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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1, Open Label Study of Intravenous GSK3745417 to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Determine RP2D and Schedule in Participants With Relapsed or Refractory Myeloid Malignancies Including Acute Myeloid Leukemia (AML) and High-risk Myelodysplastic Syndrome (HR-MDS)

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: GSK3745417


Participation Criteria
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Eligibility Criteria
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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: 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. 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose escalation<br>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<br>* GSK3745417 will be administered<br>|
| Experimental: Part 2: Dose expansion<br>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<br>* GSK3745417 will be administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of participants with Adverse Events (AEs) and number of participants per severity grade of AE in total population | Severity for each AE will be reported during the study and will assign a grade according to the National Cancer Institute - Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v5.0. | Up to 36 weeks | 
| Part 1: Number of participants with Serious Adverse Events (SAEs) and number of participants per severity grade of SAE in total population | Severity for each SAE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0. | Up to 49 weeks | 
| Part 1: Number of participants with Dose limiting toxicities (DLT) and number of participants per severity grade of DLT | An AE will be considered a DLT if the investigator considers it to be clinically relevant and attributed (definitely, probably, or possibly) to the study intervention and meets at least 1 of the DLT criteria. Severity for DLT will be reported according to the NCI-CTCAE v5.0. | Up to 4 weeks | 
| Part 1: Number of participants with withdrawals due to AEs |  | Up to 36 weeks | 
| Part 2: Overall response rate (ORR) after the daily dosing induction period of GSK3745417 | ORR is defined as the percentage of participants with a complete remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete count recovery (CRi), or a partial remission (PR) as per response criteria for AML and HR MDS respectively. | Up to 12 weeks | 
| Part 2: Number of participants with AEs and number of participants per severity grade of AE in total population during maintenance dosing | Severity for each AE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0. | Up to 36 weeks | 
| Part 2: Number of participants with SAEs and number of participants per severity grade of SAE in total population during maintenance dosing | Severity for each SAE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0. | Up to 49 weeks | 
| Part 2: Number of participants with DLT and number of participants per severity grade of DLT during maintenance dosing | An AE will be considered a DLT if the investigator considers it to be clinically relevant and attributed (definitely, probably, or possibly) to the study intervention and meets at least 1 of the DLT criteria. Severity for DLT will be reported according to the NCI-CTCAE v5.0. | Up to 4 weeks | 
| Part 2: Number of participants with withdrawals due to AEs during maintenance dosing |  | Up to 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximum concentration (Cmax) following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 1: Area under the concentration-time curve AUC(0-t) following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 1: AUC (0-tau) following administration of GSK3745417 Part 1: AUC(0-infinity) following repeated dose administration of GSK3745417 |  | Up to 36 weeks | 
| Part 1: AUC(0-infinity) following repeated dose administration of GSK3745417 |  | Up to 36 weeks | 
| Part 1: AUC(0-infinity) following single dose administration of GSK3745417 |  | Up to 36 weeks | 
| Part 1: Terminal phase elimination rate constant (Lambda Z) following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 1: Terminal phase half-life (t1/2) following single dose administration of GSK3745417 |  | Up to 36 weeks | 
| Part 1: Systemic clearance of parent drug (CL) following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 1: Volume of distribution (V) following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 2: Number of participants with AEs, leading to dose modification and dose delays |  | Up to 36 weeks | 
| Part 2: Number of participants with SAEs and AESIs leading to dose modification and dose delays |  | Up to 49 weeks | 
| Part 2: Cmax following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 2: AUC(0-t) following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 2: AUC (0-tau) following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 2: AUC(0-infinity) following repeated dose of GSK3745417 |  | Up to 36 weeks | 
| Part 2: AUC(0-infinity) following administration of single dose GSK3745417 |  | Up to 36 weeks | 
| Part 2: Lambda Z following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 2: t1/2 following administration of single dose GSK3745417 |  | Up to 36 weeks | 
| Part 2: CL following administration of GSK3745417 |  | Up to 36 weeks | 
| Part 2: V following administration of GSK3745417 |  | Up to 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK3745417, Acute myeloid leukemia, AML, high-risk myelodysplastic syndrome, HR-MDS