A Phase I Dose Escalation Study of GSK2879552 in Subjects With Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Leukaemia, Myelocytic, Acute

Intervention / Treatment
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* Drug: GSK2879552
* Drug: ATRA


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Phase (Part 1)<br>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<br>* 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.<br>Drug: ATRA<br>* ATRA (Tretinoin) will be supplied as a 10 mg capsule for oral administration. The initial dosing regimen will be continuous oral twice daily dosing<br>|
| Experimental: Expansion Phase (Part 2)<br>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<br>* 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.<br>Drug: ATRA<br>* ATRA (Tretinoin) will be supplied as a 10 mg capsule for oral administration. The initial dosing regimen will be continuous oral twice daily dosing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | Blood samples were collected to assess clinical chemistry parameters like urea/blood urea nitrogen (BUN), calcium, potassium, aspartate aminotransferase (AST), total bilirubin, direct bilirubin, creatinine, chloride, alanine aminotransferase (ALT), uric acid, glucose, total carbon dioxide (CO2), gamma glutamyl transferase (GGT), albumin, sodium, alkaline phosphatase, total protein, phosphate, lactate dehydrogenase (LDH). Laboratory values were as per local labs per site with own normal ranges. Values above range were reported as high and values below range as low. Data for worst case post Baseline is reported. | Median of 4 weeks of drug exposure | 
| Number of Participants With Clinical Chemistry Toxicity Grade Changes From Baseline | Blood samples were collected for analysis of clinical chemistry parameters based on common terminology criteria for adverse events (CTCAE) version 4.0, where Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life threatening consequences. Data for any increase in grade of worst-case on-therapy has been provided. | Median of 4 weeks of drug exposure | 
| Number of Participants With Hematology Parameters Change From Baseline With Respect to the Normal Range | Blood samples were collected to assess hematology parameters like mean corpuscle hemoglobin concentration (MCHC), mean corpuscle hemoglobin (MCH), mean corpuscle volume (MCV) mean platelet volume (MPV), basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, platelet count, Red blood cell (RBC) count, reticulocytes, White Blood Cell (WBC) count. Laboratory values were as per local labs per site with own normal ranges. Values above range were reported as high and values below range as low. Data for worst post Baseline were reported. NA indicates that data were not available as standard deviation could not be calculated for a single participant. | Median of 4 weeks of drug exposure | 
| Number of Participants With Hematology Toxicity Grade Changes From Baseline | Blood samples were collected for analysis of hematology parameters based on common terminology criteria for adverse events (CTCAE) version 4.0, where Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life threatening consequences. Data for any grade increase worst-case on-therapy has been provided. | Median of 4 weeks of drug exposure | 
| Part 1: Number of Participants With Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP and DBP were measured after resting for 5 minutes in semi-supine position. Vital signs were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4. An increase is defined as an increase in CTCAE grade relative to Baseline grade. For SBP Grade 0 (<120 millimeters of mercury [mmHg]), Grade 1 (120-139 mmHg), Grade 2 (140-159 mmHg), Grade 3 (>=160 mmHg). For DBP Grade 0 (<80 mmHg), Grade 1 (80-89 mmHg), Grade 2 (90-99 mmHg), Grade 3 (>=100 mmHg). Data for worst-case post Baseline is reported. | Median of 4 weeks of drug exposure | 
| Part 1: Number of Participants With Change From Baseline in Heart Rate | Heart rate was measured after restings for 5 minutes in semi-supine position. Data for participants with heart rate decreased to < 60 beats per minute (bpm), normal or no change, increase to > 100 bpm. Data for worst post Baseline were reported. | Median of 4 weeks of drug exposure | 
| Part 1: Number of Participants With Change From Baseline in Temperature | Temperature was measured after resting for 5 minutes in semi-supine position. Data for participants with temperature decreased to <=35 Celsius, normal or no change, increase to >=38 Celsius at worst-case post Baseline is reported. | Median of 4 weeks of drug exposure | 
| Part 1: Number of Participants With Change From Baseline in Respiratory Rate | Respiration rate was measured after resting for 5 minutes in semi-supine position. Data for worst case post-Baseline has been reported. Number of participants with respiratory rate decrease to <12 and increase to >25 has been reported. | Median of 4 weeks of drug exposure | 
| Part 1: Number of Participants With Abnormal Electrocardiograms (ECGs) Findings | A single 12-lead ECG was performed in semi-recumbent or supine position after 5 minutes of rest for the participant. An ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT intervals was used. Number of participants with any visit post-Baseline abnormal clinically significant findings and abnormal not clinically significant findings in ECG results has been reported. | Median of 4 weeks of drug exposure | 
| Part 1: Number of Participants With Abnormal Physical Examinations | Data for participants with abnormal physical examinations parameters was planned to be recorded. | Median of 4 weeks of drug exposure | 
| Part 2: Objective Response Rate of Participants | Objective response rate defined as the percentage of participants who achievied complete remission (CR), partial remission (PR), CRp (as per CR but platelet count <100 x 10^9/L) and morphologic leukemia free state per response criteria. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 

Secondary Outcome Measures

| Outcome Measure | 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. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 | 
| Part 1: AUC Over the Dosing Interval (0-tau) After Single Dose Administration | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. NA indicates that data were not available as geometric co-efficient could not be calculated for a single participant. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1 | 
| 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 | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. NA indicates that data were not available as geometric coefficient of variation could not be calculated for a single participant. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 15 | 
| Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK2879552 | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. NA indicates that data were not available as geometric coefficient of variation could not be calculated for a single participant. | 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 | 
| Part 1: Apparent Terminal Phase Half-life (t½) | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. NA indicates that data were not available as geometric coefficient of variation could not be calculated for a single participant. | 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 | 
| Part 1: Time of Occurrence of Cmax (Tmax) of GSK2879552 | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. NA indicates that data were not available as standard deviation could not be calculated for a single participant. | 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 | 
| Part 1: Accumulation Ratio for GSK2879552 | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. Accumulation ratio was determined dividing AUC (0-tau) on Day 15 by AUC (0-tau) on Day 1. The ratio of accumulation of GSK2879552 was estimated by calculating the ratio of the geometric least squares (GLS) means of the AUC(0-tau) between Day 15 and Day 1 for all dose levels and the corresponding 90 percent confidence interval (CI) for each ratio. | 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 | 
| Part 1:Time Invariance | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. The time invariance of GSK2879552 was estimated by calculating the ratio of the GLS means of the AUC (0-tau) between Day 15 and Day 1 for all dose levels and the corresponding 90 percent CI for each ratio. | 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 | 
| Part 1:Percentage of Participants With Objective Response | Objective response rate is defined as the percentage of participants who achieved CR, PR, as per CR but platelet count <100 x 10^9/L and morphologic leukemia free state per response criteria. | Median of 4 weeks drug response | 
| Part 1: AUC(0-t), AUC (0-tau) and AUC(0-inf) of ATRA | Blood samples were collected at indicated time points. The Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis. | 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 | 
| Part 1: Cmax of ATRA | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. | 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 | 
| Part 1: Apparent Terminal Phase Half-life (t½) of ATRA | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. | 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 | 
| Part 1: Time of Occurrence of Cmax (Tmax) of ATRA | Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis. | 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 | 
| Part 2: 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. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Part 2: 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. All dose reductions were due to AEs. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Part 2: 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. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Part 2: Number of Participants With Abnormal Clinical Chemistry Parameters | Data was not collected for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Part 2: Number of Participants With Abnormal Hematology Parameters | Data was not collected for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Part 2: Number of Participants With Abnormal Vital Signs | Data was not collected for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Part 2: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Part 2: Number of Participants With Abnormal Physical Examinations | This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Part 2: Clearance (CL) of GSK2879552 for Part 2 | This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | 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 | 
| Part 2: Volume of Distribution of GSK2879552 for Part 2 | This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | 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 | 
| Number of Participants With Abnormal Covariates: Part 2 | This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Duration of Response: Part 2 | This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Time to Time to Response: Part 2 | This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 
| Progression-free Survival: Part 2 | This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1. | Up to 14 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, LSD1, GSK2879552, Acute myeloid leukemia