Study to Investigate the Safety and Clinical Activity of GSK3326595 and Other Agents to Treat Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part 1: Participants receiving GSK3326595
|
Drug: GSK3326595
GSK3326595 will be administered.
|
| Experimental: Part 2 Dose escalation : Participants receiving GSK3326595+5-Azacitidine
|
Drug: GSK3326595
GSK3326595 will be administered.
Drug: 5-Azacitidine
5-Azacitidine will be administered.
|
| Experimental: Part 2 Dose expansion: Participants receiving GSK3326595+5-Azacitidine
|
Drug: GSK3326595
GSK3326595 will be administered.
Drug: 5-Azacitidine
5-Azacitidine will be administered.
|
Outcome Measures
Primary Outcome Measures
- Part 1: Percentage of participants with clinical benefit rate (CBR) [Up to 6 years]
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.
- Part 2 Dose escalation: Number of participants with adverse events and serious adverse events (AEs and SAEs) [Up to 6 years]
All AEs and SAEs will be collected.
- Part 2 Dose escalation: Number of participants achieving dose limiting toxicities (DLTs) [Up to 28 days]
An event is considered to be a DLT if the event occurs within the first 28 days of treatment and meets the Non-hematologic toxicity, hematologic toxicity and other toxicity criteria unless it can be clearly established that the event is unrelated to treatment.
- Part 2 Dose escalation: Number of participants with dose interruptions, dose reductions and treatment discontinuation due to adverse events. [Up to 6 years]
Participants with dose interruptions, dose reductions and treatment discontinuation due to adverse events will be assessed.
- Part 2 Dose expansion: Number of participants achieving CR [Up to 6 years]
Complete remission (CR) rate is defined as the percentage of participants achieving a CR per International Working Group (IWG) criteria.
Secondary Outcome Measures
- Part 1 and Part 2 Dose expansion: Number of participants with AEs and SAEs [Up to 6 years]
All AEs and SAEs will be collected.
- Part 1: Number of participants achieving DLTs [Up to 28 days]
An event is considered to be a DLT if the event occurs within the first 28 days of treatment and meets the Non-hematologic toxicity, hematologic toxicity and other toxicity criteria unless it can be clearly established that the event is unrelated to treatment.
- Part 1, Part 2 Dose escalation and dose expansion: Percentage of participants achieving overall response rate [Up to 6 years]
Overall response rate is defined as the percentage of participants achieving a CR, mCR, or PR, per IWG criteria.
- Part 1: Progression-free survival (PFS) [Up to 6 years]
PFS is defined as time from first dose to disease progression, as defined by IWG criteria, or death due to any cause, whichever occurs first.
- Part 1: Overall survival [Up to 6 years]
Overall survival is defined time from first dose to death due to any cause.
- Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine Cmax of GSK3326595.
- Part 1: Time of maximum concentration observed (Tmax) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine Tmax of GSK3326595.
- Part 1: Apparent terminal phase half-life (t1/2) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine t1/2 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 [Up to 6 years]
Blood samples will be collected to determine AUC(0-t) of GSK3326595.
- Part 1: AUC from 0 hours to the time of next dosing (AUC[0-tau]) of GSK3326595 [Up to 6 years]
Blood samples will be collected to determine AUC(0-tau) of GSK3326595.
- Part 1: AUC(0-inf) from time zero to infinity (AUC[0-inf]) of GSK3326595 [Up to 6 years]
Blood samples will be collected to determine AUC(0-inf) of GSK3326595.
- Part 1: Oral clearance (CL/F) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine CL/F of GSK3326595.
- Part 1: Time invariance (TI) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine TI of GSK3326595.
- Part 1: Accumulation ratio (AR) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine AR of GSK3326595.
- Part 2 Dose escalation: Number of participants achieving CR [Up to 6 years]
CR rate is defined as the percentage of participants achieving a CR per IWG criteria.
- Part 2 Dose escalation and dose expansion: Cmax of GSK3326595 and 5-Azacitidine in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine Cmax of GSK3326595 and 5-Azacitidine.
- Part 2 Dose escalation and dose expansion: Tmax of GSK3326595 and 5-Azacitidine in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine Tmax of GSK3326595 and 5-Azacitidine.
- Part 2 Dose escalation and dose expansion: t1/2 of GSK3326595 and 5-Azacitidine in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine t1/2 of GSK3326595 and 5-Azacitidine.
- Part 2 Dose escalation and dose expansion: AUC(0-t) of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine AUC(0-t) of GSK3326595 and 5-Azacitidine.
- Part 2 Dose escalation and dose expansion: AUC(0-inf) of GSK3326595 and 5-Azacitidine in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine AUC(0-inf) of GSK3326595 and 5-Azacitidine.
- Part 2 Dose escalation and dose expansion: AUC(0-tau) of GSK3326595 and 5-Azacitidine in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine AUC(0-tau) of GSK3326595 and 5-Azacitidine.
- Part 2 Dose escalation and dose expansion: CL/F of GSK3326595 and 5-Azacitidine in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine CL/F of GSK3326595 and 5-Azacitidine.
- Part 2 Dose escalation and dose expansion: TI of GSK3326595 and 5-Azacitidine in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine TI of GSK3326595 and 5-Azacitidine.
- Part 2 Dose escalation and dose expansion: AR of GSK3326595 and 5-Azacitidine in plasma following single- (Day 1) and repeat-dose administration [Up to 6 years]
Blood samples will be collected to determine AR of GSK3326595 and 5-Azacitidine.
- Part 2 Dose expansion: Number of participants with dose interruptions, dose reductions and treatment discontinuation due to adverse events. [Up to 6 years]
Participants with dose interruptions, dose reductions and treatment discontinuation due to adverse events will be assessed.
Eligibility Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | GSK Investigational Site | Birmingham | Alabama | United States | 35294-3300 |
| 2 | GSK Investigational Site | Miami | Florida | United States | 33136 |
| 3 | GSK Investigational Site | Boston | Massachusetts | United States | 02114 |
| 4 | GSK Investigational Site | Boston | Massachusetts | United States | 02215 |
| 5 | GSK Investigational Site | New York | New York | United States | 10065 |
| 6 | GSK Investigational Site | Houston | Texas | United States | 77030 |
| 7 | GSK Investigational Site | Milwaukee | Wisconsin | United States | 53226 |
| 8 | GSK Investigational Site | Toronto | Ontario | Canada | M5G 2M9 |
Sponsors and Collaborators
- GlaxoSmithKline
Investigators
- Study Director: GSK Clinical Trials, GlaxoSmithKline
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 208809