Safety, Clinical Activity, Pharmacokinetics (PK) and Pharmacodynamics Study of GSK2879552, Alone or With Azacitidine, in Subjects With High Risk Myelodysplastic Syndromes (MDS)

Phase 2TerminatedNCT02929498

GlaxoSmithKline7 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Myelodysplastic Syndrome Myelodysplastic Syndromes

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (6)

GSK Investigational Site

Augusta, Georgia, United States

GSK Investigational Site

Durham, North Carolina, United States

GSK Investigational Site

Philadelphia, Pennsylvania, United States

GSK Investigational Site

Houston, Texas, United States

GSK Investigational Site

Madrid, Spain

GSK Investigational Site

Valencia, Spain

Outcomes

Primary Outcomes

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

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. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention or event associated with liver injury and impaired liver function were categorized as SAE. An event was considered a DLT if it occurred within the first 28 days of treatment, and met the DLT criteria unless it could be clearly established that the event was unrelated to treatment.

Time frame: Up to 2 years

Part 1: Change From Baseline in Platelets, Neutrophils, Monocytes, Lymphocytes, Leucocyte, Eosinophils and Basophils at Indicated Time-points

Blood samples were collected from participants for evaluation of hematology parameters including platelets, neutrophils, monocytes, lymphocytes, leucocyte, eosinophils and basophils. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Mean Corpuscular Volume (MCV) at Indicated Time-points

Blood samples were collected from participants for evaluation of hematology parameters including MCV. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Mean Corpuscular Hemoglobin (MCH) at Indicated Time-points

Blood samples were collected from participants for evaluation of hematology parameters including MCH. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Mean Corpuscular Hemoglobin Concentration (MCHC) and Hemoglobin (Hb) at Indicated Time-points

Blood samples were collected from participants for evaluation of hematology parameters including MCHC and Hb. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Hematocrit at Indicated Time-points

Blood samples were collected from participants for evaluation of hematology parameters including Hematocrit. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Erythrocytes at Indicated Time-points

Blood samples were collected from participants for evaluation of hematology parameters including erythrocytes. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Percent Reticulocytes at Indicated Time-points

Blood samples were collected from participants for evaluation of hematology parameters including percent reticulocytes. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Blast/Leukocytes at Indicated Time-points

Blood samples were collected from participants for evaluation of hematology parameters including blast/leukocytes. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: Baseline and Day 1 of Cycle 1 (Cycle of 28 days)

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

Blood samples were collected from participants for evaluation of clinical chemistry parameters including ALT, ALP, AST, LDH and GGT. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, Phosphate and Urea Nitrogen at Indicated Time-points

Blood samples were collected from participants for evaluation of clinical chemistry parameters including calcium, chloride, glucose, potassium, sodium, phosphate and urea nitrogen. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Albumin and Protein at Indicated Time Points

Blood samples were collected from participants for evaluation of clinical chemistry parameters including Albumin and Protein. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Partial Pressure Carbon Dioxide (pCO2) at Indicated Time Points

Blood samples were collected from participants for evaluation of clinical chemistry parameters including pCO2. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: Baseline and Day 1 of Cycle 1 (cycle of 28 days)

Part 1: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time-points

Vital signs including SBP and DBP were measured after resting for at least 5 minutes in a semi-supine position. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Heart Rate at Indicated Time-points

Vital signs including heart rate was measured after resting for at least 5 minutes in a semi-supine position. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Respiratory Rate at Indicated Time-points

Vital signs including respiratory rate was measured after resting for at least 5 minutes in a semi-supine position. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Body Temperature at Indicated Time-points

Vital signs including body temperature was measured after resting for at least 5 minutes in a semi-supine position. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate at Indicated Time-points

Single 12-lead ECG was obtained at designated time points during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

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

Single 12-lead ECG was obtained at designated time points during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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)

Part 1: Number of Participants With Abnormal Findings During Physical Examination

A complete physical examination included, at a minimum, assessment of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. A brief physical examination included, at a minimum assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.

Time frame: Up to 2 years

Part 2: Percentage of Participants With Investigator-assessed Best Response Assessed by Clinical Benefit Rate (CBR)

CBR was defined as the percentage of participants achieving a confirmed Complete Remission (CR) or Partial Remission (PR) or Marrow Complete Remission (mCR) or confirmed Hematologic Improvement (HI) or Stable Disease (SD) prior to new anti-cancer therapy and crossover on the All Treated Subjects Population. Participants with Not Evaluable or missing response were to be treated as non-responders. International Working Group (IWG) criteria, 2006 was to be used to evaluate response.

Time frame: Up to 2.5 years

Part 2: Percentage of Participants With Investigator-assessed Best Response Assessed by Objective Response Rate (ORR)

Objective response rate was defined as the percentage of participants who achieved CR or PR or mCR or HI prior to new anti-cancer therapy on the All Treated Subjects Population. Participants with Not Evaluable or missing response were to be treated as non-responders. IWG criteria, 2006 was to be used to evaluate response.

Time frame: Up to 2.5 years

Part 1: Change From Baseline in Total Bilirubin, Direct Bilirubin, Creatinine and Urate at Indicated Time Points

Blood samples were collected from participants for evaluation of clinical chemistry parameters including Total Bilirubin, Direct Bilirubin, Creatinine and urate. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was calculated by subtracting post-dose value from Baseline value.

Time frame: 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

Part 1: Percentage of Participants With Investigator-assessed Best Response Assessed by Clinical Benefit Rate (CBR)

Clinical Benefit Rate was defined as the percentage of participants achieving a confirmed Complete Remission (CR) or Partial Remission (PR) or Marrow Complete Remission (mCR) or confirmed Hematologic Improvement (HI) or Stable Disease (SD) prior to new anti-cancer therapy and crossover on the All Treated Subjects Population. Participants with Not Evaluable or missing response were treated as non-responders. International Working Group (IWG) criteria, 2006 was used to evaluate response.

Time frame: Up to 2 years

Part 1: Percentage of Participants With Investigator-assessed Best Response Assessed by Objective Response Rate (ORR)

Objective Response Rate was defined as the percentage of participants who achieved Complete Remission (CR) or Partial Remission (PR) or Marrow Complete Remission (mCR) or confirmed Hematologic Improvement (HI) prior to new anti-cancer therapy on the All Treated Subjects Population. Participants with Not Evaluable or missing response were treated as non-responders. International Working Group (IWG) criteria, 2006 was used to evaluate response.

Time frame: Up to 2 years

Part 1: Plasma Concentration of GSK2879552

Blood samples were collected at indicated time points to evaluate concentration of GSK2879552. Each Pharmacokinetic (PK) sample was collected as close as possible to the planned time relative to the dose (i.e., time zero) administered to the participant on PK days. PK Concentration Population consisted of all participants in the All Treated Subject Population for whom a blood sample for pharmacokinetics was obtained and analyzed.

Time frame: 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)

Part 1: Plasma Concentration of Azacitidine

Blood samples were to be collected at indicated time points to evaluate concentration of Azacitidine.

Part 1: Duration of Response

Duration of response is defined as the subset of participants (responders) who show a response (CR, mCR, PR, or HI), the time from first documented evidence of response until the first documented sign of disease progression or death. If no disease progression or death, the DOR was to be censored at last disease assessment.

Time frame: Up to 2 years

Part 1: Progression-free Survival

Progression-free survival (PFS) is defined as the time from first treatment dose until the first documented sign of disease progression or death. If the participant missed more than one visit prior to the date of documented events, PFS was censored at the last adequate assessment prior to missing. Otherwise, if the participant did not have a documented date of events, PFS was censored at the date of the last adequate assessment.

Time frame: Up to 2 years

Part 1: Overall Survival

Overall survival (OS) is defined as the time from first treatment dose until death due to any reason. For the analysis of overall survival (OS), the last date of known contact was used for those participants who had not died at the time of analysis; such participants were considered censored.

Time frame: Up to 2 years

Part 1: Proportion of Participants With Disease Progression to Acute Myeloblastic Leukemia (AML)

The proportion of participants with disease progression to AML is defined as the percentage of participants experiencing AML on the All Treated Subjects Population.

Time frame: Up to 2 years

Part 1: Time to AML Progression

Time to AML progression is defined as the time from first treatment dose until AML progression or crossover if using the All Treated Subjects Population. For the analysis of time to AML, if the participant did not experience AML, time to AML was censored at the last treatment prior to the initiation of anti-cancer therapy or crossover.

Time frame: Up to 2 years

Part 1: Number of Participants With Documented Platelet and Red Blood Cell (RBC) Transfusions Per Month

Number of participants with documented platelet and RBC transfusions have been presented.

Time frame: Up to 2 years

Part 2: Number of Participants With Any AEs and SAEs

Time frame: Up to 2.5 years

Part 2: Change From Baseline in Platelets, Neutrophils, Monocytes, Lymphocytes, Leucocyte, Eosinophils and Basophils at Indicated Time-points

Blood samples were to be collected from participants for evaluation of hematology parameters including platelets, neutrophils, monocytes, lymphocytes, leucocyte, eosinophils and basophils. Baseline was defined as the value obtained prior to first dosing (Day 1). Change from Baseline was to be calculated by subtracting post-dose value from Baseline value.