A Phase I Dose Escalation Study of GSK2879552 in Subjects... | NCT02177812

NCT02177812

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Dose Escalation Phase (Part 1)	Experimental	The safety and PK/PD data will be reviewed prior to the dose decision, and the dose escalation will be guided by the Neuenschwander -continuous reassessment method (N-CRM).The dose escalation will complete when RP2D is determined. The RP2D will be the MTD or a lower dose that provides adequate PK exposure and biologic activity with superior tolerability.	Drug: GSK2879552 Drug: ATRA
Expansion Phase (Part 2)	Experimental	Once the MTD and/or RP2D has been determined in Part 1, an expansion cohort of up to 30 subjects will be enrolled in order to characterize the clinical activity and safety profile of the RP2D. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, or withdrawal of consent.	Drug: GSK2879552 Drug: ATRA

Interventions

Name	Type	Description	Arm Group Labels	Other Names
GSK2879552	Drug	GSK2879552 capsules contain 0.25 mg, 0.5 mg, 2 mg or 5 mg of GSK2879552 as parent. The initial dosing regimen will be continuous oral daily dosing.	Dose Escalation Phase (Part 1)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	An AE is any untoward medical occurrence in a 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, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function.	Median of 4 weeks of drug exposure
Part 1: Number of Participants With Dose Limiting Toxicities (DLT)	An event was considered a DLT if it occursed within the first 28 days of treatment, and meets one of the following criteria unless it can be clearly established that the event was unrelated to treatment: hematologic DLT included myelosuppression, Grade >=3 non-hematologic toxicity that is considered clinically significant and lasts >72 hours, Grade 2 toxicity that in the judgment of the investigator and GSK Medical Monitor is dose-limiting and treatment delay of >=42 days due to unresolved toxicity.	Median of 4 weeks of drug exposure
Part 1: Number of Participants With AE Leading to Dose Reductions or Delays	The number of participants who had any dose reduction or delay have been presented.	Median of 4 weeks of drug exposure
Part 1: Number of Participants With Withdrawals Due to Toxicities	Participants were monitored from start of the study till the development of toxicity. The data for number of participants withdrawn due to toxicities has been presented.	Median of 4 weeks of drug exposure
Number of Participants With Clinical Chemistry Parameters Changes From Baseline With Respect to the Normal Range

Secondary Outcomes

Measure	Description	Time Frame
Part 1: Area Under the Plasma Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration [AUC(0-t)] and From Time Zero (Pre-dose) Extrapolated to Infinite Time [(AUC(0-inf)] After Single Dose Administration	Blood samples were collected at indicated time points. The Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis. NA indicates that data were not available as geometric co-efficient of variation could not be calculated for a single participant.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subjects >=18 years of age and provided signed written informed consent.
Subjects must have relapsed/refractory AML by world health organization (WHO) classification for which no standard therapies are available or anticipated to result in a durable remission. French- American- British system (FAB) subtype M3 will be excluded.
Subjects >= 60 years of age with AML who are not candidates for or have refused standard chemotherapy.
Subjects who have previously received an autologous stem cell transplant are allowed if a minimum of 3 months has elapsed from the time of transplant and the subject has recovered from transplant-associated toxicities prior to the first dose of GSK2879552.
Subjects with a history of allogeneic stem cell transplant are eligible for study participation provided the following eligibility criteria are met: transplant was >60 days prior to study enrolment; subject has not taken immunosuppressive medications for at least 1 month; no signs or symptoms of graft versus host disease other than Grade 1 skin involvement; no active infection.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Subjects must be stable and, in the opinion of the investigator, be expected to complete 4 week treatment period.
Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
All prior treatment-related toxicities must be National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 <=Grade 1 at the time of enrollment (except for alopecia).
Adequate baseline organ function.
Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, during the study and for 7 days (GSK2879552 mono therapy) or 30 days (combination with ATRA), following the last dose of study treatment.
Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from the administration of the first dose of study treatment until 3 months after the last dose of study treatment to allow for clearance of any altered sperm.

Exclusion Criteria:

Active human immunodeficiency virus (HIV), Hepatitis B Virus (HBV) or hepatitis C virus (HCV) infections at the time of screening. Subjects with laboratory evidence of HCV clearance may be enrolled.
History of or concurrent malignancy of solid tumours, except: subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled even if less than 5 years have elapsed since treatment. Consult GlaxoSmithKline (GSK) Medical Monitor if unsure whether second malignancies meet requirements specified above.
Currently receiving cancer therapy. Hydroxyurea will be allowed.
Received major surgery, radiotherapy, or immunotherapy within 4 weeks of GSK2879552 administration.
Prior treatment with temozolomide, dacarbazine or procarbazine
Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (eg., olaparib, ABT-888)
Baseline Montreal Cognitive Assessment (MOCA) score of 22 or lower
Evidence of severe or uncontrolled systemic diseases. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator
Current active liver or biliary disease.
Patients at risk of non-AML related major bleeding (e.g. recent gastrointestinal [GI] hemorrhage or neurosurgery).
Symptomatic or untreated central nervous system (CNS) leukemia. Subjects are permitted to enroll if previously treated for CNS disease, free of symptoms at the time of screening, and have not required intrathecal chemotherapy at least 1 month prior to study Day 1.
Cardiac abnormalities
Administration of an investigational drug within 14 days or 5 half-lives, whichever is shorter with a minimum of 14 days preceding the first dose of study treatment(s) in this study.
Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates their participation.
Lactating female.
Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, pommelos, or exotic citrus fruits, from 1 day prior to the first dose of study treatment(s) until the last dose of study drug.
Current use of a prohibited medication including anticoagulants or platelet inhibitors or expected to require any of these medications during treatment with the investigational drug.
Previous treatment with GSK2879552 For ATRA Combination arm ONLY
Known hypersensitivity to ATRA, parabens (preservatives in the gelatin capsule) or other retinoids.
ATRA capsule contains sorbitol. Subjects with rare hereditary problems of fructose intolerance are excluded.
History of seizure within 12 months or brain tumor (primary)
History of taking mega-dose vitamin A (>25,000 USP U/day) within 3 months from the dosing start.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director
GSK Clinical Trials	GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Augusta	Georgia	30912	United States
GSK Investigational Site

Arm/Group Information

ID	Title	Description
FG000	Part 1:GSK2879552 1mg QD	Participants received GSK2879552 1 milligram (mg) orally once daily (QD) in fasted condition with approximately 200 milliliter (mL) of water
FG001	Part 1: GSK2879552 2mg QD	Participants received GSK2879552 2 mg orally once daily in fasted condition with approximately 200 mL of water
FG002	Part 1: GSK2879552 4mg QD	Participants received GSK2879552 4 mg orally once daily in fasted condition with approximately 200 mL of water.
FG003	Part 1: GSK2879552 8mg QD	Participants received GSK2879552 8 mg orally once daily in fasted condition with approximately 200 mL of water
FG004	Part 1: GSK2879552 12mg QD	Participants received GSK2879552 12 mg orally once daily in fasted condition with approximately 200 mL of water.
FG005	Part 1: GSK2879552 20mg QD	Participants received GSK2879552 20 mg orally once daily in fasted condition with approximately 200 mL of water.
FG006	Part 1: GSK2879552 2mg QD/ATRA 45mg/m^2/Day	Participants received GSK2879552 2 mg capsule orally once daily in fasted condition with approximately 200 mL of water in combination with All-Trans Retinoic Acid (ATRA) at a dose of 45 mg per meter square per day (mg/m^2/day).
FG007	Part 1: GSK2879552 20mg QD PK/PD Expansion	Participants received GSK2879552 20 mg capsule orally once daily in fasted condition with approximately 200 mL of water in Pharmacokinetic/Pharmacodynamics (PK/PD) Expansion cohort to collect adequate data on safety, PK or PD.
FG008	Part 2: Expansion Cohort	In Part 2, participants were planned to receive the recommended Phase 2 dose of GSK2879552 orally once daily in fasted condition with approximately 200 mL of water alone or in combination with ATRA

ID	Title	Description
BG000	Part 1:GSK2879552 1mg QD	Participants received GSK2879552 1 mg orally QD in fasted condition with approximately 200 mL of water.
BG001	Part 1: GSK2879552 2mg QD	Participants received GSK2879552 2 mg orally once daily in fasted condition with approximately 200 mL of water.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

An AE is any untoward medical occurrence in a 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, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function.

All Treated Subjects Population comprised of all participants who received at least one dose of study treatment.

Posted

Count of Participants

Participants

Median of 4 weeks of drug exposure

ID	Title	Description
OG000	Part 1:GSK2879552 1mg QD	Participants received GSK2879552 1 mg orally QD in fasted condition with approximately 200 mL of water.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Part 1:GSK2879552 1mg QD	Participants received GSK2879552 1 mg orally QD in fasted condition with approximately 200 mL of water.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 6, 2017	Oct 24, 2018	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Jun 26, 2018	Oct 24, 2018	SAP_001.pdf

ID	Term
D007938	Leukemia
D009369	Neoplasms
D015470	Leukemia, Myeloid, Acute

ID	Term
D009370	Neoplasms by Histologic Type
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D007951	Leukemia, Myeloid