Clinical trial NCT05424380: 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
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Leukemia, Myeloid, Acute
Keywords: GSK3745417
Acute myeloid leukemia
AML
high-risk myelodysplastic syndrome
HR-MDS
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2022-06-21
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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).

Primary outcomes:
measure: Part 1: Number of Participants With Treatment-emergent (TE) Adverse Events (AEs) and TE Serious AEs (SAEs)
timeFrame: Up to 11.3 weeks
measure: Part 1: Number of Participants With TEAEs and TESAEs by Severity Grades
timeFrame: Up to 11.3 weeks
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLT)
timeFrame: Up to 28 days
measure: Part 1: Number of Participants With Withdrawals Due to AEs
timeFrame: Up to 11.3 weeks
measure: Part 2: Objective Response Rate (ORR)
timeFrame: Up to Day 84
measure: Part 2: Number of Participants With TEAEs and TESAEs
timeFrame: Up to 49 weeks
measure: Part 2: Number of Participants With TEAEs and TESAEs by Severity Grades
timeFrame: Up to 49 weeks
measure: Part 2: Number of Participants With Dose Limiting Toxicities (DLT)
timeFrame: Up to 28 days
measure: Part 2: Number of Participants With Withdrawals Due to AEs
timeFrame: Up to 49 weeks
Secondary outcomes:
measure: Part 1: Maximum Concentration (Cmax) Following Administration of GSK3745417 12.5 µg, 25 ug, 50 µg and 200 µg
timeFrame: 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
measure: Part 1: Maximum Concentration (Cmax) Following Administration of GSK3745417 100 µg
timeFrame: 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
measure: Part 1: Maximum Concentration (Cmax) Following Administration of GSK3745417 300 µg
timeFrame: 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
measure: 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
timeFrame: 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
measure: Part 1: Area Under the Concentration-time Curve AUC(0-t) Following Administration of GSK3745417 100 µg
timeFrame: 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
measure: Part 1: Area Under the Concentration-time Curve AUC(0-t) Following Administration of GSK3745417 300 µg
timeFrame: 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
measure: Part 1: AUC (0-tau) Following Administration of GSK3745417 12.5 µg, 25 µg, 50 µg and 200 µg
timeFrame: 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
measure: Part 1: AUC (0-tau) Following Administration of GSK3745417 100 µg
timeFrame: 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
measure: Part 1: AUC (0-tau) Following Administration of GSK3745417 300 µg
timeFrame: 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
measure: Part 1: AUC(0-infinity) Following Administration of GSK3745417 12.5 µg, 25 µg, 50 µg and 200 µg
timeFrame: 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
measure: Part 1: AUC(0-infinity) Following Administration of GSK3745417 100 µg
timeFrame: 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
measure: Part 1: AUC(0-infinity) Following Administration of GSK3745417 300 µg
timeFrame: 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
measure: Part 1: Terminal Phase Elimination Rate Constant (Lambda Z) Following Administration of GSK3745417 12.5 µg, 25 µg, 50 µg and 200 µg
timeFrame: 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
measure: Part 1: Terminal Phase Elimination Rate Constant (Lambda Z) Following Administration of GSK3745417 100 µg
timeFrame: 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
measure: Part 1: Terminal Phase Elimination Rate Constant (Lambda Z) Following Administration of GSK3745417 300 µg
timeFrame: 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
measure: Part 1: Terminal Phase Half-life (t1/2) Following Administration of GSK3745417 12.5 µg, 25 µg, 50 µg and 200 µg
timeFrame: 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
measure: Part 1: Terminal Phase Half-life (t1/2) Following Administration of GSK3745417 100 µg
timeFrame: 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
measure: Part 1: Terminal Phase Half-life (t1/2) Following Administration of GSK3745417 300 µg
timeFrame: 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
measure: Part 1: Systemic Clearance of Parent Drug (CL) Following Administration of GSK3745417 12.5 µg, 25 µg, 50 µg and 200 µg
timeFrame: 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
measure: Part 1: Systemic Clearance of Parent Drug (CL) Following Administration of GSK3745417 100 µg
timeFrame: 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
measure: Part 1: Systemic Clearance of Parent Drug (CL) Following Administration of GSK3745417 300 µg
timeFrame: 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
measure: Part 1: Volume of Distribution (V) Following Administration of GSK3745417 12.5 µg, 25 µg, 50 µg and 200 µg
timeFrame: 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
measure: Part 1: Volume of Distribution (V) Following Administration of GSK3745417 100 µg
timeFrame: 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
measure: Part 1: Volume of Distribution (V) Following Administration of GSK3745417 300 µg
timeFrame: 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
measure: Part 2: Number of Participants With AEs, SAEs and Adverse Events of Special Interest (AESIs) Leading to Dose Modification and Dose Delays
timeFrame: Up to 49 weeks
measure: Part 2: Cmax Following Administration of GSK3745417
timeFrame: Pre-dose, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 8, 12 and 24 hours on Day 1; Predose on Day 4; Pre-dose and 5 minutes, 4, 8, 24 hours on Day 5; Predose and 4, 8, 12 and 24 hours on Day 8; Pre-dose, 1, 4, 8, 12 and 24 hours on Day 12
measure: Part 2: AUC(0-t) Following Administration of GSK3745417
timeFrame: Pre-dose, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 8, 12 and 24 hours on Day 1; Predose on Day 4; Pre-dose and 5 minutes, 4, 8, 24 hours on Day 5; Predose and 4, 8, 12 and 24 hours on Day 8; Pre-dose, 1, 4, 8, 12 and 24 hours on Day 12
measure: Part 2: AUC(0-tau) Following Administration of GSK3745417
timeFrame: Pre-dose, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 8, 12 and 24 hours on Day 1; Predose on Day 4; Pre-dose and 5 minutes, 4, 8, 24 hours on Day 5; Predose and 4, 8, 12 and 24 hours on Day 8; Pre-dose, 1, 4, 8, 12 and 24 hours on Day 12
measure: Part 2: AUC(0-infinity) Following Administration of GSK3745417
timeFrame: Pre-dose, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 8, 12 and 24 hours on Day 1; Predose on Day 4; Pre-dose and 5 minutes, 4, 8, 24 hours on Day 5; Predose and 4, 8, 12 and 24 hours on Day 8; Pre-dose, 1, 4, 8, 12 and 24 hours on Day 12
measure: Part 2: Terminal Phase Elimination Rate Constant (Lambda Z) Following Administration of GSK3745417
timeFrame: Pre-dose, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 8, 12 and 24 hours on Day 1; Predose on Day 4; Pre-dose and 5 minutes, 4, 8, 24 hours on Day 5; Predose and 4, 8, 12 and 24 hours on Day 8; Pre-dose, 1, 4, 8, 12 and 24 hours on Day 12
measure: Part 2: Terminal Phase Half-life (t1/2) Following Administration of Single Dose GSK3745417
timeFrame: Pre-dose, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 8, 12 and 24 hours on Day 1; Predose on Day 4; Pre-dose and 5 minutes, 4, 8, 24 hours on Day 5; Predose and 4, 8, 12 and 24 hours on Day 8; Pre-dose, 1, 4, 8, 12 and 24 hours on Day 12
measure: Part 2: Systemic Clearance of Parent Drug (CL) Following Administration of GSK3745417
timeFrame: Pre-dose, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 8, 12 and 24 hours on Day 1; Predose on Day 4; Pre-dose and 5 minutes, 4, 8, 24 hours on Day 5; Predose and 4, 8, 12 and 24 hours on Day 8; Pre-dose, 1, 4, 8, 12 and 24 hours on Day 12
measure: Part 2: Volume of Distribution (V) Following Administration of GSK3745417
timeFrame: Pre-dose, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 8, 12 and 24 hours on Day 1; Predose on Day 4; Pre-dose and 5 minutes, 4, 8, 24 hours on Day 5; Predose and 4, 8, 12 and 24 hours on Day 8; Pre-dose, 1, 4, 8, 12 and 24 hours on Day 12
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Dresden
country: Germany
facility: GSK Investigational Site
city: Leipzig
country: Germany
facility: GSK Investigational Site
city: Meldola FC
country: Italy
facility: GSK Investigational Site
city: Perugia
country: Italy
facility: GSK Investigational Site
city: Roma
country: Italy
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
Study officials:
References: