A Phase 1, Open Label Study of Intravenous GSK3745417 to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Determine RP2D & Schedule in Participants With Relapsed or Refractory Myeloid Malignancies Including AML and HR MDS

NCT05424380 | Terminated Phase 1 Results

• 1 other identifier: 209809
• Study Type: interventional
• Target: 18
• Locations: 5 countries
• Sites: 10

Brief Summary

This is a Phase 1, open label, two-part study to determine recommended phase 2 dose (RP2D) and schedule of GSK3745417 administration in participants with relapsed/refractory AML or HR-MDS.

Conditions

Leukemia, Myeloid, Acute

Keywords

GSK3745417; Acute myeloid leukemia; AML; high-risk myelodysplastic syndrome; HR-MDS

Outcome Measures

Primary Outcomes (9)

• Part 1: Number of Participants With Treatment-emergent (TE) Adverse Events (AEs) and TE Serious AEs (SAEs)

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment. A TEAE is an event that emerges during treatment having been absent pretreatment or worsens relative to the pretreatment state.

  Up to 11.3 weeks

• Part 1: Number of Participants With TEAEs and TESAEs by Severity Grades

  AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment. TEAE is an event that emerges during treatment having been absent pretreatment or worsens relative to the pretreatment state. AEs were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version 5.0): Grade(G) 1=Mild, G2=Moderate, G3=Severe or medically significant but not immediately life-threatening, G4=Life-threatening consequences, G5=Death related AE.

  Up to 11.3 weeks

• Part 1: Number of Participants With Dose Limiting Toxicities (DLT)

  An AE is considered to be a DLT if it is considered by the investigator to be clinically relevant and attributed (definitely, probably, or possibly) to the study intervention and meets at least 1 of the criteria listed below. Criteria for DLT included Grade(G)3 or 4 Cytokine Release Syndrome (CRS); G3 or 4 tumor lysis syndrome (TLS) that cannot be managed/ is not resolved within 72 hours (h); Liver Toxicity included Alanine aminotransferase (ALT)\>=3\* upper limit of normal (ULN), plus bilirubin\>=2\* ULN (\>35 percent \[%\] direct) or plus international normalized ratio (INR)\>1.5 (Possible Hy's law); G\>=3 non-hematologic toxicity of any duration; G\>=3 immune-related toxicity that does not resolve to G\<=1 or Baseline within 8 days despite adequate immune suppressive therapy. Any other event which in the judgment of the investigator and GSK Medical Monitor is considered to be a DLT.

  Up to 28 days

• Part 1: Number of Participants With Withdrawals Due to AEs

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.

  Up to 11.3 weeks

• Part 2: Objective Response Rate (ORR)

  Overall response rate (ORR) defined as the percentage of participants with a complete remission (CR), CR with incomplete platelet recovery (CRp), incomplete count recovery (CRi), or a partial remission (PR) as per response criteria for AML and HR-MDS. CR=The participant must achieve a morphologic leukemia-free state (\<= 5% blasts) and have no evidence of extramedullary disease. The participant must be free of all symptoms related to leukemia, have an absolute neutrophil count \>= 1\*10\^9/Liter (L) and platelet count \>=100\*10\^9/L, and be transfusion independent. CRp: Marrow response as per CR but platelet count \<100 × 10\^9/L. CRi: Marrow response as per CR but platelet count \<100\*10\^9/L or neutrophil count \<1\*10\^9/L. PR=A decrease from Baseline of at least 50% in the number of bone marrow blasts, to between 5% and 25% of the bone marrow aspirate.

  Up to Day 84

• Part 2: Number of Participants With TEAEs and TESAEs

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment. A TEAE is an event that emerges during treatment having been absent pretreatment or worsens relative to the pretreatment state.

  Up to 49 weeks

• Part 2: Number of Participants With TEAEs and TESAEs by Severity Grades

  AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or is a congenital anomaly/birth defect, other situations which involved medical or scientific judgment. TEAE is an event that emerges during treatment having been absent pretreatment or worsens relative to the pretreatment state. AEs were graded by the investigator according to NCI-CTCAE (version 5.0): G1=Mild, G2=Moderate, G3=Severe or medically significant but not immediately life-threatening, G4=Life-threatening consequences, G5=Death related AE.

  Up to 49 weeks

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

  An AE is considered to be a DLT if it is considered by the investigator to be clinically relevant and attributed (definitely, probably, or possibly) to the study intervention and meets at least 1 of the criteria listed below. Criteria for DLT included Grade(G)3 or 4 Cytokine Release Syndrome (CRS); G3 or 4 TLS that cannot be managed/ is not resolved within 72 hours (h); Liver Toxicity included ALT\>=3\*upper limit of normal (ULN), plus bilirubin\>=2\*ULN (\>35% direct) or plus international normalized ratio (INR)\>1.5 (Possible Hy's law); G\>=3 non-hematologic toxicity of any duration; G\>=3 immune-related toxicity that does not resolve to G\<=1 or Baseline within 8 days despite adequate immune suppressive therapy. Any other event which in the judgment of the investigator and GSK Medical Monitor is considered to be a DLT.

  Up to 28 days

• Part 2: Number of Participants With Withdrawals Due to AEs

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.

  Up to 49 weeks

Secondary Outcomes (33)

• Part 1: Maximum Concentration (Cmax) Following Administration of GSK3745417 12.5 µg, 25 ug, 50 µg and 200 µg

  Pre-dose, 5, 15, 30 and 45 minutes, 1, 2, 4, 6, 8, 12, 24 hours on Day 1; Pre-dose, 5 minutes, 4, 8, 24 hours on Day 5

• Part 1: Maximum Concentration (Cmax) Following Administration of GSK3745417 100 µg

  Pre-dose, 5, 15, 30 and 45 minutes, 1, 2, 4, 6, 8, 12, 24 hours on Day 1; Pre-dose, 5 minutes, 1, 4, 8, 12, 24 hours on Day 5; Pre-dose, 5 minutes, 4, 8, 12 and 24 hours on Day 8; Pre-dose, 5 minutes, 4, 8 and 24 hours on Day 12

• Part 1: Maximum Concentration (Cmax) Following Administration of GSK3745417 300 µg

  Pre-dose, 5 minutes, 1, 4, 8, 12, 24 hours on Day 1; Pre-dose, 5 minutes, 1, 4, 8, 12, 24 hours on Day 5; Pre-dose, 5 minutes, 4, 8, 24 hours on Day 8

• Part 1: Area Under the Concentration-time Curve AUC(0-t) Following Administration of GSK3745417 12.5 µg, 25 µg, 50 µg and 200 µg

  Pre-dose, 5, 15, 30 and 45 minutes, 1, 2, 4, 6, 8, 12, 24 hours on Day 1; Pre-dose, 5 minutes, 4, 8, 24 hours on Day 5

• Part 1: Area Under the Concentration-time Curve AUC(0-t) Following Administration of GSK3745417 100 µg

  Pre-dose, 5, 15, 30 and 45 minutes, 1, 2, 4, 6, 8, 12, 24 hours on Day 1; Pre-dose, 5 minutes, 1, 4, 8, 12, 24 hours on Day 5; Pre-dose, 5 minutes, 4, 8, 12 and 24 hours on Day 8; Pre-dose, 5 minutes, 4, 8 and 24 hours on Day 12

Study Arms (2)

Part 1: Dose escalation

EXPERIMENTAL

Part 1 will evaluate a dosing schedule for a total of 28 days in each cycle. The starting dose for Cycle 1 will be escalated in the next dose escalation cohort until MTD is reached.

Drug: GSK3745417

Part 2: Dose expansion

EXPERIMENTAL

Part 2 will evaluate efficacy after an induction phase. The induction phase consists of a treatment regimen at RP2D determined in Part 1.

Drug: GSK3745417

Interventions

GSK3745417 DRUG

GSK3745417 will be administered

Part 1: Dose escalation; Part 2: Dose expansion

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must be ≥18 years of age and ≤75 years of age at the time of signing the informed consent for dose escalation and \>18 years of age at the time of signing the informed consent for the dose expansion.
• Participants must be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
• Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Participants with AML/HR MDS are eligible for participation in Part 1 and Part 2 if they have:
• A diagnosis of AML according to the World Health Organization 2016 criteria with relapsed or refractory disease and ineligible for or have exhausted standard therapeutic options.
• Have high-risk or high/very high by Revised International Prognostic Scoring System (IPSS-R) for MDS (restricted to Part 1) that has relapsed after or been refractory to prior therapy with hypomethylating agent.
• Participants with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if:
• No clinical signs or symptoms of graft versus host disease (other than Grade 1 GVHD (\<25% skin surface affected) and the participant is off all systemic immunosuppression. (Note: topical steroids for G1 skin GVHD are permitted on study)
• Participants must agree to abide by the gender specific contraceptive requirements below:
• Female participants are eligible to participate if they are not either pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a woman of childbearing potential (WOCBP), or
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), The effectiveness of the contraceptive method will be evaluated by the investigator in relationship to the first dose of study treatment.

You may not qualify if:

• Diagnosis of acute promyelocytic leukemia (APML or t(15;17) PML-RARA fusion). Patients with biphenotypic disease are excluded.
• Active central nervous system (CNS) involvement or disorder; and well controlled with ongoing treatment
• Participants with Immediate life-threatening, severe complications of leukemia (sepsis, hemorrhage).
• Participants with extramedullary disease as the sole site of AML
• Participants with active severe or uncontrolled infection,
• Participants with active autoimmune disease that has required systemic disease modifying or immunosuppressive treatment within the last 2 years.
• Participants with concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study treatment.
• Participants with history of vasculitis at any time prior to study treatment.
• Participant with a history of other malignancies less than 2 years prior to study entry,
• Participants with QT interval corrected using Fridericia's formula (QTcF) \>450 millisecond (msec) for male participants, \>470 msec for female participants, or \>480 msec for participants with bundle branch block.
• Participants with recent history of allergen desensitization therapy within 4 weeks of starting study treatment.
• Participants with history or evidence of cardiovascular (CV) risk history of immune myocarditis or pericarditis.
• Participants with prior STING therapy.
• Participants with prior solid organ transplantation.
• Participants with recent prior therapy defined as follows: any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is longer, prior to start of study treatment; prior therapy with biological agents (including monoclonal antibodies) within 28 days prior to start of study treatment; any radiotherapy or major surgery within 14 days prior to start of study treatment; currently receiving investigational therapy in a clinical trial

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (10)

GSK Investigational Site

Toronto, Ontario, M5G 2M9, Canada

Location

GSK Investigational Site

Dresden, 01307, Germany

Location

GSK Investigational Site

Leipzig, 04103, Germany

Location

GSK Investigational Site

Meldola FC, 47014, Italy

Location

GSK Investigational Site

Perugia, 06132, Italy

Location

GSK Investigational Site

Roma, 00168, Italy

Location

GSK Investigational Site

Rotterdam, 3015 GD, Netherlands

Location

GSK Investigational Site

Madrid, 28033, Spain

Location

GSK Investigational Site

Madrid, 28040, Spain

Location

GSK Investigational Site

Valencia, 46026, Spain

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

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: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2022
• First Posted: June 21, 2022
• Study Start: September 20, 2022
• Primary Completion: March 4, 2024
• Study Completion: March 4, 2024
• Last Updated: March 25, 2025
• Results First Posted: March 25, 2025

Record last verified: 2025-02

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, a 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

IT (3); CA (1); DE (2); NL (1); ES (3)