Clinical trial NCT02177812: A Phase I Dose Escalation Study of GSK2879552 in Subjects With Acute Myeloid Leukemia (AML)
Official title: A Phase I Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2879552 Given Orally in Subjects With Relapsed/Refractory Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Leukaemia, Myelocytic, Acute
Keywords: Oncology
LSD1
GSK2879552
Acute myeloid leukemia
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-06-30
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is a phase I, open-label study to determine recommended phase 2 dose (RP2D) and regimen for the orally administered lysine specific demethylase 1 (LSD1) inhibitor GSK2879552, alone or in combination with All-Trans Retinoic Acid (ATRA). The recommended dose and regimen will be selected based on the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles observed after the treatment of subjects with relapsed/refractory AML. The study consists of two parts. Part 1 will identify the maximum tolerated dose (MTD) and/or RP2D using a dose-escalation procedure. Dose escalations will be guided by the Neuenschwander-continual reassessment method (N-CRM). PK/PD expansion cohorts will also be included in Part 1 to characterize the range of biologically effective doses by assessing PD markers and obtain additional PK data. Part 2 will explore further the safety, tolerability, and clinical activity of GSK2879552, alone or in combination with ATRA, at the RP2D in subjects with AML.


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.

Primary outcomes:
measure: Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Median of 4 weeks of drug exposure
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLT)
timeFrame: Median of 4 weeks of drug exposure
measure: Part 1: Number of Participants With AE Leading to Dose Reductions or Delays
timeFrame: Median of 4 weeks of drug exposure
measure: Part 1: Number of Participants With Withdrawals Due to Toxicities
timeFrame: Median of 4 weeks of drug exposure
measure: Number of Participants With Clinical Chemistry Parameters Changes From Baseline With Respect to the Normal Range
timeFrame: Median of 4 weeks of drug exposure
measure: Number of Participants With Clinical Chemistry Toxicity Grade Changes From Baseline
timeFrame: Median of 4 weeks of drug exposure
measure: Number of Participants With Hematology Parameters Change From Baseline With Respect to the Normal Range
timeFrame: Median of 4 weeks of drug exposure
measure: Number of Participants With Hematology Toxicity Grade Changes From Baseline
timeFrame: Median of 4 weeks of drug exposure
measure: Part 1: Number of Participants With Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Median of 4 weeks of drug exposure
measure: Part 1: Number of Participants With Change From Baseline in Heart Rate
timeFrame: Median of 4 weeks of drug exposure
measure: Part 1: Number of Participants With Change From Baseline in Temperature
timeFrame: Median of 4 weeks of drug exposure
measure: Part 1: Number of Participants With Change From Baseline in Respiratory Rate
timeFrame: Median of 4 weeks of drug exposure
measure: Part 1: Number of Participants With Abnormal Electrocardiograms (ECGs) Findings
timeFrame: Median of 4 weeks of drug exposure
measure: Part 1: Number of Participants With Abnormal Physical Examinations
timeFrame: Median of 4 weeks of drug exposure
measure: Part 2: Objective Response Rate of Participants
timeFrame: Up to 14 months
Secondary outcomes:
measure: 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
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1
measure: Part 1: AUC Over the Dosing Interval (0-tau) After Single Dose Administration
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1
measure: Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration [AUC(0-t)] and AUC Over the Dosing Interval (0-tau) After Repeated Administration
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 15
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK2879552
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 and 15
measure: Part 1: Apparent Terminal Phase Half-life (t½)
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 and 15
measure: Part 1: Time of Occurrence of Cmax (Tmax) of GSK2879552
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 and 15
measure: Part 1: Accumulation Ratio for GSK2879552
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 and 15
measure: Part 1:Time Invariance
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 and 15
measure: Part 1:Percentage of Participants With Objective Response
timeFrame: Median of 4 weeks drug response
measure: Part 1: AUC(0-t), AUC (0-tau) and AUC(0-inf) of ATRA
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1and Day 15
measure: Part 1: Cmax of ATRA
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 and 15
measure: Part 1: Apparent Terminal Phase Half-life (t½) of ATRA
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 and 15
measure: Part 1: Time of Occurrence of Cmax (Tmax) of ATRA
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 and 15
measure: Part 2: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to 14 months
measure: Part 2: Number of Participants With AE Leading to Dose Reductions or Delays
timeFrame: Up to 14 months
measure: Part 2: Number of Participants With Withdrawals Due to Toxicities
timeFrame: Up to 14 months
measure: Part 2: Number of Participants With Abnormal Clinical Chemistry Parameters
timeFrame: Up to 14 months
measure: Part 2: Number of Participants With Abnormal Hematology Parameters
timeFrame: Up to 14 months
measure: Part 2: Number of Participants With Abnormal Vital Signs
timeFrame: Up to 14 months
measure: Part 2: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to 14 months
measure: Part 2: Number of Participants With Abnormal Physical Examinations
timeFrame: Up to 14 months
measure: Part 2: Clearance (CL) of GSK2879552 for Part 2
timeFrame: Day 1 (pre-dose, 0.5 and 3 hours post dose), Days 4, 8 (pre-dose), Day 15 (pre-dose, 0.5, 1, 4, 6 hours), Weeks 4, 5, 6, 7, 8 and every 4 weeks up to Week 48
measure: Part 2: Volume of Distribution of GSK2879552 for Part 2
timeFrame: Day 1 (pre-dose, 0.5 and 3 hours post dose), Days 4, 8 (pre-dose), Day 15 (pre-dose, 0.5, 1, 4, 6 hours), Weeks 4, 5, 6, 7, 8 and every 4 weeks up to Week 48
measure: Number of Participants With Abnormal Covariates: Part 2
timeFrame: Up to 14 months
measure: Duration of Response: Part 2
timeFrame: Up to 14 months
measure: Time to Time to Response: Part 2
timeFrame: Up to 14 months
measure: Progression-free Survival: Part 2
timeFrame: Up to 14 months
Other outcomes:
Locations:
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: