Study to Investigate the Safety and Clinical Activity of GSK3326595 and Other Agents to Treat Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Phase 2TerminatedNCT03614728

GlaxoSmithKline30 enrolled

Overview

This study will evaluate the safety, tolerability, and clinical activity of GSK3326595 in participants with relapsed and refractory MDS, chronic myelomonocytic leukemia (CMML), and AML. The study will be conducted in 2 parts: Part 1 will determine the clinical benefit rate (CBR) of GSK3326595 in monotherapy and Part 2 will be expanded to study GSK3326595 in combination with 5-Azacitidine which will be composed of a dose escalation phase followed by dose expansion cohort of GSK3326595.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Neoplasms

Interventions

GSK3326595DRUG

GSK3326595 will be administered.

5-AzacitidineDRUG

5-Azacitidine will be administered.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Males and females greater than or equal to (\>=)18 years of age (at the time consent is obtained). * Diagnosis of MDS, CMML or AML * Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 or 2 * Adequate organ function * A woman of childbearing potential (WOCBP) must have a negative highly sensitive serum pregnancy test within 7 days before the first dose of study intervention. Exclusion Criteria: * History of, or known, central nervous system (CNS) involvement * Prior solid organ transplantation * Known allergies, hypersensitivity, or intolerance to GSK3326595 or 5-Azacitidine or its excipient * Prior therapy with any Protein arginine methyl transferase 5 (PRMT5) inhibitor * History of a second malignancy, excluding non-melanoma skin cell cancer, within the last three years * Active severe or uncontrolled infection * History of optic nerve neuropathy or neuritis. * History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

Locations (8)

GSK Investigational Site

Birmingham, Alabama, United States

GSK Investigational Site

Miami, Florida, United States

GSK Investigational Site

Boston, Massachusetts, United States

GSK Investigational Site

Boston, Massachusetts, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

Houston, Texas, United States

GSK Investigational Site

Milwaukee, Wisconsin, United States

GSK Investigational Site

Toronto, Ontario, Canada

Outcomes

Primary Outcomes

Part 1: Percentage of Participants With Clinical Benefit Rate (CBR)

CBR is defined as the percentage of participants achieving a complete remission (CR), complete marrow remission (mCR), partial remission (PR), stable disease (SD) lasting at least 8 weeks, or hematologic improvement (HI), per International Working Group (IWG) criteria, where CR=Bone marrow:\<=5 percent(%) myeloblasts with normal maturation of all cell lines; PR=Bone marrow blasts decreased by \>=50% over pre-treatment but still \>5%; mCR=Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pre-treatment; SD= Failure to achieve at least PR, but no evidence of progression \>8 weeks; HI=Erythroid (E): hemoglobin increase of \>1.5 grams per deciliter (g/dL), HI-Platelet: increase of \>30,000/milliliter (mL) (starting with \>20,000/mL) and increase from \<20,000/mL to \>20,000/mL by \>100%; HI-Neutrophil: increase of \>100% and \>500/microliter. Percentage values are rounded off.

Time frame: Up to 30.8 months

Part 2: Number of Participants With Non-serious Treatment-emergent Adverse Events (Non-STEAEs) and Serious Treatment Emergent Adverse Events (STEAEs)

An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. Treatment emergent adverse event (TEAE) is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. Number of participants with non-STEAEs and STEAEs were planned to be assessed.

Time frame: Up to 3 years and 2 months

Part 2: Number of Participants With AEs by Severity

Time frame: Up to 3 years and 2 months

Part 2: Number of Participants With Dose Limiting Toxicities (DLTs)

An event is considered to be a DLT if the event occurs within the first 28 days of treatment meeting one of the following criteria of toxicity, Hematologic: Grade 4 or greater treatment-emergent neutropenia, anemia, or thrombocytopenia, lasting for \>=14 days in the absence of Investigational Product, that cannot be attributed to underlying disease as described in National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4; Non-hematologic: Hepatic toxicity that meets Liver Stopping Criteria, Grade 3 nausea, vomiting or diarrhea that does not improve within 72 hours despite appropriate supportive treatments, Grade 4 or greater nausea, vomiting, or diarrhea of any duration, Any other Grade 3 or greater clinically significant non-hematologic toxicity; Other: Inability to receive all planned doses, dose interruption and Grade 2 or higher toxicity. Number of participants with DLTs were planned to be assessed.

Time frame: Up to 28 days

Part 2: Number of Participants With AEs Leading to Dose Interruptions, Dose Reductions and Treatment Discontinuation Due to AEs

Number of participants with AEs leading to dose interruptions, dose reductions and treatment discontinuation due to AEs were planned to be assessed.

Time frame: Up to 3 years and 2 months

Secondary Outcomes

Part 1: Number of Participants With Common Non-STEAEs and STEAEs

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgement. TEAE is any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. TEAEs which were not serious, were considered as non-STEAEs.

Time frame: Up to 30.8 months

Part 1: Number of Participants With AEs by Severity

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Severity of each AE was reported during the study and was assigned a grade according to the NCI-CTCAE. AEs severity were graded as: Grade 1=mild; Grade 2=moderate; Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening consequences and Grade 5=death related to AE.

Time frame: Up to 30.8 months

Part 1: Number of Participants With DLTs

An event is considered to be a DLT if the event occurs within the first 28 days of treatment meeting one of the following criteria of toxicity, Hematologic: Grade 4 or greater treatment-emergent neutropenia, anemia, or thrombocytopenia, lasting for \>=14 days in the absence of Investigational Product, that cannot be attributed to underlying disease as described in NCI-CTCAE version 4; Non-hematologic: Hepatic toxicity that meets Liver Stopping Criteria, Grade 3 nausea, vomiting or diarrhea that does not improve within 72 hours despite appropriate supportive treatments, Grade 4 or greater nausea, vomiting, or diarrhea of any duration, Any other Grade 3 or greater clinically significant non-hematologic toxicity; Other: Inability to receive all planned doses, dose interruption and Grade 2 or higher toxicity.

Time frame: Up to 28 days

Part 1: Overall Response Rate

Data from ClinicalTrials.gov

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Overall response rate is defined as the percentage of participants achieving a CR, mCR, or PR, per IWG criteria, where CR=Bone marrow: \<=5% myeloblasts with normal maturation of all cell lines; PR=Bone marrow blasts decreased by \>=50% over pre-treatment but still \>5%; mCR= Bone marrow: ≤ 5% myeloblasts and decrease by \>=50% over pre-treatment. Percentage values are rounded off.

Time frame: Up to 30.8 months

Part 1: Progression Free Survival

Progression free survival is defined as time from first dose to disease progression, as defined by IWG criteria, or death due to any cause, whichever occurs earlier. Progressive Disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study.

Time frame: Up to 30.8 months

Part 1: Overall Survival

Overall survival is defined as time from first dose to death due to any cause.

Time frame: Up to 30.8 months

Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3326595 Following Administration of Single Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Time frame: Day 1:Pre-dose(within 1 hour prior to dosing),5minute(+/-2minute),30minute(+/-5minute),1hour(+/-5minute),2hours(+/-5minute),3hours(+/-5minute),4hours(+/-10minute),6hours(+/-10minute),8hours(+/-15minute),12hours(+/-2hour), 24hours(+/-2hour) post-dose

Part 1: Cmax of GSK3326595 Following Administration of Repeat Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Time frame: Day 15:Pre-dose(within 1 hour prior to dosing),5minute(+/-2minute),30minute(+/-5minute),1hour(+/-5minute),2hours(+/-5minute),3hours(+/-5minute),4hours(+/-10minute),6hours(+/-10minute),8hours(+/-15minute),12hours(+/-2hour), 24hours(+/-2hour) post-dose

Part 1: Time of Maximum Concentration Observed (Tmax) of GSK3326595 Following Administration of Single Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: Tmax of GSK3326595 Following Administration of Repeat Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: Apparent Terminal Phase Half-life (t1/2) of GSK3326595 Following Administration of Single Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: t1/2 of GSK3326595 Following Administration of Repeat Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: Area Under Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within Participant Across All Treatments (AUC[0-t]) of GSK3326595 Following Administration of Single Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: AUC(0-t) of GSK3326595 Following Administration of Repeat Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: AUC From 0 Hours to the Time of Next Dosing (AUC[0-tau]) of GSK3326595

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC[0-inf]) of GSK3326595 Following Administration of Single Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: AUC(0-inf) of GSK3326595 Following Administration of Repeat Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: Oral Clearance (CL/F) of GSK3326595 Following Administration of Single Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: CL/F of GSK3326595 Following Administration of Repeat Dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 1: Time Invariance Following Administration of GSK3326595

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595. Time invariance was calculated as the ratio of AUC(0-24) on Day 15 divided by AUC(0-infinity) on Day 1 for GSK3326595.

Time frame: Days1and15:Pre-dose(within 1hour prior to dosing),5minute(+/-2minute),30minute(+/-5minute),1hour(+/-5minute),2hour(+/-5minute),3hours(+/-5minute),4hours(+/-10minute),6hours(+/-10minute),8hours(+/-15minute),12hours(+/-2hour),24hours(+/-2hour)post-dose

Part 1: Accumulation Ratio Following Administration of GSK3326595

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595. Accumulation ratio was calculated as the ratio of AUC(0-24) on Day 15 divided by AUC(0-24) on Day 1 for GSK3326595.

Part 2: Complete Remission (CR) Rate

Complete remission rate is defined as percentage of participants achieving a CR per IWG criteria.

Time frame: Up to 3 years and 2 months

Part 2: Cmax of GSK3326595 Following Administration of Single Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Part 2: Cmax of GSK3326595 Following Administration of Repeat Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of GSK3326595.

Time frame: Day 8:Pre-dose(within 1 hour prior to dosing),5minute(+/-2minute),30minute(+/-5minute),1hour(+/-5minute),2hours(+/-5minute),3hours(+/-5minute),4hours(+/-10minute),6hours(+/-10minute),8hours(+/-15minute),12hours(+/-2hour), 24hours(+/-2hour) post-dose

Part 2: Cmax of 5-Azacitidine Following Administration of Single Dose