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NCT03614728 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase
PHASE1, PHASE2
Status at capture
TERMINATED
Registry last update
2023-02-06

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Part 2: Number of Participants With AEs by Severity

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Part 1: Number of Participants With AEs by Severity

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outcome · POSTED

Part 1: Number of Participants With DLTs

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outcome · POSTED

Part 1: Overall Response Rate

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outcome · POSTED

Part 1: Progression Free Survival

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outcome · POSTED

Part 1: Overall Survival

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outcome · POSTED

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

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outcome · POSTED

Part 1: Cmax of GSK3326595 Following Administration of Repeat Dose

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outcome · POSTED

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

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outcome · POSTED

Part 1: Tmax of GSK3326595 Following Administration of Repeat Dose

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Part 1: Time Invariance Following Administration of GSK3326595

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outcome · POSTED

Part 1: Accumulation Ratio Following Administration of GSK3326595

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outcome · POSTED

Part 2: Complete Remission (CR) Rate

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outcome · POSTED

Part 2: Cmax of GSK3326595 Following Administration of Single Dose

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outcome · POSTED

Part 2: Cmax of GSK3326595 Following Administration of Repeat Dose

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Part 2: Tmax of GSK3326595 Following Administration of Single Dose

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outcome · POSTED

Part 2: Tmax of GSK3326595 Following Administration of Repeat Dose

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

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

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outcome · POSTED

Part 2: Time Invariance Following Administration of GSK3326595

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outcome · POSTED

Part 2: Time Invariance Following Administration of 5-Azacitidine

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outcome · POSTED

Part 2: Accumulation Ratio Following Administration of GSK3326595

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outcome · POSTED

Part 2: Accumulation Ratio Following Administration of 5-Azacitidine

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outcome · POSTED

Part 2: Overall Response Rate

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
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.
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. intervention Names
    1. Drug: GSK3326595
    label
    Part 1: Participants receiving GSK3326595
    type
    EXPERIMENTAL
  2. intervention Names
    1. Drug: GSK3326595
    2. Drug: 5-Azacitidine
    label
    Part 2 Dose escalation : Participants receiving GSK3326595+5-Azacitidine
    type
    EXPERIMENTAL
  3. intervention Names
    1. Drug: GSK3326595
    2. Drug: 5-Azacitidine
    label
    Part 2 Dose expansion: Participants receiving GSK3326595+5-Azacitidine
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Part 1: Participants receiving GSK3326595
    2. Part 2 Dose escalation : Participants receiving GSK3326595+5-Azacitidine
    3. Part 2 Dose expansion: Participants receiving GSK3326595+5-Azacitidine
    description
    GSK3326595 will be administered.
    name
    GSK3326595
    type
    DRUG
  2. arm Group Labels
    1. Part 2 Dose escalation : Participants receiving GSK3326595+5-Azacitidine
    2. Part 2 Dose expansion: Participants receiving GSK3326595+5-Azacitidine
    description
    5-Azacitidine will be administered.
    name
    5-Azacitidine
    type
    DRUG
Study design
allocation
NON_RANDOMIZED
intervention Model
SEQUENTIAL
intervention Model Description
This is an open-label, multicenter, multi-part study.
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
30
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    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.
    measure
    Part 1: Percentage of Participants With Clinical Benefit Rate (CBR)
    time Frame
    Up to 30.8 months
  2. description
    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.
    measure
    Part 2: Number of Participants With Non-serious Treatment-emergent Adverse Events (Non-STEAEs) and Serious Treatment Emergent Adverse Events (STEAEs)
    time Frame
    Up to 3 years and 2 months
  3. 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. Number of participants with AEs by severity were planned to be assessed.
    measure
    Part 2: Number of Participants With AEs by Severity
    time Frame
    Up to 3 years and 2 months
  4. 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 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.
    measure
    Part 2: Number of Participants With Dose Limiting Toxicities (DLTs)
    time Frame
    Up to 28 days
  5. description
    Number of participants with AEs leading to dose interruptions, dose reductions and treatment discontinuation due to AEs were planned to be assessed.
    measure
    Part 2: Number of Participants With AEs Leading to Dose Interruptions, Dose Reductions and Treatment Discontinuation Due to AEs
    time Frame
    Up to 3 years and 2 months
secondary Outcomes
  1. 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. 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.
    measure
    Part 1: Number of Participants With Common Non-STEAEs and STEAEs
    time Frame
    Up to 30.8 months
  2. 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.
    measure
    Part 1: Number of Participants With AEs by Severity
    time Frame
    Up to 30.8 months
  3. 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.
    measure
    Part 1: Number of Participants With DLTs
    time Frame
    Up to 28 days
  4. description
    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.
    measure
    Part 1: Overall Response Rate
    time Frame
    Up to 30.8 months
  5. description
    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.
    measure
    Part 1: Progression Free Survival
    time Frame
    Up to 30.8 months
  6. description
    Overall survival is defined as time from first dose to death due to any cause.
    measure
    Part 1: Overall Survival
    time Frame
    Up to 30.8 months
  7. description
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.
    measure
    Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3326595 Following Administration of Single Dose
    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
  8. description
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.
    measure
    Part 1: Cmax of GSK3326595 Following Administration of Repeat Dose
    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
  9. description
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.
    measure
    Part 1: Time of Maximum Concentration Observed (Tmax) of GSK3326595 Following Administration of Single Dose
    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
  10. description
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.
    measure
    Part 1: Tmax of GSK3326595 Following Administration of Repeat Dose
    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
  11. description
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.
    measure
    Part 1: Apparent Terminal Phase Half-life (t1/2) of GSK3326595 Following Administration of Single Dose
    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
  12. description
    Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3326595.
    measure
    Part 1: t1/2 of GSK3326595 Following Administration of Repeat Dose
    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
Full 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.
Source references
references
  1. citation
    Watts J, Minden MD, Bachiashvili K, Brunner AM, Abedin S, Crossman T, Zajac M, Moroz V, Egger JL, Tarkar A, Kremer BE, Barbash O, Borthakur G. Phase I/II study of the clinical activity and safety of GSK3326595 in patients with myeloid neoplasms. Ther Adv Hematol. 2024 Sep 14;15:20406207241275376. doi: 10.1177/20406207241275376. eCollection 2024.
    pmid
    39290981
    type
    DERIVED
Source notices and limitations
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    Preserved source evidence · Not medical advice