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

NCT03614728 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 208809
• Study Type: interventional
• Target: 30
• Locations: 2 countries
• Sites: 8

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.

Conditions

Neoplasms

Keywords

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

Outcome Measures

Primary Outcomes (5)

• 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.

  Up to 30.8 months

• 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.

  Up to 3 years and 2 months

• Part 2: 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. Number of participants with AEs by severity were planned to be assessed.

  Up to 3 years and 2 months

• 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.

  Up to 28 days

• 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.

  Up to 3 years and 2 months

Secondary Outcomes (53)

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

  Up to 30.8 months

• Part 1: Number of Participants With AEs by Severity

  Up to 30.8 months

• Part 1: Number of Participants With DLTs

  Up to 28 days

• Part 1: Overall Response Rate

  Up to 30.8 months

• Part 1: Progression Free Survival

  Up to 30.8 months

Study Arms (3)

Part 1: Participants receiving GSK3326595

EXPERIMENTAL

Drug: GSK3326595

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

EXPERIMENTAL

Drug: GSK3326595; Drug: 5-Azacitidine

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

EXPERIMENTAL

Drug: GSK3326595; Drug: 5-Azacitidine

Interventions

GSK3326595 DRUG

GSK3326595 will be administered.

Part 1: Participants receiving GSK3326595; Part 2 Dose escalation : Participants receiving GSK3326595+5-Azacitidine; Part 2 Dose expansion: Participants receiving GSK3326595+5-Azacitidine

5-Azacitidine DRUG

5-Azacitidine will be administered.

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (8)

GSK Investigational Site

Birmingham, Alabama, 35294-3300, United States

Location

GSK Investigational Site

Miami, Florida, 33136, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02114, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02215, United States

Location

GSK Investigational Site

New York, New York, 10065, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

GSK Investigational Site

Milwaukee, Wisconsin, 53226, United States

Location

GSK Investigational Site

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (1)

• 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 DERIVED

MeSH Terms

Conditions

Neoplasms; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Interventions

GSK-3326595; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: July 30, 2018
• First Posted: August 3, 2018
• Study Start: October 16, 2018
• Primary Completion: January 11, 2022
• Study Completion: January 11, 2022
• Last Updated: February 6, 2023
• Results First Posted: February 6, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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.
• 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.

Locations

US (7); CA (1)