy CL, Stern M, Pene Dumitrescu T, Wang X, Frey S, Carver J, Horner T, Oh C, Khaled A, Dhar A, Johnson PWM. Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors. Clin Cancer Res. 2019 Dec 15;25(24):7331-7339. doi: 10.1158/1078-0432.CCR-18-4121. Epub 2019 Aug 30.