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

Primary Purpose

Neoplasms

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

GSK3326595

5-Azacitidine

About this trial

This is an interventional treatment trial for Neoplasms focused on measuring Acute myeloid leukemia, Myelodysplastic syndrome, Chronic myelomonocytic leukemia, GSK3326595, 5-Azacitidine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Part 1: Participants receiving GSK3326595

Part 2 Dose escalation : Participants receiving GSK3326595+5-Azacitidine

Part 2 Dose expansion: Participants receiving GSK3326595+5-Azacitidine

Arm Description

Outcomes

Primary Outcome Measures

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.

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.

Part 2: Number of Participants With AEs by Severity

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.

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.

Secondary Outcome Measures

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.

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.

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.

Part 1: Overall Response Rate

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.

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.

Part 1: Overall Survival

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

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.

Part 1: Cmax of GSK3326595 Following Administration of Repeat Dose

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

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.

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.

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.

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

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

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

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: Tmax 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: Tmax of GSK3326595 Following Administration of Repeat Dose

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

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

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: Tmax of 5-Azacitidine Following Administration of Repeat Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

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

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

Part 2: t1/2 of 5-Azacitidine Following Administration of Single Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: t1/2 of 5-Azacitidine Following Administration of Repeat Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: AUC(0-t) 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: AUC(0-t) of GSK3326595 Following Administration of Repeat Dose

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

Part 2: AUC(0-t) of 5-Azacitidine Following Administration of Single Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: AUC(0-t) of 5-Azacitidine Following Administration of Repeat Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: AUC(0-inf) 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: AUC(0-inf) of GSK3326595 Following Administration of Repeat Dose

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

Part 2: AUC(0-inf) of 5-Azacitidine Following Administration of Single Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: AUC(0-inf) of 5-Azacitidine Following Administration of Repeat Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: AUC(0-tau) Following Administration of GSK3326595

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

Part 2: AUC(0-tau) Following Administration of 5-Azacitidine

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: CL/F 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: CL/F of GSK3326595 Following Administration of Repeat Dose

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

Part 2: CL/F of 5-Azacitidine Following Administration of Single Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: CL/F of 5-Azacitidine Following Administration of Repeat Dose

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: Time Invariance Following Administration of GSK3326595

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

Part 2: Time Invariance Following Administration of 5-Azacitidine

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: Accumulation Ratio Following Administration of GSK3326595

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

Part 2: Accumulation Ratio Following Administration of 5-Azacitidine

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Part 2: Overall Response Rate

Overall response rate is defined as the percentage of participants achieving a CR, mCR, or PR, per IWG criteria.

Full Information

NCT ID

NCT03614728

First Posted

July 30, 2018

Last Updated

January 6, 2023

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT03614728

Brief Title

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

Official Title

A Phase I/II Study to Investigate the Safety and Clinical Activity of GSK3326595 and Other Agents in Participants With Myelodysplastic Syndrome and Acute Myeloid Leukaemia

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Terminated

Why Stopped

Trial terminated due to internal review of clinical data in context of indication under investigation

Study Start Date

October 16, 2018 (Actual)

Primary Completion Date

January 11, 2022 (Actual)

Study Completion Date

January 11, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neoplasms

Keywords

Acute myeloid leukemia, Myelodysplastic syndrome, Chronic myelomonocytic leukemia, GSK3326595, 5-Azacitidine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Model Description

This is an open-label, multicenter, multi-part study.

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: Participants receiving GSK3326595

Arm Type

Experimental

Arm Title

Part 2 Dose escalation : Participants receiving GSK3326595+5-Azacitidine

Arm Type

Experimental

Arm Title

Part 2 Dose expansion: Participants receiving GSK3326595+5-Azacitidine

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

GSK3326595

Intervention Description

GSK3326595 will be administered.

Intervention Type

Drug

Intervention Name(s)

5-Azacitidine

Intervention Description

5-Azacitidine will be administered.

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Up to 30.8 months

Title

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

Description

Time Frame

Up to 3 years and 2 months

Title

Part 2: Number of Participants With AEs by Severity

Description

Time Frame

Up to 3 years and 2 months

Title

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

Description

Time Frame

Up to 28 days

Title

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

Description

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 Outcome Measure Information:

Title

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

Description

Time Frame

Up to 30.8 months

Title

Part 1: Number of Participants With AEs by Severity

Description

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

Title

Part 1: Number of Participants With DLTs

Description

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

Title

Part 1: Overall Response Rate

Description

Time Frame

Up to 30.8 months

Title

Part 1: Progression Free Survival

Description

Time Frame

Up to 30.8 months

Title

Part 1: Overall Survival

Description

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

Time Frame

Up to 30.8 months

Title

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

Description

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

Title

Part 1: Cmax of GSK3326595 Following Administration of Repeat Dose

Description

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

Title

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

Description

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

Time Frame

Title

Part 1: Tmax of GSK3326595 Following Administration of Repeat Dose

Description

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

Time Frame

Title

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

Description

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

Time Frame

Title

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

Description

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

Time Frame

Title

Description

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

Time Frame

Title

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

Description

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

Time Frame

Title

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

Description

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

Time Frame

Title

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

Description

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

Time Frame

Title

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

Description

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

Time Frame

Title

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

Description

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

Time Frame

Title

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

Description

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

Time Frame

Title

Part 1: Time Invariance Following Administration of GSK3326595

Description

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

Title

Part 1: Accumulation Ratio Following Administration of GSK3326595

Description

Time Frame

Title

Part 2: Complete Remission (CR) Rate

Description

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

Time Frame

Up to 3 years and 2 months

Title

Part 2: Cmax of GSK3326595 Following Administration of Single Dose

Description

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

Time Frame

Title

Part 2: Cmax of GSK3326595 Following Administration of Repeat Dose

Description

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

Title

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

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

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

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: Tmax of GSK3326595 Following Administration of Single Dose

Description

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

Time Frame

Title

Part 2: Tmax of GSK3326595 Following Administration of Repeat Dose

Description

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

Time Frame

Title

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

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: Tmax of 5-Azacitidine Following Administration of Repeat Dose

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: t1/2 of GSK3326595 Following Administration of Single Dose

Description

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

Time Frame

Title

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

Description

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

Time Frame

Title

Part 2: t1/2 of 5-Azacitidine Following Administration of Single Dose

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: t1/2 of 5-Azacitidine Following Administration of Repeat Dose

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: AUC(0-t) of GSK3326595 Following Administration of Single Dose

Description

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

Time Frame

Title

Part 2: AUC(0-t) of GSK3326595 Following Administration of Repeat Dose

Description

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

Time Frame

Title

Part 2: AUC(0-t) of 5-Azacitidine Following Administration of Single Dose

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: AUC(0-t) of 5-Azacitidine Following Administration of Repeat Dose

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: AUC(0-inf) of GSK3326595 Following Administration of Single Dose

Description

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

Time Frame

Title

Part 2: AUC(0-inf) of GSK3326595 Following Administration of Repeat Dose

Description

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

Time Frame

Title

Part 2: AUC(0-inf) of 5-Azacitidine Following Administration of Single Dose

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: AUC(0-inf) of 5-Azacitidine Following Administration of Repeat Dose

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: AUC(0-tau) Following Administration of GSK3326595

Description

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

Time Frame

Title

Part 2: AUC(0-tau) Following Administration of 5-Azacitidine

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: CL/F of GSK3326595 Following Administration of Single Dose

Description

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

Time Frame

Title

Part 2: CL/F of GSK3326595 Following Administration of Repeat Dose

Description

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

Time Frame

Title

Part 2: CL/F of 5-Azacitidine Following Administration of Single Dose

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: CL/F of 5-Azacitidine Following Administration of Repeat Dose

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: Time Invariance Following Administration of GSK3326595

Description

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

Time Frame

Days 1 and 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

Title

Part 2: Time Invariance Following Administration of 5-Azacitidine

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: Accumulation Ratio Following Administration of GSK3326595

Description

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

Time Frame

Day 1 and 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

Title

Part 2: Accumulation Ratio Following Administration of 5-Azacitidine

Description

Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of 5-Azacitidine.

Time Frame

Title

Part 2: Overall Response Rate

Description

Overall response rate is defined as the percentage of participants achieving a CR, mCR, or PR, per IWG criteria.

Time Frame

Up to 3 years and 2 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Birmingham

State/Province

Alabama

ZIP/Postal Code

35294-3300

Country

United States

Facility Name

GSK Investigational Site

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

Facility Name

GSK Investigational Site

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

GSK Investigational Site

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

GSK Investigational Site

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Facility Name

GSK Investigational Site

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

GSK Investigational Site

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53226

Country

United States

Facility Name

GSK Investigational Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2M9

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

IPD for this study will be made available via the Clinical Study Data Request site.

IPD Sharing Time Frame

IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.

IPD Sharing Access Criteria

Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

IPD Sharing URL

http://clinicalstudydatarequest.com

Learn more about this trial

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

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

Neoplasms

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial