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Azacitidine

GSK-3326595

Antimetabolites

Enzyme Inhibitors

GSK3326595

5-Azacitidine

GSK Clinical Trials

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.

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

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

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

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

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.

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.

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. Number of participants with AEs by severity were planned to be assessed.

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.

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

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.

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.

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.

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.

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.

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

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

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.

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

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

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

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

GlaxoSmithKline

All-cause mortality, common non-STEAEs and STEAEs were collected in Part A from All Treated Population. Data has been reported for only Part A and data were not collected for Part 2 as the study was terminated early and no participants were enrolled in Part 2 of the study.

Participants received GSK3326595 400 mg, tablets, orally, once daily until progression, unacceptable toxicity, or withdrawal of consent during Part 1 of the study.

Part 1: GSK3326595 400 mg

Participants received GSK3326595 300 mg, tablets, orally, once daily until progression, unacceptable toxicity, or withdrawal of consent during Part 1 of the study.

Part 1: GSK3326595 300 mg

Participants received GSK3326595 400 milligram (mg), tablets, orally, once daily until progression, unacceptable toxicity, or withdrawal of consent during Part 1 of the study.

Participants were planned to receive GSK3326595 in combination with 5-Azacitidine in dose escalation cohort during Part 2 of the study.

Part 2-Dose Escalation: GSK3326595+5-Azacitidine

Participants were planned to receive GSK3326595 in combination with 5-Azacitidine in dose expansion cohort during Part 2 of the study.

Part 2-Dose Expansion: GSK3326595+5-Azacitidine

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

All Treated Population consisted of all participants who received at least one dose of GSK3326595 as monotherapy or at least one dose of both combination drugs as combination treatment. Data was not collected in Part 2 of the study as no participant was enrolled in Part 2.

GSK Response Center

All Treated Population consisted of all participants who received at least one dose of GSK3326595 as monotherapy or at least one dose of both combination drugs as combination treatment.

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

All Treated Population. Data was not collected as no participants were enrolled in Part 2.

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

Part 2: Number of Participants With AEs by Severity

DLT Evaluable Population is defined as participants who received at least 75 percent (%) of the planned doses of GSK3326595 and all seven planned doses of 5-Azacitidine (Part 2) within the 28-day DLT observation period or those who have had a DLT. Data was not collected as no participants were enrolled in Part 2.

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

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

Common non-STEAEs

STEAEs

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

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Part 1: Number of Participants With AEs by Severity

DLT Evaluable Population. Only those participants with data available at the indicated time points were analyzed.

Part 1: Number of Participants With DLTs

Part 1: Overall Response Rate

Part 1: Progression Free Survival

Part 1: Overall Survival

Pharmacokinetic (PK) Population consisted of all participants from the All Treated Population for whom a PK sample was obtained and analyzed.

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

PK Population. Only those participants with data available at the indicated time points were analyzed.

Part 1: Cmax of GSK3326595 Following Administration of Repeat Dose

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

Part 1: Tmax of GSK3326595 Following Administration of Repeat Dose

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

PK Population. Only those participants with data available at the specified time points were analyzed.

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

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

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

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

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

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

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

Part 1: Time Invariance Following Administration of GSK3326595

Part 1: Accumulation Ratio Following Administration of GSK3326595

Part 2: Complete Remission (CR) Rate

PK Population. Data was not collected as no participants were enrolled in Part 2.

Spots Global Cancer Trial Database for 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 Description

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