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

Phase 1TerminatedNCT05424380

GlaxoSmithKline18 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Leukemia, Myeloid, Acute

Interventions

GSK3745417DRUG

GSK3745417 will be administered

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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: 1. 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. 2. 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: 1. Is not a woman of childbearing potential (WOCBP), or 2. 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. Exclusion Criteria: * 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 * Participants with immune-related toxicity related to prior treatment that has not resolved to Grade ≤1 (except alopecia, hearing loss or Grade ≤2 neuropathy or endocrinopathy managed with replacement therapy).

Locations (10)

GSK Investigational Site

Toronto, Ontario, Canada

GSK Investigational Site

Dresden, Germany

GSK Investigational Site

Leipzig, Germany

GSK Investigational Site

Meldola FC, Italy

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK3745417.

Time frame: 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