Clinical trial NCT02929498: Safety, Clinical Activity, Pharmacokinetics (PK) and Pharmacodynamics Study of GSK2879552, Alone or With Azacitidine, in Subjects With High Risk Myelodysplastic Syndromes (MDS)
Official title: A Phase I/II, Open-label, 2 Arm Study to Investigate the Safety, Clinical Activity, Pharmacokinetics and Pharmacodynamics of GSK2879552 Administered Alone or in Combination With Azacitidine, in Adult Subjects With IPSS-R High and Very High Risk Myelodysplastic Syndromes (MDS) Previously Treated With Hypomethylating Agents (HMA)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Myelodysplastic Syndrome
Myelodysplastic Syndromes
Keywords: GSK2879552
Revised International Prognostic Scoring System (IPSS-R)
azacitidine
hypomethylating agents
myelodysplastic syndrome
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2016-10-11
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase I/II, open-label, 2 arm study to evaluate the safety and clinical activity of GSK2879552 alone, or in combination with azacitidine in subjects with MDS. The study consisted of 2 parts. The objective of Part 1 is to determine the recommended phase 2 dose (RP2D) of GSK2879552 administered alone and in combination with azacitidine in adult subjects with high risk MDS previously treated with HMA. The objective of Part 2 is to evaluate clinical activity after treatment with GSK2879552, alone or in combination with azacitidine, in adult subjects with high risk MDS previously treated with HMA.


Eligibility criteria: Inclusion Criteria:

* \>=18 years of age and provided signed written informed consent
* Subjects must have IPSS-R high or very high risk myelodysplastic syndromes (MDS) by World Health Organization (WHO) classification
* Subjects must have failed hypomethylating treatment where "failure" is defined as: Progression (according to 2006 International Working Group \[IWG\] criteria) at any time after initiation of the hypomethylating treatment OR Failure to achieve complete or partial response or hematological improvement (HI) (according to 2006 IWG) after at least 4 cycles treatment OR Relapse after initial complete or partial response or HI (according to 2006 IWG criteria).
* Subjects are not a candidate, or have failed allogeneic stem cell transplantation. Subjects who underwent allo-transplant in the past are eligible under following conditions: transplant was \>2 year prior to enrolment, and no evidence of active graft-versus-host disease (GVHD)
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
* Subjects must have a life expectancy of at least 12 weeks, in the opinion of the investigator.
* 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 defined by: International Normalization Ratio (INR) and activated partial thromboplastin time (aPTT) \<=1.3xupper limit of normal (ULN); platelet count (PLT) \>=10,000 (transfusions permitted to bring PLT to \>10,000); total bilirubin \<=1.5xULN (Isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35% or subject has a diagnosis of Gilbert's syndrome); Alanine transaminase (ALT) \<=2.5xULN; creatinine \<=1.5xULN OR calculated creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or measured from 24 hour urine \>=50 milliliters (mL)/minute (min); and Ejection fraction \>=lower limit of normal (LLN) by Echocardiogram (ECHO) or multigated acquisition scan (MUGA)
* 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 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:

* AML according to world health organization (WHO) criteria (i.e. bone marrow blasts \>20%)
* Active hepatitis B or hepatitis C treatment
* Baseline Montreal Cognitive Assessment (MOCA) score of 22 or lower
* History of or concurrent malignancy of solid tumours, except for below:

Exception: Subjects who have been disease-free for 2 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.

* Prior treatment with temozolomide, dacarbazine or procarbazine
* Prior treatment with poly adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (example (e.g.), olaparib, veliparib \[ABT-888\])
* Currently receiving other anti-cancer therapy (chemotherapy, radiation therapy, immuno- therapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization)
* Received major surgery, radiotherapy, or immunotherapy within 4 weeks of GSK2879552 administration
* Evidence of severe or uncontrolled systemic diseases (e.g., severe/chronic infection, unstable or uncompensated respiratory, renal, or cardiac disease). Any serious and/or unstable pre-existing medical (aside from malignancy exception above), 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 (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator's assessment)
* Patients with any major bleeding current or within the past 4 weeks. (e.g. recent gastrointestinal \[GI\] hemorrhage or neurosurgery).
* Administration of an investigational drug within 14 days or 5 half-lives, whichever is shorter, preceding the first dose of study treatment(s) in this study.
* Cardiac abnormalities as evidenced by any of the following: clinically significant uncontrolled arrhythmias or uncontrolled hypertension; history or evidence of current \>=Class II congestive heart failure as defined by New York Heart Association (NYHA); history of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months; baseline Corrected QT (QTc) interval using Fridericia's formula \>450 milliseconds (msec) or \>480 msec in subjects with Bundle Branch Block. QTc value based on single or average of triplicate ECGs obtained over a brief recording period
* 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
* 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
* Lactating female
* Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2879552 or lysine-specific demethylase 1 (LSD1) inhibitors that contraindicates their participation
* Known hypersensitivity to azacitidine or mannitol

Primary outcomes:
measure: Part 1: Number of Participants With Any Non-serious Adverse Event (Non-SAE), Serious AE (SAE), Dose Limiting Toxicities (DLT), Dose Reductions or Delays and Withdrawals Due to Toxicities
timeFrame: Up to 2 years
measure: Part 1: Change From Baseline in Platelets, Neutrophils, Monocytes, Lymphocytes, Leucocyte, Eosinophils and Basophils at Indicated Time-points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Mean Corpuscular Volume (MCV) at Indicated Time-points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Mean Corpuscular Hemoglobin (MCH) at Indicated Time-points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Mean Corpuscular Hemoglobin Concentration (MCHC) and Hemoglobin (Hb) at Indicated Time-points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Hematocrit at Indicated Time-points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Erythrocytes at Indicated Time-points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Percent Reticulocytes at Indicated Time-points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Blast/Leukocytes at Indicated Time-points
timeFrame: Baseline and Day 1 of Cycle 1 (Cycle of 28 days)
measure: Part 1: Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Lactate Dehydrogenase (LDH) and Gamma Glutamyl Transferase (GGT) at Indicated Time-points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, Phosphate and Urea Nitrogen at Indicated Time-points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Albumin and Protein at Indicated Time Points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Partial Pressure Carbon Dioxide (pCO2) at Indicated Time Points
timeFrame: Baseline and Day 1 of Cycle 1 (cycle of 28 days)
measure: Part 1: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time-points
timeFrame: Baseline and Cycle 1 (Days 7, 15), Cycle 2 (Day 1), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Heart Rate at Indicated Time-points
timeFrame: Baseline and Cycle 1 (Days 7, 15), Cycle 2 (Day 1), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Respiratory Rate at Indicated Time-points
timeFrame: Baseline and Cycle 1 (Days 7, 15), Cycle 2 (Day 1), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Body Temperature at Indicated Time-points
timeFrame: Baseline and Cycle 1 (Days 7, 15), Cycle 2 (Day 1), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate at Indicated Time-points
timeFrame: Baseline and Cycle 1 (Days 1, 7), Cycle 2 (Day 1), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Change From Baseline in ECG PR Interval, QRS Duration, QT Interval, QTc Corrected by Bazett's Formula (QTcB) and QTc Corrected by Fridericia's Formula (QTcF) at Indicated Time-points
timeFrame: Baseline and Cycle 1 (Days 1,7), Cycle 2 (Day 1), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
measure: Part 1: Number of Participants With Abnormal Findings During Physical Examination
timeFrame: Up to 2 years
measure: Part 2: Percentage of Participants With Investigator-assessed Best Response Assessed by Clinical Benefit Rate (CBR)
timeFrame: Up to 2.5 years
measure: Part 2: Percentage of Participants With Investigator-assessed Best Response Assessed by Objective Response Rate (ORR)
timeFrame: Up to 2.5 years
measure: Part 1: Change From Baseline in Total Bilirubin, Direct Bilirubin, Creatinine and Urate at Indicated Time Points
timeFrame: Baseline and Cycle 1(Days 1, 7, 15, 22), Cycle 2 (Days 1, 7, 15 ,22), Cycle 3 (Day 1), Cycle 4 (Day 1), Cycle 5 (Day 1) (each cycle of 28 days)
Secondary outcomes:
measure: Part 1: Percentage of Participants With Investigator-assessed Best Response Assessed by Clinical Benefit Rate (CBR)
timeFrame: Up to 2 years
measure: Part 1: Percentage of Participants With Investigator-assessed Best Response Assessed by Objective Response Rate (ORR)
timeFrame: Up to 2 years
measure: Part 1: Plasma Concentration of GSK2879552
timeFrame: Cycle 1, Day 1: pre-dose, 0.5, 1, 3 hour; pre-dose on Days 2,4; Day 7: pre-dose, 0.5, 1, 3 hour; Day 15: pre-dose, 0.5-1 hour post-dose; pre-dose on Day 22; Cycle 2: pre-dose on Days 1, 7, 15, 22; Pre-dose on Day 1 of Cycles 3,4,5 (each cycle of 28 days)
measure: Part 1: Plasma Concentration of Azacitidine
timeFrame: Cycle 1, Day 1: pre-dose, 0.5, 1, 3 hour; pre-dose on Days 2,4; Day 7: pre-dose, 0.5, 1, 3 hour; Day 15: pre-dose, 0.5-1 hour post-dose; pre-dose on Day 22; Cycle 2: pre-dose on Days 1, 7, 15, 22; Pre-dose on Day 1 of Cycles 3,4,5 (each cycle of 28 days)
measure: Part 1: Duration of Response
timeFrame: Up to 2 years
measure: Part 1: Progression-free Survival
timeFrame: Up to 2 years
measure: Part 1: Overall Survival
timeFrame: Up to 2 years
measure: Part 1: Proportion of Participants With Disease Progression to Acute Myeloblastic Leukemia (AML)
timeFrame: Up to 2 years
measure: Part 1: Time to AML Progression
timeFrame: Up to 2 years
measure: Part 1: Number of Participants With Documented Platelet and Red Blood Cell (RBC) Transfusions Per Month
timeFrame: Up to 2 years
measure: Part 2: Number of Participants With Any AEs and SAEs
timeFrame: Up to 2.5 years
measure: Part 2: Change From Baseline in Platelets, Neutrophils, Monocytes, Lymphocytes, Leucocyte, Eosinophils and Basophils at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in MCV at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in MCH at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in MCHC and Hb at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Hematocrit at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Erythrocytes at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Percent Reticulocytes at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Blast/Leukocytes at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in ALT, ALP, AST, LDH and GGT at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, Phosphate and Urea Nitrogen at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Total Bilirubin, Direct Bilirubin, Creatinine and Urate at Indicated Time Points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Albumin and Protein at Indicated Time Points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in pCO2 at Indicated Time Points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in SBP and DBP at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Heart Rate at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Respiratory Rate at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in Body Temperature at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in ECG Mean Heart Rate at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Change From Baseline in ECG PR Interval, QRS Duration, QT Interval, QTcB and QTcF at Indicated Time-points
timeFrame: Baseline and up to 2.5 years
measure: Part 2: Number of Participants With Abnormal Findings During Physical Examination
timeFrame: Up to 2.5 years
measure: Part 2: Plasma Clearance (CL/F) of GSK2879552
timeFrame: Cycle 1, Day 1: pre-dose, 0.5, 1, 3 hour; pre-dose on Day 4; Day 7: pre-dose, 0.5, 1, 3 hour; Day 15: pre-dose, 0.5-1 hour post-dose; pre-dose on Day 22; Cycle 2: pre-dose on Days 1, 7, 15, 22; Pre-dose on Day 1 of Cycles 3 to 1 (each cycle of 28 days)
measure: Part 2: Duration of Response
timeFrame: Up to 2.5 years
measure: Part 2: Progression-free Survival
timeFrame: Up to 2.5 years
measure: Part 2: Overall Survival
timeFrame: Up to 2.5 years
measure: Part 2: Percentage of Participants With Disease Progression to AML
timeFrame: Up to 2.5 years
measure: Part 2: Time to AML Progression
timeFrame: Up to 2.5 years
measure: Part 2: Number of Participants With Documented Platelet and Red Blood Cell (RBC) Transfusions Per Month
timeFrame: Up to 2.5 years
Other outcomes:
Locations:
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: