Clinical trial NCT03614728: 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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Neoplasms
Keywords: Acute myeloid leukemia
Myelodysplastic syndrome
Chronic myelomonocytic leukemia
GSK3326595
5-Azacitidine
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2018-08-03
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is an open-label, multicenter, multi-part study.
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Part 1: Percentage of Participants With Clinical Benefit Rate (CBR)
timeFrame: Up to 30.8 months
measure: Part 2: Number of Participants With Non-serious Treatment-emergent Adverse Events (Non-STEAEs) and Serious Treatment Emergent Adverse Events (STEAEs)
timeFrame: Up to 3 years and 2 months
measure: Part 2: Number of Participants With AEs by Severity
timeFrame: Up to 3 years and 2 months
measure: Part 2: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 28 days
measure: Part 2: Number of Participants With AEs Leading to Dose Interruptions, Dose Reductions and Treatment Discontinuation Due to AEs
timeFrame: Up to 3 years and 2 months
Secondary outcomes:
measure: Part 1: Number of Participants With Common Non-STEAEs and STEAEs
timeFrame: Up to 30.8 months
measure: Part 1: Number of Participants With AEs by Severity
timeFrame: Up to 30.8 months
measure: Part 1: Number of Participants With DLTs
timeFrame: Up to 28 days
measure: Part 1: Overall Response Rate
timeFrame: Up to 30.8 months
measure: Part 1: Progression Free Survival
timeFrame: Up to 30.8 months
measure: Part 1: Overall Survival
timeFrame: Up to 30.8 months
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 1: Cmax of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 1: Time of Maximum Concentration Observed (Tmax) of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 1: Tmax of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 1: Apparent Terminal Phase Half-life (t1/2) of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 1: t1/2 of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: 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
timeFrame: 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
measure: Part 1: AUC(0-t) of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 1: AUC From 0 Hours to the Time of Next Dosing (AUC[0-tau]) of GSK3326595
timeFrame: 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
measure: Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC[0-inf]) of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 1: AUC(0-inf) of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 1: Oral Clearance (CL/F) of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 1: CL/F of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 1: Time Invariance Following Administration of GSK3326595
timeFrame: 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
measure: Part 1: Accumulation Ratio Following Administration of GSK3326595
timeFrame: 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
measure: Part 2: Complete Remission (CR) Rate
timeFrame: Up to 3 years and 2 months
measure: Part 2: Cmax of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 2: Cmax of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 2: Cmax of 5-Azacitidine Following Administration of Single Dose
timeFrame: 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) post-dose
measure: Part 2: Cmax of 5-Azacitidine Following Administration of Repeat Dose
timeFrame: 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) post-dose
measure: Part 2: Tmax of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 2: Tmax of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 2: Tmax of 5-Azacitidine Following Administration of Single Dose
timeFrame: 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) post-dose
measure: Part 2: Tmax of 5-Azacitidine Following Administration of Repeat Dose
timeFrame: 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) post-dose
measure: Part 2: t1/2 of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 2: t1/2 of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 2: t1/2 of 5-Azacitidine Following Administration of Single Dose
timeFrame: 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) post-dose
measure: Part 2: t1/2 of 5-Azacitidine Following Administration of Repeat Dose
timeFrame: 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) post-dose
measure: Part 2: AUC(0-t) of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 2: AUC(0-t) of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 2: AUC(0-t) of 5-Azacitidine Following Administration of Single Dose
timeFrame: 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) post-dose
measure: Part 2: AUC(0-t) of 5-Azacitidine Following Administration of Repeat Dose
timeFrame: 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) post-dose
measure: Part 2: AUC(0-inf) of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 2: AUC(0-inf) of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 2: AUC(0-inf) of 5-Azacitidine Following Administration of Single Dose
timeFrame: 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) post-dose
measure: Part 2: AUC(0-inf) of 5-Azacitidine Following Administration of Repeat Dose
timeFrame: 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) post-dose
measure: Part 2: AUC(0-tau) Following Administration of GSK3326595
timeFrame: 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
measure: Part 2: AUC(0-tau) Following Administration of 5-Azacitidine
timeFrame: 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) post-dose
measure: Part 2: CL/F of GSK3326595 Following Administration of Single Dose
timeFrame: 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
measure: Part 2: CL/F of GSK3326595 Following Administration of Repeat Dose
timeFrame: 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
measure: Part 2: CL/F of 5-Azacitidine Following Administration of Single Dose
timeFrame: 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) post-dose
measure: Part 2: CL/F of 5-Azacitidine Following Administration of Repeat Dose
timeFrame: 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) post-dose
measure: Part 2: Time Invariance Following Administration of GSK3326595
timeFrame: 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
measure: Part 2: Time Invariance Following Administration of 5-Azacitidine
timeFrame: 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) post-dose
measure: Part 2: Accumulation Ratio Following Administration of GSK3326595
timeFrame: 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
measure: Part 2: Accumulation Ratio Following Administration of 5-Azacitidine
timeFrame: 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) post-dose
measure: Part 2: Overall Response Rate
timeFrame: Up to 3 years and 2 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Milwaukee
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: